Surface-modified Nanobiomaterials for Electrochemical and Biomedicine Applications [1st ed.] 9783030555016, 9783030555023

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Topics in Current Chemistry Collections

Alain R. Puente-Santiago Daily Rodríguez-Padrón   Editors

Surface-modified Nanobiomaterials for Electrochemical and Biomedicine Applications

Topics in Current Chemistry Collections

Journal Editors Massimo Olivucci, Siena, Italy and Bowling Green, USA Wai-Yeung Wong, Hong Kong, China Series Editors Hagan Bayley, Oxford, UK Greg Hughes, Codexis Inc, USA Christopher A. Hunter, Cambridge, UK Seong-Ju Hwang, Seoul, South Korea Kazuaki Ishihara, Nagoya, Japan Barbara Kirchner, Bonn, Germany Michael J. Krische, Austin, USA Delmar Larsen, Davis, USA Jean-Marie Lehn, Strasbourg, France Rafael Luque, Córdoba, Spain Jay S. Siegel, Tianjin, China Joachim Thiem, Hamburg, Germany Margherita Venturi, Bologna, Italy Chi-Huey Wong, Taipei, Taiwan Henry N.C. Wong, Hong Kong, China Vivian Wing-Wah Yam, Hong Kong, China Chunhua Yan, Beijing, China Shu-Li You, Shanghai, China

Aims and Scope The series Topics in Current Chemistry Collections presents critical reviews from the journal Topics in Current Chemistry organized in topical volumes. The scope of coverage is all areas of chemical science including the interfaces with related disciplines such as biology, medicine and materials science. The goal of each thematic volume is to give the non-specialist reader, whether in academia or industry, a comprehensive insight into an area where new research is emerging which is of interest to a larger scientific audience. Each review within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5 to 10 years are presented using selected examples to illustrate the principles discussed. The coverage is not intended to be an exhaustive summary of the field or include large quantities of data, but should rather be conceptual, concentrating on the methodological thinking that will allow the non-specialist reader to understand the information presented. Contributions also offer an outlook on potential future developments in the field. More information about this series at http://www.springer.com/series/14181

Alain R. Puente-Santiago Daily Rodríguez-Padrón Editors

Surface-modified Nanobiomaterials for Electrochemical and Biomedicine Applications With contributions from Md Ariful Ahsan • David Alba‑Molina • Francisco Javier García Alonso Manuel Antuch • Ashish Avasthi • Daniel Calle • Manuel Cano Carlos Caro • Jose Manuel Costa‑Fernandez • Alicia M. Díaz‑García María Díaz‑González • Alfredo de la Escosura‑Muñiz Maria Teresa Fernandez‑Argüelles • María Luisa García‑Martín Juan J. Giner‑Casares • Yiran Guan • Claudia Iriarte‑Mesa Manuel Pernia Leal • Yeisy C. López • Pilar López‑Larrubia Rafael Luque • Xiangui Ma • Yasser Matos‑Peralta • Viviana Negri Greter A. Ortega • Jesús Pacheco‑Torres • Esther Pozo‑Torres Daily Rodriguez‑Padron • Mohamed Fathi Sanad Alain R. Puente Santiago • José Raúl Sosa‑Acosta Karen de la Vega‑Hernández • Chao Wang • Fengxia Wu Guobao Xu

Editors Alain R. Puente-Santiago Department of Chemistry The University of Texas at El Paso El Paso, TX, USA

Daily Rodríguez-Padrón Department of Organic Chemistry University of Cordoba Córdoba, Córdoba, Spain

Partly previously published in Top Curr Chem (Z) Volume 378 (2020). ISSN 2367-4067 Topics in Current Chemistry Collections ISBN 978-3-030-55501-6 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

Preface .............................................................................................................. TiO2 Nanomaterials in Photoelectrochemical and Electrochemiluminescent Biosensing ............................................................. Xiangui Ma, Chao Wang, Fengxia Wu, Yiran Guan and Guobao Xu: Top Curr Chem (Z) 2020, 378:28 (3, March 2020) https://doi.org/10.1007/s41061-020-0291-y DNA–Iron Oxide Nanoparticles Conjugates: Functional Magnetic Nanoplatforms in Biomedical Applications ................................................... José Raúl Sosa‑Acosta, Claudia Iriarte‑Mesa, Greter A. Ortega and Alicia M. Díaz‑García: Top Curr Chem (Z) 2020, 378:13 (10, January 2020) https://doi.org/10.1007/s41061-019-0277-9 Magnetic Nanoparticles as MRI Contrast Agents ........................................ Ashish Avasthi, Carlos Caro, Esther Pozo‑Torres, Manuel Pernia Leal and María Luisa García‑Martín: Top Curr Chem (Z) 2020, 378:40 (7, May 2020) https://doi.org/10.1007/s41061-020-00302-w Gold, Silver and Iron Oxide Nanoparticles: Synthesis and Bionanoconjugation Strategies Aimed at Electrochemical Applications...................................................................................................... Claudia Iriarte‑Mesa,·Yeisy C. López, Yasser Matos‑Peralta, Karen de la Vega‑Hernández and Manuel Antuch: Top Curr Chem (Z) 2020, 378:12 (7, January 2020) https://doi.org/10.1007/s41061-019-0275-y Quantum Dot Bioconjugates for Diagnostic Applications ........................... María Díaz‑González, Alfredo de la Escosura‑Muñiz, Maria Teresa Fernandez‑Argüelles, Francisco Javier García Alonso and Jose Manuel Costa‑Fernandez: Top Curr Chem (Z) 2020, 378:35 (26, March 2020) https://doi.org/10.1007/s41061-020-0296-6

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Carbon Nanotubes in Biomedicine ................................................................. Viviana Negri, Jesús Pacheco‑Torres, Daniel Calle and Pilar López‑Larrubia: Top Curr Chem (Z) 2020, 378:15 (14, January 2020) https://doi.org/10.1007/s41061-019-0278-8 Bioconjugated Plasmonic Nanoparticles for Enhanced Skin Penetration .............................................................................................. David Alba‑Molina, Juan J. Giner‑Casares and Manuel Cano: Top Curr Chem (Z) 2020, 378:8 (16, December 2019) https://doi.org/10.1007/s41061-019-0273-0 Proteins‑Based Nanocatalysts for Energy Conversion Reactions ............... Daily Rodriguez‑Padron, Md Ariful Ahsan, Mohamed Fathi Sanad, Rafael Luque and Alain R. Puente Santiago: Top Curr Chem (Z) 2020, 378:43 (10, June 2020) https://doi.org/10.1007/s41061-020-00306-6

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The recent advances in the nanoscience field have opened new horizons towards the development of exciting nanoscale materials with promising applications.[1] Surface-decorated nanoarchitectures, from functionalized 0D-quantum dots to 3Dprotein nanohybrids, have been successfully used as functional materials for sensing, energy conversion and theranostic. [2] [3] [4] In this topical collection, the development of surface-functionalized nanobiosystems for electrochemical and biomedical applications is comprehensively addressed. The functionalization strategies of low-dimensional interfaces with biological structures such as DNA, proteins or genes to construct bioinorganic heterostructures, are carefully discussed. Furthermore, seminal examples correlate the structural effects of the interfacial functionalization on the improved catalytic, sensing and biomedical properties of the resulting nanobioassemblies, thus providing valuable information for the material science, biotechnology and catalysis communities. In this regard, Guobao Xu and coworkers summarize the most recent developments as well as the future prospects in photoelectrochemical and electrochemiluminescent biosensing using TiO2 nanocomposites. Alicia Garcia et al. discuss how the interfacial interactions of iron oxide nanoparticles (IONPs) and DNA molecules can facilitate the development of nanocarriers and gene delivered vectors as efficient magnetic hybrids. In this direction, Maria Luisa, Manuel Antuch and their coworkers, extensively review the use of IONPs-based biomaterials for MRI and electrochemical applications, respectively. Jose Manuel and collaborators elegantly describe the crucial role of the surface functionalization of quantum dots (QDs) to develop highly stable colloidal nanosupensions for biomolecule targeting, luminescent imaging and drug delivery. The contribution of Pilar Lopez et. al. is particularly interesting due to the analysis of the interaction of carbon nanotubes (CNTs) with living cells and their implication on the proteome and genome. Also, Manuel Cano and colleagues highlight the bioconjugation of plasmonic nanoparticles with different biological materials to fabricate efficient biocompatible materials for skin penetration. Finally Alain R. and collaborators address the role of the synergistic interactions between different types of proteins and low-dimensional nanomaterials to assemble superior bioelectrocatalytic nanosystems.

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In summary, this topical collection provides in-depth information about the interfacial interactions that govern the assembly of diverse types of nanobiomaterials as well as their implications for electrochemical and biomedical applications. We believe this collection will motivate many researchers towards the development of the next generation of bio-inspired materials.

Alain R. Puente-Santiago Department of Chemistry, University of Texas at El Paso, El Paso, USA

Daily Rodríguez-Padrón Department of Organic Chemistry, University of Cordoba, Cordoba, Spain

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References 1. Jeong GH, Sasikala SP, Yun T, Lee GY, Lee WJ, Kim SO (2020) Adv. Mater.: 1907006. doi:10.1002/adma.201907006 2. Patel KD, Singh RK, Kim HW (2019) Mater. Horizons 6: 434. doi:10.1039/ c8mh00966j 3. Yan YB, Zhai D, Liu Y, Gong J, Chen J, Zan P, Zeng ZP, Li SZ, Huang W, Chen P (2020) ACS Nano 14: 1185. doi:10.1021/acsnano.9b09554 4. Le Goff A, Holzinger M (2018) Sustain. Energ. Fuels 2: 2555. doi:10.1039/ c8se00374b

Topics in Current Chemistry (2020) 378:28 https://doi.org/10.1007/s41061-020-0291-y REVIEW

TiO2 Nanomaterials in Photoelectrochemical and Electrochemiluminescent Biosensing Xiangui Ma1,2 · Chao Wang1,3 · Fengxia Wu1 · Yiran Guan1 · Guobao Xu1,2  Received: 30 December 2019 / Accepted: 14 February 2020 / Published online: 3 March 2020 © Springer Nature Switzerland AG 2020

Abstract Titanium dioxide ­ (TiO2) is increasingly being used in biosensing applications. Herein, we review the most recent developments in photoelectrochemical (PEC) and electrochemiluminescent (ECL) biosensing based on ­TiO2 nanomaterials, as well as the mechanisms that lead to the improved performance of biosensors that incorporate these nanomaterials. The merits of ­TiO2-based ECL and PEC biosensing strategies are summarized by highlighting some illustrative examples that have been reported within the last 5 years. The future prospects for and challenges in this field are also discussed. Keywords TiO2 · Biosensing · Photoelectrochemistry · Electrochemiluminescence · Nanomaterials

1 Introduction Photoelectrochemical biosensing is promising novel detection method that focuses on photoelectron transfer processes at biomodified electrode/solution interfaces. The resulting photocurrent reflects the production of an electron donor/acceptor in

Chapter 1 was originally published as Ma, X., Wang, C., Wu, F., Guan, Y. & Xu, G. Topics in Current Chemistry (2020) 378: 28. https://doi.org/10.1007/s41061-020-0291-y. * Yiran Guan [email protected] * Guobao Xu [email protected] 1

State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Jilin, People’s Republic of China

2

University of Science and Technology of China, Hefei 230026, Anhui, People’s Republic of China

3

College of Chemistry and Bioengineering, Guilin University of Technology, Guilin 541004, People’s Republic of China



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a target-recognition process when it is irradiated by light of a suitable wavelength. PEC sensing analysis is more sensitive and has a lower background than traditional electrochemical and optical detection techniques because it separates the excitation source (light) from the output signal (photocurrent). Because of its low cost, high sensitivity, very low background noise, short response time, ease of use, and ability to be miniaturized, PEC biosensing has rapidly been applied in various contexts, including for food detection, environmental monitoring, gene testing, and early clinical diagnosis [1–3]. Electrochemiluminescence (ECL)—electrogenerated chemiluminescence—can be considered the reverse of PEC. ECL is the electrochemical process in which an excited species is electrogenerated at an electrode surface and then allowed to relax to a less excited state, resulting in the emission of light. As it is a combined electrochemical and spectroscopic technique, ECL permits both spectral and temporospatial resolution, which makes it a powerful tool for both sensing and imaging [4, 5]. The literature on ECL biosensing methods is extensive, which reflects their inherent advantages, including rapidity, simplicity, high sensitivity, low cost, and nearzero background signal. The integration of nanotechnology into ECL biosensors has also significantly enhanced the sensitivity and diversity of ECL biosensors in recent years [6]. TiO2 nanomaterials are commonly used in PEC and ECL biosensors due to their advantageous properties, such as strong light absorption, chemical and mechanical stability, good catalytic ability, high biocompatibility, and large specific surface areas [7, 8]. There are three crystalline forms of ­TiO2: anatase, rutile, and brookite. The utilization of T ­ iO2 nanomorphologies such as nanosheets [9], nanopillars [10], nanoarrays [11], nanoparticles [12], nanorods [13], nanowires [14], nanoneedles [15, 16], nanoflowers [17], nanocubes [18], and mesocrystals [19, 20] in many advanced bioanalytical strategies is frequently reported. In this mini review, we present recent advances in PEC and ECL biosensing based on ­TiO2 nanomaterials, exploring in detail the sensing strategies used and response mechanisms involved. However, given the limited space available in a mini review, we concentrate on the most significant aspects of and important advances in this field.

2 Applications of ­TiO2 Nanomaterials in Photoelectrochemistry Biosensing In PEC biosensing, the photoactive material significantly influences the analytical performance. However, a well-known disadvantage of ­TiO2-based photoelectrochemistry is that the wide band gap of ­TiO2 results in peak photoabsorption in the ultraviolet (UV; λ ≤ 387 nm) [14, 21]. UV light decreases biomolecular activity, which implies that the applicability of T ­ iO2 to PEC bioanalysis is limited [22]. Low surface charge-transfer efficiency and high electron–hole pair recombination also limit the sensitivities of T ­ iO2-based biosensors. Therefore, attempts have been made to identify new photoactive forms of ­TiO2 that could be used to develop improved biosensors. Countless works in the fields of materials and physical chemistry have

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provided us with the theoretical basis for developing ­ TiO2 nanomaterials with enhanced properties [3, 8]. In this section, the rational design and engineering of various ­TiO2 nanomaterials to minimize the shortcomings of pure ­TiO2 are discussed. Many methods have been used to obtain high-performance PEC biosensors based on ­TiO2 nanomaterials, including the coupling of T ­ iO2 with a narrow bandgap semiconductor, the dye sensitization of ­TiO2, the deposition of noble metal nanoparticles onto ­TiO2, the doping of ­TiO2 with metal and nonmetal atoms, and the preparation of ­TiO2 with engineered defects. Due to the ability to control their band gap and size, quantum dots (QDs) are commonly combined with other photoactive materials to achieve improved PEC behavior [23]. Chen et  al. [9] reported a PEC immunoassay strategy (see Fig.  1a) utilizing ­TiO2 nanosheets and CdS QDs. Due to the narrower band gap of the CdS QDs (2.4 eV) than that of the anatase ­TiO2 nanosheets (3.2 eV), the QDs effectively sensitized the ­TiO2 nanosheets to visible light. The ­TiO2/CdS QDs composite produced strong and stable photoelectric signals and showed strong and broad absorption in the visible light region. This biocompatible nanocomposite also provided

Fig. 1  a Schematic of electron transfer between a CdS-sensitized ­TiO2 nanosheet electrode and Ag@ Cu2O–Ab2 composites used as a label in the PEC detection of cTnI. b Schematic of the PEC mechanism for ­MgIn2S4–TiO2 heterojunction-based aptasensing of ATP. c Schematic of a PEC bioassay for CEA that utilizes porphyrin-sensitized ­TiO2. Reproduced with permission from [9, 11, 12] Reprinted from the journal

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numerous functional groups at which to immobilize antibodies ­(Ab1) for cTnI (cardiac troponin I). In another study, mesoporous T ­ iO2 functionalized with CdS QDs (acting as a sensitizer) was synthesized to facilitate enhanced PEC aptasensing of PSA (prostate-specific antigen) [24]. Ordered mesoporous T ­ iO2 is an ideal platform for incorporating CdS QDs due to its multiple scattering properties and large surface area. The combination of QDs and mesoporous ­TiO2 was found to promote charge transfer and electron–hole pair separation at the interface. Recently, graphite-like carbon nitride (g-C3N4) QDs and N-doped graphene QDs (N-GQDs) [10] were used to sensitize ­TiO2 nanopillars and therefore achieve stronger visible light absorbance for the sensitive PEC detection of pcDNA3-HBV (hepatitis B virus). The band gaps of the T ­ iO2, the g-C3N4 QDs, and the N-GQDs were 3.2, 2.76, and 1.7 eV, respectively. After incorporating the g-C3N4 and N-GQDs, the charge transfer and electron–hole separation efficiency improved considerably due to photosensitization and the formation of a heterojunction between g-C3N4 and ­TiO2. The utilization of a heterostructure comprising ­TiO2 and a semiconductor with a suitable band gap and matched energy levels can tremendously decrease charge recombination, enhance the electron transfer efficiency, and increase light absorption in PEC biosensors. Liu et al. [13] presented a PEC biosensing strategy based on a heterostructure containing ­MoS2 nanosheets and ­TiO2 nanorods. The ­TiO2 nanorods served as hydrothermal growth templates for the ­MoS2 nanosheets, which were a few layers thick. The band edge of the ­MoS2 nanosheets was well matched to that of ­TiO2, facilitating the separation and transfer of the photogenerated charge. Due to the excellent biocompatibility of this system, glucose oxidase (GOx) was immobilized onto a ­MoS2/TiO2 nanocomposite-modified ITO electrode for the sensitive detection of glucose under visible light irradiation. In addition, a T ­ iO2–BiVO4 heterostructure [21] for PEC biosensing has been obtained by depositing B ­ iVO4 NPs onto ­TiO2 nanospheres using a solvothermal method. The narrow energy gap (2.34 eV) of ­BiVO4 was found to improve the absorption of the heterostructure in the visible light region. The high surface area and biocompatible microenvironment of the ­TiO2–BiVO4 heterostructure permitted improved loading of recognition biomolecules for 17β-estradiol measurements. Also, as shown in Fig.  1b, a heterojunction consisting of M ­ gIn2S4 nanoplates and a T ­ iO2 nanoarray was developed [11] for the PEC aptasensing of adenosine triphosphate (ATP). Interestingly, the ­TiO2 nanoarray was observed to have better photoelectric properties than T ­ iO2 NPs, including a narrower bandgap (~ 3.0 eV), higher conductivity, and reduced recombination of electron–hole pairs. The presence of the ­MgIn2S4/TiO2 nanoarray heterojunction improved visible light absorption, resulting in a ~ 6.8-fold increase in photocurrent compared with a more conventional ­TiO2 electrode. Ferrocene, an electron donor employed as a label, has been used to accelerate electron–hole separation and thus enhance the photocurrent in PEC biosensors. In particular, Wei’s group [15] reported the cytosensing of RAW264.7 macrophage cells utilizing a ­TiO2 nanoneedles@MoO3 array p–n heterojunction. ­MoO3 is a p-type semiconductor with a relatively wide band gap of 2.9 eV; its absorption peak is near to the UV light region. Coupling ­MoO3 with ­TiO2 yielded a p–n heterojunction that promoted visible light absorption due to the offset of 2.61 eV between the valence band (VB) of ­TiO2 and the conduction band (CB) of M ­ oO3. Immobilizing F4/80 antibodies used

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as recognition molecules onto this system allowed RAW264.7 cells to be measured directly by steric hindrance. Another common strategy for enhancing PEC biosensing is dye sensitization. For example, Tang’s group [12] reported an ultrasensitive PEC immunoassay of CEA based on porphyrin-sensitized T ­ iO2 nanoparticles (NPs) (Fig.  1c). Linking the water-soluble species 5,10,15,20-tetra(4-sulfophenyl)-21H,23H-porphyrin (TSPP) through its sulfo groups to the ­TiO2 led to an improvement in photoelectron transfer. Compared with T ­ iO2, TSPP has a narrower band gap (2.8 eV) and absorbs more strongly in the visible region due to its delocalized π-electron system. Closely matched energy levels of T ­ iO2 and TSPP result in fast electron transfer and slow charge recombination. The resulting system was then used in combination with glucose oxidase (GOx)-labeled ­Ab2 to fabricate a stable and sensitive PEC biosensor for the detection of CEA. When glucose was present, the GOx oxidized it to ­H2O2, which scavenged photogenerated holes in ­TiO2 at low potential, amplifying the photocurrent. Liu et al. [19] demonstrated that adding a chelating assembly of polydopamine (PDA) to the surfaces of rutile ­TiO2 mesocrystals enhanced the PEC performance of an immunoassay for zearalenone. The benzoquinone groups of the PDA received photoelectrons from the ­TiO2 mesocrystals and enhanced the photocathodic current. Due to its special chemical structure, PDA absorbs long-wavelength light, improving charge-carrier separation. Similarly, polymerized l-DOPA (PD) [25] was applied to improve the enzymatic performance of a PEC glucose sensor by coupling the PD to a core–shell gold nanorod@TiO2 heterostructure. The PD not only enhanced the light absorption of the PEC system but it also provided a biocompatible matrix for surface functionalization and biointeractions. The core–shell heterostructure was found to efficiently assist interfacial charge transfer. The photoactive current density of PD/AuNR@TiO2/FTO was about 8.4 times that of ­TiO2/FTO and 2.6 times that of AuNR@TiO2/FTO. Immobilizing GOx and HRP (horseradish peroxidase) on the composite yielded a sensitive enzymatic PEC sensor for glucose with a low detection limit. Yan [26] reported a turn-on PEC strategy based on localized surface plasmon resonance (LSPR) enhancement and dye sensitization for detecting the activity of protein kinase A (PKA) under visible light ­ iO2/ITO was irradiation. In the presence of PKA and ATP, the kemptide on the T phosphorylated and then linked with DNA-conjugated gold nanoparticle (AuNP) probes. [Ru(bpy)3]2+ was intercalated into the DNA grooves, where it could absorb visible light and generate photoexcited electrons and thus photocurrent under visible light irradiation. Meanwhile, the AuNPs were able to load a considerable amount of [Ru(bpy)3]2+-intercalated DNA, which enhanced the photocurrent transfer efficiency through LSPR. This phenomenon is the collective oscillation of electron clouds in highly conductive metal nanoparticles under suitable light irradiation. For nanoparticles of noble metals such as Ag and Au  [27], this oscillatory resonance occurs at visible wavelengths. Thus, these nanoparticles can facilitate electron transfer and electron–hole pair seperation via the LSPR effect. In 2014, Da et al. [14] reported a PEC biosensing strategy that utilized ­TiO2 nanowires decorated with Au NPs and was based on surface plasmon resonance (Fig. 2a). In this method, Au NPs were attached directly to T ­ iO2 nanowires, which led to double the photocurrent density compared Reprinted from the journal

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Fig. 2  a Schematic of a T ­ iO2 PEC biosensor decorated with Au NPs. b Schematic of PEC detection based on Cu-doped ­TiO2. Reproduced with permission from [14, 30]

to that of pure T ­ iO2. Cholera toxin subunit B, which was used as a test analyte, was sensitively detected in real time using the proposed PEC strategy. Ju’s group [28] prepared a ternary compound consisting of ­TiO2 nanotubes, polyaniline (PANI), and gold NPs for a novel PEC bioassay based on LSPR. The LSPR band of the Au NPs improved the system’s capacity to absorb light at ~ 540 nm and enhanced its photocurrent transfer efficiency. The electrochromism of PANI enhanced the ability of the system to harvest visible light and to separate the charge. The biocompatibility of the ternary composite permitted the immobilization of lactate dehydrogenase (LDH) and ­NAD+ on the electrode, facilitating l-lactate PEC sensing with a detection limit of 0.15 μM. Hao et al. [29] synthesized Ag/TiO2-decorated, 3D-nitrogendoped graphene hydrogel (3DNGH) to promote PEC performance. The 3DNGH had a porous structure and a large surface area that could accommodate a considerable amount of Ag and ­TiO2 NPs. Under light irradiation, electrons on the Ag surface were transferred to T ­ iO2. This Ag/TiO2/3DNGH nanocomposite exhibited a photocurrent that was approximately 60 times greater than that afforded by pristine T ­ iO2 NPs, and a sensitive label-free PEC thrombin aptasensor was constructed from this nanocomposite. The rational design of metal- and nonmetal-doped ­TiO2 can reduce its band gap and improve its response to visible light. Tang et al. [18] reported a PEC strategy for aflatoxin B1 (AFB1) detection based on Ce-doped T ­ iO2 nanocube@MoSe2 nanosheets. Ce was doped into the T ­ iO2 nanocubes using a one-step hydrothermal method. The CB of the Ce-doped ­TiO2 is at a lower energy than that of of ­TiO2, so it has a smaller energy gap. ­MoSe2 nanosheets were then grown on the ­TiO2 nanocubes, yielding a system with a large surface area, and the resulting heterojunction composite presented enhanced visible light absorption. Finally, the AuNPs were introduced as a quenching label that markedly decreased the photocurrent, yielding an ultrasensitive assay for AFB1. Wei’s group [30] developed a Cu-doped ­TiO2/g-C3N4 PEC immunosensor for CEA (Fig. 2b). Doping Cu into ­TiO2 to give a Cu:TiO2 nanocomposite caused the band gap energy to shrink to 2.85 eV, leading to much stronger light absorption and significantly enhanced photocurrent. The PEC performance was further improved upon the addition of g-C3N4 due to the resulting photosensitation and a synergistic effect. Alkaline phosphatase (ALP) was employed

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as a label for A ­ b2 in order to catalyze the hydrolysis of ascorbic acid 2-phosphate to ascorbic acid, which acted as an electron donor, leading to even more detection sensitivity for CEA. Zhang et al. [31] presented a PEC aptasensor for the supersensitive detection of CEA based on nonmetal-doped ­TiO2 and CdS QDs used as a sensitizer. In that study, Br and N were codoped into T ­ iO2, which narrowed its band gap from 3.2  eV to 2.88  eV. The band gap of the (Br, N)-codoped T ­ iO2 was well matched to that of CdS QDs (2.4  eV), meaning that these QDs could be used to intensify the photocurrent. Exonuclease III (Exo-III)-assisted cycling was also applied in this strategy to achieve the supersensitive detection of CEA. The physicochemical properties of ­TiO2 semiconductors also depend on their intrinsic defects and extrinsic impurities. Tang’s group [32] developed ­TiO2 with engineered defects, ­TiO2–x ­(dTiO2–x), and modified the ­dTiO2–x with Au NPs to create a novel photoelectric material for sensitive PEC biosensing (Fig.  3). Oxygen vacancies were induced in the d­ TiO2–x by doping it with F ­ e3+, which narrowed the band gap (to 2.5 eV), extended the absorption edge, and intensified the visible light absorption. When the defective ­TiO2 was irradiated with 580-nm light, the photocurrent was found to be as much as 6.7-fold higher in the presence of Au NPs than in their absence due to the hot electron transfer facilitated by the LSPR of the Au NPs. A significantly smaller (only 2.4-fold) jump in photocurrent in the presence of Au NPs was observed for pristine ­TiO2 under the same conditions. As a result, the Au NPs acted as a photocurrent-enhancing label that facilitated sensitive PEC

Fig. 3  Schematics of PEC biosensor strategies based on the application of d­ TiO2–x (a) and pristine T ­ iO2 (b). c Effects of different excitation wavelengths on the photocurrent intensity. Reproduced with permission from [32] Reprinted from the journal

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DNA detection. Guided by density functional theory (DFT) calculations, Fu et  al. [22] developed plasmonic Au-modified, bulk/surface defect-engineered ­TiO2 nanotube photonic crystals (Au/bsDE-TiO2 NTPCs) for the in  vivo near-infrared PEC aptasensing of tetracycline (TET). Bulk defects were introduced into the ­TiO2 lattice by high-temperature annealing in a reducing atmosphere or vacuum, and then Au NPs were sputtered onto the defective T ­ iO2 surface. The PEC response of the resulting Au/bsDE-TiO2 NTPCs nanocomposite extended into the near-infrared region (900  nm). The photocurrent of the proposed PEC system increased significantly when TET was captured by an aptamer on the nanocomposite. A thin (0.1 mm diameter) Ti wire modified with Au/bsDE-TiO2 NTPCs was then successfully used to monitor the TET in a mouse tail in vivo under near-infrared (NIR) light. Speaking of NIR PEC detection, Qiu et  al. [33] reported the application of core–shell ­NaYF4:Yb,Tm@TiO2 upconversion microrods for the detection of CEA (carcinoembryonic antigen). The ­Yb3+ ions acted as a photosensitizer, absorbing the near-infrared light at 980  nm and generating two emission peaks at 453 and 479 nm. At the same time, the doped ­Tm3+ emitted UV light (with emission peaks at 291, 348, and 363 nm) that overlapped closely with the absorption peak of ­TiO2. After modifying the the ­NaYF4:Yb,Tm with ­TiO2, the peak intensity of the photoluminescence of the resulting system in the UV region markedly decreased. The proposed PEC system exhibited a good response to the guanine bases generated during CEA aptasensing. Due to its low phototoxicity in biological systems, this ­NaYF4:Yb,Tm@TiO2-based biosensor should expand the application of upconversion materials to PEC detection.

3 Applications of ­TiO2 Nanomaterials in Electrochemiluminescence Biosensing Recently, ­TiO2 nanomaterials and their composites have drawn considerable interest from those working in the field of ECL biosensing, given the biocompatibility, large surface area, and unique ECL properties of these materials. ­TiO2 nanomaterials can be applied in a variety of roles in ECL biosensors, including as a matrix for biomolecules, as an ECL luminophore, and as a catalyst for the ECL reaction. In this section, ECL bioassays based on T ­ iO2 nanomaterials are explored via a number of illustrative examples. TiO2 is an ideal matrix for immobilizing biomolecules on an electrode. For instance, Dai and coauthors [20] presented a dual-signal ECL biosensor based on ­TiO2 mesocrystals and CdTe QDs for the detection of metallothioneins. A considerable amount of Ru(bpy)2+ TiO2 mesocrystal struc3 was immbolized in the porous ­ ture through ion exchange. In addition, the presence of ­TiO2 mesocrystals on the nanocomposite surface resulted in a higher pH, thus increasing the ECL intensity of Ru(bpy)2+ 3 . ­TiO2 is able to link to metallothioneins efficiently via strong interactions with the sulfhydryl groups of metallothioneins, which blocks electron transfer and hinders the diffusion of coreactants, thus decreasing the ECL intensity of Ru(bpy)2+ 3 . The CdTe QDs can link to the remaining SH groups of metallothioneins, generating a cathodic ECL. Therefore, a ratiometric biosensor was constructed for

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metallothioneins, which presented a LOD that reached down to the ng/mL level. Interestingly, Tsuneyasu et al. [34] proved that T ­ iO2 NPs amplify the ECL intensity of Ru(bpy)2+ , thus improving the properties of an ECL device based on Ru(bpy)2+ 3 3 . The optical and electrochemical properties of the resulting system were studied in detail, and it was found that the ECL improvement induced by the ­TiO2 NPs was due to their ability to suppress the nonradiative quenching of the excited states of Ru(bpy)2+ 3 . In another study, a dual-amplified ECL sensor based on tetragonal rutile ­TiO2 mesocrystals (TRM) was developed for sensitive zearalenone (ZEA) detection [35]. As shown in Fig. 4, the nanoporous TRM were functionalized with poly(amidoamine) dendrimers (PAAD) in order to generate a biocompatible substrate with a surface area large enough to immobilize sufficient A ­ b1 of ZEA. On the other hand, the TRM were employed to adsorb large amounts of Ru(bpy)2+ 3 and to immobilize ­Ab2. A sensitive sandwich-type ECL strategy was realized through these two TRM-based amplification techniques. Electron transfer from the reduced species of Ru(bpy)2+ 3 and extensive light scattering by TRM led to strong ECL emission and the sensitive detection of ZEA. In another approach to improving ECL performance, ­TiO2 MOFs [36] were synthesized via the calcination of MIL-125 (Tibased MOFs). These ­TiO2 MOFs had a highly regular pore structure and a large specific surface area, allowing the immobilization of large amounts of Ru(bpy)2+ 3 , β-cyclodextrin (β-CD), and antibody. Fluoro-coumarin silicon phthalocyanine, used as a sensitizer, was then encapsulated in the β-CD to decrease the electron transfer distance and thus increase the ECL signal. A competitive-type ECL immunosensor based on this system was constructed that permitted the stable and sensitive detection of deoxynivalenol. TiO2 nanomaterials can act as ECL luminophores in ECL detection methods. Deng et al. [37] reported the use of flower-like ­TiO2 nanostructures as an ECL emitter label in a PSA assay. This flower-like morphology of T ­ iO2 provides plenty of binding sites for biomolecules and nanomaterials due to its porosity and large specific surface area. In subsequent study, ­TiO2 nanoflowers@g-C3N4-Au [38] were

Fig. 4  Schematic of a dual-amplified ECL immunosensor in which TRM plays two roles. Reproduced with permission from [35] Reprinted from the journal

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synthesized for an ECL immunoassay of N-terminal brain natriuretic peptide. The band levels of ­TiO2 and g-C3N4 are well matched, increasing the ECL emission efficiency. Polydopamine (PDA) linked with A ­ b2 was employed as a ECL quencher to improve detection sensitivity. Wei’s group [39] reported an ECL immunosensor for CEA based on the composite Au-FrGO-CeO2@TiO2, where Au-FrGO refers to ­Fe3O4 capped with reduced graphene oxide functionalized with Au NPs. When ­K2S2O8 was employed as a coreactant, C ­ eO2@TiO2 was found to yield greater ECL intensity than ­TiO2. The resulting ­CeO2@TiO2 heterojunction presented a smaller band gap than T ­ iO2, facilitating electron transfer between the ­CeO2@TiO2 composite and its coreactant. The Au-FrGO was included to further amplify the ECL signal. When tested, the ECL biosensor displayed a sensitive response to CEA. Tian et al. [40] presented an ECL immunosensor based on ­TiO2 nanotube arrays functionalized with graphene quantum dots (GQDs). Vertically aligned ­TiO2 nanotubes were included to provide a large surface area on which to immobilize the GQDs and antibody. The ECL intensity was enhanced sixfold after immobilizing the GQDs to form a hybrid structure (GQD/TiO2 NTs). Under optimized conditions, PSA was sensitively detected using CdTe NPs modified with ­Fe3O4 magnetic nanoparticles (CdTe/ MNPs) as a quenching label. Cui and coauthors [41] developed a potential-resolved ECL strategy for the label-free ratiometric aptasensing of cTnI that involved wrapping titanium dioxide in nanographene oxide (nGO@TiO2 NLPs) employing a “one-pot” hydrothermal method (Fig. 5a). Using K ­ 2S2O8 as a coreactant, as shown in Fig. 5b, this nanocomposite yielded dual ECL emission (ECL-1 and ECL-2) at − 1.27 V and − 1.85 V, respectively (black line). In contrast, ­TiO2 (green line) and nGO (blue line) each provided just one ECL emission peak under the same conditions. ECL-1 and ECL-2 were found to correspond with the ECL emissions of ­TiO2 and nGO by comparing ECL potentials and emission wavelengths (Fig. 5b–d), but the intensities of ECL-1 and ECL-2 were observed to be considerably stronger than the corresponding ECL emission intensities of ­TiO2 and nGO alone due to a synergistic effect. After capturing the target, the aptamer moved away from the electrode surface because of its rigidity, reducing the resistance of the electrode and enhancing the two ECL signals from the nGO@TiO2 NLPs. Furthermore, the intensity of ECL-1 and the ECL intensity of T ­ iO2 were observed to increase in an oxygen atmosphere and to decrease in a nitrogen atmosphere because some of the ­O2 was electroreduced and subsequently reacted with ­S2O82− to generate SO•− 4 . Similarly, Dai et al. [42] proposed a simple dual coreactant strategy to enhance the ECL performance of T ­ iO2 nanotubes. When K ­ 2S2O8 and ­H2O2 were added simultaneously, the ECL intensity of ­TiO2 increased 6.3-fold and 107-fold, respectively, compared to when only ­K2S2O8 or ­H2O2 was added as a coreactant, which was attributed to the increased concentration of SO•− ­ 2O2 on the electrode 4 caused by the presence of H surface. This mechanistic study of the ECL enhancement caused by dual coreactants could provide a general strategy for improving ECL-based applications of semiconductor nanomaterials. Besides acting as an immobilization substrate, T ­ iO2 catalyzes the oxidation of ­ H2O2, which makes ­ TiO2 suitable for fabricating biofunctional ECL electrodes. Wu et  al. [43] reported an enzymatic ECL choline sensor based on a ­Fe3O4-TiO2-choline oxidase (ChO) biocomposite. Choline was oxidized with

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Fig. 5  a Schematic of the fabrication of a label-free ratiometric ECL aptasensor. b ECL curves of the nGO@TiO2 NLPs (black line), nGO (blue line), T ­ iO2 (green line), and the FTO electrode (red line). Comparison of the ECL emission wavelengths of ECL-1/TiO2 (c) and ECL-2/nGO (d). Reproduced with permission from [41]

dissolved ­O2 by ChO to generate ­H2O2, which was then measured quantitatively based on the ECL signal from the luminol/H2O2 reaction. In this system, ­Fe3O4 nanospheres catalyzed the electrooxidation of ­H2O2. At the same time, the presence of ­TiO2 increased electron transfer and the ECL signal from luminol. Tang et  al. [44] presented a system comprising Au NPs/ionic liquid/hollowed ­TiO2 nanoshells for the sensitive ECL biosensing of cholesterol. The synthesized nanocomposite exhibited more intense luminol/H2O2 ECL emission than AuNPs or ­TiO2 alone. Cholesterol oxidase (ChOx) was immobilized on the nanofunctionalized electrode surface by glutaraldehyde (GD) and bovine serum albumin (BSA). This strategy permitted the sensitive quantification of cholesterol. A disposable biosensor [45] for glucose detection was prepared using a Au/TiO2 nanocomposite to intensify the ECL of luminol. After crosslinking glucose oxidase via GD and BSA, the ECL biosensor showed excellent stability, sensitivity, and simplicity when used for glucose detection. Moreover, Li et al. [46] reported a ECL immunosensor that used AuPdPt–MoS2@TiO2 to increase the ECL intensity of luminol by catalyzing the electrochemical reaction of ­H2O2. The nanocomposite was covalently linked directly to the amino group of luminol and the resulting

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matrix was employed to anchor A ­ b1. Finally, insulin was sensitively measured with ­MnO2@C nanospheres used as an energy-transfer quenching label. Various applications of ECL microscopy appear in the literature due to the extremely low background light and high throughput of this technique. Because of the steric hindrance and low electrical conductivity of cells, it is difficult to perform ECL cell imaging directly. Zhu and coauthors [47] designed a direct ECL imaging strategy for single cells on a chitosan- and nano-TiO2-modified FTO glass electrode that utilized the electrocatalytic ability of nano-TiO2 (Fig. 6a). The permeable chitosan film provided a favorable microenvironment for cell immobilization and increased the space available between the cells and electrode for L012 (a luminol analog). Meanwhile, the nanosized ­TiO2 amplified the ECL signal from L012 and ­H2O2 released from the cells and permitted imaging with a high signal-to-noise ratio. Those authors subsequently investigated [48] the application of the steadystate ECL of individual rutile T ­ iO2 NPs in a biosensor targeting the local efflux from single cells (Fig.  6b). The T ­ iO2 accelerated electron transfer, enhancing the ECL intensity. In addition, oxygen vacancies in the rutile ­TiO2 adsorbed ­H2O2 and were stable from passivation by applying voltage  in the investigated range, leading to a constant ECL signal from L012/H2O2 under physiological conditions. This steadystate luminescence made it possible to visualize the H ­ 2O2 efflux from single cells using single ­TiO2 nanoparticles with high spatial and temporal resolution. Besides the luminol/H2O2 system, T ­ iO2 also strongly catalyzes other ECL systems. Yuan’s group [17] designed a system containing Ag nanoclusters/TiO2 nanoflowers (Ag NCs–TiO2 NFs) for use as a highly efficient ECL probe for the detection of amyloid-β. Due to the large surface area of the nanoflower structure and its

Fig. 6  a Schematic of the ECL imaging of cells on a chitosan- and nano-TiO2-modified electrode. b Schematic of the ECL sensing strategy involving the visualization of single T ­ iO2 NPs as a means to monitor the ­H2O2 efflux from single cells. c The ECL mechanism of Ag NCs–TiO2 NFs and comparison of the ECL intensities of the Ag NCs and the Ag NCs–TiO2 NFs. Reproduced with permission from [17, 47, 48]

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strongly catalytic properties, the T ­ iO2 NFs promoted the reduction of dissolved O ­2 to yield ­OH• radicals, which reacted with the Ag NCs, leading to stronger ECL emission (Fig.  6c). Ferrocene-labeled DNA was employed as an ECL quenching probe to further improve the sensitivity of the proposed biosensor. The catalysis of the reduction of dissolved ­O2 by ­TiO2 has also been applied to enhance the cathodic ECL intensity of A ­ u25 NCs in a sensitive ECL biosensor [49]. Oxygen vacancies of ­TiO2 could improve the electrocatalytic performance [50]. And using X-ray photoelectron spectroscopy, Liang et al. [51] discovered that oxygen vacancies in Cudoped ­TiO2 NPs could act as reactive centers for the conversion of dissolved ­O2 into superoxide radicals (­O2•−), which intensified the ECL of luminol. In another study, ­S2O82− was employed as a coreactant and ­TiO2 as its accelerator [52] in order to enhance the ECL efficiency of the Cu NCs used in an ultrasensitive ECL biosensor for microRNA detection. In the presence of the target, a cascade leading to signal amplification and a hybridization chain reaction were triggered, causing AT-rich double-stranded DNA to be generated on the ­TiO2. The Cu NCs that acted as the ECL luminophore in this detection system were then generated in situ on the dsDNA via A–Cu2+–T bonding. The ­TiO2 not only provided a platform for the dsDNA functionalized with Cu NCs, but it also helped to generate SO•− 4 , which improved the performance of the ECL biosensor. Zhang et al. [16] prepared a ternary ECL biosensor based on Ru(bpy)2(cpaphen)2+/TPrA/TiO2 nanoneedles for the detection of glutathione. The electrode was modified with T ­ iO2 nanoneedles in order to immobilize long dsDNA structures that adsorbed Ru(bpy)2(cpaphen)2+, the ECL luminophor. The ­TiO2 nanoneedles also acted as an accelerator for the oxidation of tripropylamine (TPrA), significantly intensifying the ECL signal from Ru(bpy)2(cpaphen)2+. When a voltage was applied to the system, electrons tunneled from the VB of ­TiO2 to the CB. The holes generated in the VB were filled by electrons from TPrA, generating T ­ PrA+•. Finally, GSH recognition was achieved with this system by including M ­ nO2 nanosheets, which were reduced by the GSH to ­Mn2+; and then Mn2+ worked as cofactor to cleave the Ru-dsDNA structures.

4 Conclusion and Future Perspectives This review has focused on the development of novel ­TiO2-based nanomaterials and innovative applications of them in PEC and ECL biosensing. Such biosensors based on ­TiO2 nanomaterials are particularly interesting mechanistically and from the perspective of biosensing applications due to the special photoelectric interconversion processes they use to probe biorecognition and biocatalytic events. However, there are still several challenges in the practical application of ­TiO2 nanomaterials to PEC and ECL biosensing. First, T ­ iO2 nanomaterials have relatively low PEC and ECL efficiencies, so other nanomaterials such as QDs or noble metal NPs are usually incorporated into the biosensing system to optimize its performance. In many cases, the strategies used to synthesize the T ­ iO2-based nanomaterials have been taken directly from energy and photocatalysis research, and the resulting nanomaterials may be not suitable for use in bioassays. More effort should be directed into designing ­TiO2 nanomaterials that are specifically for PEC and ECL biosensing. Second, Reprinted from the journal

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even though there have been a few attempts to achieve bioimaging and biodetection in vivo using ­TiO2-based nanomaterials, near-infrared PEC and ECL biosensing are only rarely addressed in the literature and therefore require detailed investigation. The detection or imaging of a single molecule, cell, or particle may be an important area of research in the future. Third, in some situations, the function and mechanism of the T ­ iO2-based nanomaterial in the biosensing methods is still unclear and therefore requires further study that makes use of the advances that are currently being made in nanotechnology and instrument characterization. In a word, for the foreseeable future, the use of rationally designed and modified ­TiO2 nanomaterials in PEC and ECL biosensors has the potential to substantially broaden the range of applications of these detection systems. Acknowledgements  Funding from the National Natural Science Foundation of China (nos. 21874126 and 21675148) and The National Key Research and Development Program of China (no. 2016YFA0201300) are greatly appreciated.

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31. Zhang Y, Li M, Wang H, Yuan R, Wei S (2019) Supersensitive photoelectrochemical aptasensor based on Br, N-codoped T ­ iO2 sensitized by quantum dots. Anal Chem 91(16):10864–10869. https​://doi.org/10.1021/acs.analc​hem.9b026​00 32. Shu J, Qiu Z, Lv S, Zhang K, Tang D (2018) Plasmonic enhancement coupling with defect-engineered ­TiO2–x: a mode for sensitive photoelectrochemical biosensing. Anal Chem 90(4):2425– 2429. https​://doi.org/10.1021/acs.analc​hem.7b052​96 33. Qiu Z, Shu J, Tang D (2018) Near-infrared-to-ultraviolet light-mediated photoelectrochemical aptasensing platform for cancer biomarker based on core–shell NaYF4:Yb, Tm@TiO2 upconversion microrods. Anal Chem 90(1):1021–1028. https​://doi.org/10.1021/acs.analc​hem.7b044​79 34. Tsuneyasu S, Ichihara K, Nakamura K, Kobayashi N (2016) Why were alternating-currentdriven electrochemiluminescence properties from Ru(bpy)32+ dramatically improved by the addition of titanium dioxide nanoparticles? Phys Chem Chem Phys 18(24):16317–16324. https​://doi. org/10.1039/C6CP0​2881K​ 35. Zheng H, Yi H, Lin W, Dai H, Hong Z, Lin Y, Li X (2018) A dual-amplified electrochemiluminescence immunosensor constructed on dual-roles of rutile ­TiO2 mesocrystals for ultrasensitive zearalenone detection. Electrochim Acta 260:847–854. https​://doi.org/10.1016/j.elect​ acta.2017.12.054 36. Zheng H, Yi H, Dai H, Fang D, Hong Z, Lin D, Zheng X, Lin Y (2018) Fluoro-coumarin silicon phthalocyanine sensitized integrated electrochemiluminescence bioprobe constructed on ­TiO2 MOFs for the sensing of deoxynivalenol. Sens Actuators B Chem 269:27–35. https​://doi. org/10.1016/j.snb.2018.04.149 37. Deng W, Chu C, Ge S, Yu J, Yan M, Song X (2015) Electrochemiluminescence PSA assay using an ITO electrode modified with gold and palladium, and flower-like titanium dioxide microparticles as ECL labels. Microchim Acta 182(5):1009–1016. https​://doi.org/10.1007/s0060​ 4-014-1423-2 38. Zhao Y, Li L, Hu L, Zhang Y, Wu D, Ma H, Wei Q (2019) An electrochemiluminescence immunosensor for the N-terminal brain natriuretic peptide based on the high quenching ability of polydopamine. Microchim Acta 186(9):606. https​://doi.org/10.1007/s0060​4-019-3709-x 39. Yang L, Zhu W, Ren X, Khan MS, Zhang Y, Du B, Wei Q (2017) Macroporous graphene capped ­Fe3O4 for amplified electrochemiluminescence immunosensing of carcinoembryonic antigen detection based on ­ CeO2@TiO2. Biosens Bioelectron 91:842–848. https​://doi.org/10.1016/j. bios.2017.01.055 40. Tian C, Wang L, Luan F, Zhuang X (2019) An electrochemiluminescence sensor for the detection of prostate protein antigen based on the graphene quantum dots infilled ­TiO2 nanotube arrays. Talanta 191:103–108. https​://doi.org/10.1016/j.talan​ta.2018.08.050 41. Han Z, Shu J, Liang X, Cui H (2019) Label-free ratiometric electrochemiluminescence aptasensor based on nanographene oxide wrapped titanium dioxide nanoparticles with potential-resolved electrochemiluminescence. Anal Chem 91(19):12260–12267. https​://doi.org/10.1021/acs.analc​ hem.9b023​18 42. Dai P, Yu T, Shi H, Xu J, Chen H (2015) General strategy for enhancing electrochemiluminescence of semiconductor nanocrystals by hydrogen peroxide and potassium persulfate as dual coreactants. Anal Chem 87(24):12372–12379. https​://doi.org/10.1021/acs.analc​hem.5b038​90 43. Wu X, Chai Y, Yuan R, Liang W, Yuan D (2014) A novel electrochemiluminescence choline biosensor based on biofunctional AMs-ChO biocomposite. Sens Actuators B Chem 204:429–436. https​ ://doi.org/10.1016/j.snb.2014.07.125 44. Tang S, Zhao Q, Tu Y (2016) A sensitive electrochemiluminescent cholesterol biosensor based on Au/hollowed-TiO2 nano-composite pre-functionalized electrode. Sens Actuators B Chem 237:416– 422. https​://doi.org/10.1016/j.snb.2016.06.110 45. Yu L, Wei X, Fang C, Tu Y (2016) A disposable biosensor for noninvasive diabetic diagnosis rest on the Au/TiO2 nano-composite intensified electrochemiluminescence. Electrochim Acta 211:27– 35. https​://doi.org/10.1016/j.elect​acta.2016.06.034 46. Li X, Sun X, Fan D, Yan T, Feng R, Wang H, Wu D, Wei Q (2019) A ternary quenching electrochemiluminescence insulin immunosensor based on M ­ n2+ released from M ­ nO2@carbon core-shell nanospheres with ascorbic acid quenching AuPdPt–MoS2@TiO2 enhanced luminol. Biosens Bioelectron 142:111551. https​://doi.org/10.1016/j.bios.2019.11155​1 47. Liu G, Ma C, Jin B, Chen Z, Zhu J (2018) Direct electrochemiluminescence imaging of a single cell on a chitosan film modified electrode. Anal Chem 90(7):4801–4806. https​://doi.org/10.1021/ acs.analc​hem.8b001​94

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Topics in Current Chemistry (2020) 378:13 https://doi.org/10.1007/s41061-019-0277-9 REVIEW

DNA–Iron Oxide Nanoparticles Conjugates: Functional Magnetic Nanoplatforms in Biomedical Applications José Raúl Sosa‑Acosta1,2 · Claudia Iriarte‑Mesa1 · Greter A. Ortega1,3 · Alicia M. Díaz‑García1  Received: 24 July 2019 / Accepted: 20 December 2019 / Published online: 10 January 2020 © Springer Nature Switzerland AG 2020

Abstract The use of magnetic nanoparticles (MNPs), such as iron oxide nanoparticles (IONPs), in biomedicine is considered to be a valuable alternative to the more traditional materials due to their chemical stability, cost-effectiveness, surface functionalization, and the possibility to selectively attach and transport targeted species to the desired location under a magnetic field. One of the many main applications of MNPs is DNA separation, which enables genetic material manipulation; consequently, MNPs are used in numerous biotechnological methods, such as gene transfection and molecular recognition systems. In addition, the interaction between the surfaces of MNPs and DNA molecules and the magnetic nature of the resulting composite have facilitated the development of safe and effective gene delivery vectors to treat significant diseases, such as cancer and neurological disorders. Furthermore, the special recognition properties of nucleic acids based on the binding capacity of DNA and the magnetic behavior of the nanoparticles allowing magnetic separation and concentration of analytes have led to the development of biosensors and diagnostic assays; however, both of these applications face important challenges in terms of the improvement of selective nanocarriers and biosensing capacity. In this review, we discuss some aspects of the properties and surface functionalization of MNPs, the interactions between DNA and IONPs, the preparation of DNA nanoplatforms and their biotechnological applications, such as the magnetic separation of DNA, magnetofection, preparation of DNA vaccines, and molecular recognition tools. Keywords  Magnetic nanoparticles · DNA conjugation · Nucleic acid separation · DNA-based therapeutics

Chapter 2 was originally published as Sosa‑Acosta, J. R., Iriarte‑Mesa, C., Ortega, G. A. & Díaz‑García, A. M. Topics in Current Chemistry (2020) 378: 13. https://doi.org/10.1007/s41061-019-0277-9. * Alicia M. Díaz‑García [email protected] Extended author information available on the last page of the article Reprinted from the journal

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Abbreviations APTES (3-Aminopropyl) triethoxysilane CuAAC​ Cu(I)-catalyzed azide-alkyne cycloaddition IONPs Iron oxide nanoparticles MNPs Magnetic nanoparticles ODN Oligonucleotide PAMAM Polyamidoamine dendrimers PEG Polyethylene glycol PEI Polyethylenimine pHEMA Poly(2-hydroxyethyl methacrylate) PNA 4-Pyridyldithiol-derivatized peptide nucleic acid siRNAs Small interfering RNAs ssDNA Single-stranded DNA ssODN Single-stranded oligonucleotide TEOS Tetraethyl orthosilane TMOS Tetramethyl orthosilane

1 Introduction The increasing amount of scientific research that is focusing on nanomaterials has resulted in significant progress in many practical applications. This class of compounds is referred to as ‘nanoscaled’ due to the size of the particles, a term which means that at least one of the three dimensions is in the range of 1–100  nm. As a multipurpose science, nanotechnology has extended the interest of researchers into novel systems at this small scale due to the exceptional properties and applications of the nanomaterials. Nanomaterials comprise many materials, such as carbon nanotubes, fullerenes, nanocomposites, nanopolymers, nanovectors, nanoparticles, nanofibers, nanowires, nanorods, among many others [1]. The primary applications of these materials are in the technological and biomedical fields, including water treatment [2, 3], catalysis and electrocatalysis [4–10], air purification [11], photovoltaics [12], cancer treatment [13], among others. Magnetic nanoparticles (MNPs) are considered to be the center of nanotechnology-based structures and have had a substantial impact in the fields of nanomedicine, analytical chemistry, electronics, and biosensing [14–17]. To date, significant improvements have been made in the synthesis and characterization of such systems, with a focus on achieving and maintaining a desired size, morphology, composition, and surface chemistry. The use of MNPs and in particular ferrite colloids in the field of biomedicine is associated with their physical properties, magnetic susceptibility, biocompatibility, and low toxicity [18]. The surface functionalization of such materials allows many structures to be designed while taking into consideration the conjugated (bio)molecule and the specific target. The conjugation of MNPs to DNA fragments is just one example of unique magnetic properties and biological selectivity combinations that are aimed at improving the efficiency of diagnosis and therapy of diseases [19, 20]. Several approaches to conjugate nucleic acids with MNPs have been reported

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in the literature [21–23]; these include the direct binding of a nucleic acid molecule to MNPs or the formation of chemical bonds that requires preliminary modification of the nanoparticles’ surface and/or DNA molecules. Thus, the design of DNA-based magnetic nanocomposites for applications in nanomedicine is not easily implemented and depends on the ultimate purpose for which that nanocomposite is intended [24–27]. Over the last decades, a number of authors have pointed out that magnetofection or gene delivery is a fundamental stage in nanomedicine development [28–30]. It is well known that one of the fundamental steps of gene delivery is specificity in DNA separation. However, such methodology is also important in many other applications, such as magnetosensitive biosensors [31], theranostics [32], and vaccine preparation [33]. Even though the DNA isolation process itself remains a challenge in terms of optimization and solid phase support selection, the use of magnetic separation is still advantageous compared to traditional techniques [34]. The aim of this review article is to briefly outline the main properties of MNPs and MNPs/DNA biocomposites. Current information on synthesis methods, surface modification, and DNA interactions are also discussed. Additionally, we consider a systematic description of the DNA isolation process using MNPs and the functioning principles of other nucleic acid-based nanobiohybrid systems.

2 Synthesis, Properties, and Surface Functionalization Strategies of Magnetic Nanoparticles The term magnetic nanoparticle covers a wide spectrum of nanostructured materials that have the advantageous property of being magnetic in nature, thereby enabling their use for different applications. This description covers a wide range of nanoparticles, including metallic [35], bimetallic [36], and metal oxide nanoparticles [37], in diverse architectures, such as core–shell structures [38] or Janus-type nanoparticles [39]. Among these structures are the iron oxide systems that have been intensively studied for biomedical and technological applications [29]. Magnetic iron oxide nanoparticles (IONPs) have significant advantages because they are inexpensive to produce, exhibit sufficient physical and chemical stability, and have sufficient biocompatibility [15]. These properties together with a proper magnetic response are the factors determining the use of IONPs in targeted drug delivery, hyperthermia, magnetic resonance imaging, detection of cancer biomarkers, clinical diagnosis, bioremediation, and DNA isolation [40–43], among others. (Fig. 1). Particle size control, phase purity, colloidal stability, and magnetic nature have been the focus of attention during the development of methodologies [44–46]. These features are fundamental to achieving an appropriate nanocolloid and therefore fulfilling the requirements for its use in practical applications. The main pathways for the synthesis of IONPs, such as magnetite (­ Fe3O4), can be classified as: (1) physical methods, such as gas-phase deposition and electron beam lithography, which are difficult techniques in terms of controlling particle size [47]; (2) chemical preparation methods, such as sol–gel, thermal decomposition, chemical coprecipitation, hydrothermal reactions, flow injection, electrochemical, and syntheses using nanoreactors Reprinted from the journal

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Fig. 1  Schematic illustration of the main applications of magnetic nanoparticles (MNPs) as a function of their cargo or carrier characteristics

[48, 49]; and (3) microbial methods, which ensure good reproducibility and scalability at a low cost and moderate preparation temperatures [50, 51]. Among the chemical routes, coprecipitation is considered to be the simplest, cheapest and most environmentally friendly procedure. This route involves the simultaneous precipitation of ­Fe2+ and ­Fe3+ ions in basic aqueous media. The reaction temperature is limited by the boiling point of water, and the IONPs synthesized under these conditions usually exhibit a low degree of crystallinity and large polydispersity [52, 53]. Because of the large number of possible synthesis parameters, the coprecipitation method makes it possible to study how the final properties of IONPs can be controlled by various factors, such as the nature of the starting reagents, molar ratio of ­Fe2+ to ­Fe3+, alkali type, pH, stirring, ionic strength, surfactant, and temperature [54]. For example, the slow addition of an ammonia solution typically results in an increased size of nanoparticles, whereas the fast addition leads to slightly smaller ones. Compared with coprecipitation, thermal decomposition is a useful technique by which to prepare colloidally stable nanoparticles with a narrow particle size distribution (Fig.  2). In this methodology, the reaction mixture typically consists of an organometallic precursor as a metal source, surfactants, and an organic solvent with a high boiling point [55]. Airless synthetic techniques are often required when this pathway is employed  due to the use of air-sensitive molecular precursors, and the method cannot be regarded as the most environmentally friendly one due to the use of often toxic chemicals during synthesis [55, 56]. However, the high temperatures at which the reactions take place and the presence of amphiphilic surfactant molecules in a non-polar medium limit the use of nanoparticles produced in this way in most biomedical applications unless modification occurs. The hydrothermal or solvothermal technique is also considered to be employ high-temperature pathways to obtain magnetic nanocolloids. This method is dominated by the classical synthesis of nanoparticles via coprecipitation, followed by the growth of the particles under hydrothermal conditions, which ensures a high crystallinity degree as well as magnetization values. However, the use of a sealed Teflon container and the heating treatment above the boiling temperature of the water allow the production of IONPs with a broader particle size distribution in comparison to thermal decomposition products [54, 56].

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Fig. 2  Iron oxide nanoparticles (IONPs) coated with oleic acid synthesized by coprecipitation (a) and thermal decomposition (b) (authors’ own unpublished results)

IONPs are not the only iron-containing materials with important magnetic properties. Spinel ferrites are, in general, complex systems derived from iron oxides that are chemically combined with one or more metallic elements to improve their magnetic response. Such nanostructures have a common component and formula, ­MFe2O4, where M can be C ­ o2+, ­Mn2+, ­Ni2+, ­Zn2+, and others divalent metal ions [15, 57]. Metal-doped iron oxides with a spinel structure have been prepared by a high-temperature reaction between corresponding divalent metal chloride and iron tris-2,4-pentadioate [58], but various other synthetic methods have been reported, such as electrospinning [57], coprecipitation [59], and polyol [15]. In addition to preventing agglomeration and enhance colloidal stability, the functionalization of IONPs allows higher water compatibility and better magnetic control. Surface modification is also necessary to the conjugation of biologically active substances, an important process for nanomaterial applications to biology and medicine. Chemical modification methods for the surface of MNPs can be conditionally divided into two groups, noncovalent (or nonspecific) and covalent modification [60]. Such processes encompass ligand addition [61], ligand exchange [62], and encapsulation of diverse materials, including small molecules [63], organic or polymeric ligands [64, 65], dense polymer matrix [66], and inorganic materials [67]. In general, so-called core–shell structures representing a magnetic core grafted with a layer of a polymer or inorganic material are the most widely used MNPs. They combine the properties of both materials in a single smart and multifunctional system [68, 69]. The coating method is dependent on the nature of the grafting materials and the intended final application. Surface modification of IONPs is normally achieved in a single step during the synthesis procedure or subsequently in a post-synthesis protocol. In the former case, the coating process starts as soon as nucleation occurs, preventing further particle growth. Several ligands have been used for direct functionalization, including carboxylates [70], phosphonates [71], thiol [72], or amino groups [52]. Molecules such as citrate and amino acids may Reprinted from the journal

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be adsorbed onto the surface of the IONPs via coordination of carboxylate functionalities, thereby exposing new terminal groups for further modification [73]. The post-synthesis protocols are always divided into two steps: the first step consists of IONPs synthesis, followed by surface modification as a separate step. Such techniques are performed mainly via ligand addition or exchange and encapsulation using polymeric matrixes [74]. One advantage of these methodologies is the possibility to design multiple nanostructures using either one protocol or another as well as a combination of both. Some examples of magnetic platforms based on IONPs for the conjugation of DNA are given in Table 1. The synthesis and coating methods are also presented, showing the diversity of strategies used for obtaining functional conjugates.

3 Interaction of DNA–Magnetic Nanoparticles: Preparation of Nanoplatforms DNA molecules play an important role in transferring genetic information through generations. Such structures consist of several nucleosides sharing a phosphate backbone with sequences generated from assemblies of bases able to form a double helix structure [84]. Due to its programmability, cost-effectiveness, ease of modification, and the ability to recognize a broad range of analytes, DNA is a highly attractive molecule for use in designing hybrid materials [85]. Such features together with the extraordinary properties of MNPs allow the fabrication of nanoplatforms as powerful molecular recognition tools and targeted drug delivery carriers [86, 87]. Nanoplatform design depends on the type of interaction between DNA and the nanoparticle surface. Since a large number of coupling agents are commercially available, the covalent immobilization of nucleic acids, as well as of other biomolecules, is easy to achieve (Fig. 3). Such methodologies include traditional methods of bioconjugation and the ‘click’-chemistry approaches, such as carbodiimide activation, thiol-disulfide exchange, aldehyde-amine condensation, and azide-alkyne cycloaddition [88, 89]. Covalent immobilization is also attained with thiolated and aminated molecules [90]. To this end, amino, sulfhydryl, carboxyl, and azido groups are initially formed on the surface of the nanoparticles. Although all of these methodologies are well described, some key parameters need to be considered, such as biomolecule orientation and the specific activity [17]. The covalent immobilization of DNA onto the surface of MNPs is not the only interaction of such biocomposites, but it is certainly considered to be a very useful alternative for in  vitro diagnosis [24]. However, different methods are often employed to achieve bioconjugation, such as physical adsorption, Van der Waals, electrostatic or high-affinity noncovalent interactions [25–27]. Knowledge of the relevant adsorption mechanisms provides valuable information in terms of nanomaterial surface design with the aim to manipulate or suppress highly specific binding and to control bonds between the components of the biocomposites [17]. For example, the use of an electrostatic approach could have advantages in terms of time and resources, but a high-affinity methodology could be more specific.

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Specific adsorption of DNA

Molecular recognition

DNA exaction for prenatal diagnosis

Glutaraldehyde cross-linking Immobilization of enzymes

Electrostatic adsorption

Detection of cancer biomarkers

Gene delivery

DNA extraction

Gene detection

DNA storage

Detection of mutated DNA

DNA exaction

Application

[83]

[82]

[81]

[80]

[79]

[67]

[78]

[77]

[76]

[75]

References

APTES, 3-(Aminopropyl) triethoxysilane; PEI, polyethyleneimine; ssDNA, single-stranded DNA; CaP, calcium phosphate; PEG, polyethylene glycol; PAA, polyacrylic acid; PDA, polydopamine

5-Methyl cytosine antibody (Abcam, Cambridge, UK)

PDA

Hydrothermal

Co-precipitation

Fe3O4

Core–shell gold-coated magnetic nanoparticles ­(Fe3O4-Au-NP)

Co-precipitation PAA and free radical polymerization

Fe3O4

Encapsulation (siRNA)

Adsorption

Covalent coupling

Encapsulation

Molecular recognition

Electrostatic adsorption

DNA interaction

PAA–poly(PEG) block-copolymer Covalent coupling (PAA-b-PEGMA)

CaP and PEG-polyanion block copolymers

Co-precipitation

Co-precipitation

Fe3O4 coated with silica shell

Fe3O4

Silica

Labeled ssDNA

Solvothermal

Fe3O4@SiO2@Au

Solvothermal

PEI

–

Fe3O4@SiO2

Thiolated DNA

Co-precipitation

APTES

Co-precipitation and reverse microemulsion

Synthetic method Coating agent

Graphene-coated iron nanoparticles (Fe/C) with a sulfonate functionalization

Au-Fe3O4 yolk-shell

Fe3O4

Magnetic nanoparticles

Table 1  Magnetic platforms based on DNA-conjugated iron oxide nanoparticles

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Fig. 3  Some examples of bioconjugation using the covalent approach. Left, the use of coupling agents, such as carbodiimide [90] and ­SOCl2 [91] is shown; right, the direct bioconjugation approach using biomolecule-modified acetic anhydride- (A) [17], N-hydroxysuccinimide- (B) [88], and epoxy group- (C) functionalized biomolecules [17] is shown. NHS N-Hydroxysuccinimide

Electrostatic or the Coulomb interaction between IONPs and negatively charged DNA is the main functioning principle associated with DNA isolation. Modification with cationic materials is fundamental to the preparation of such systems. The use of positively charge nanoparticles in DNA immobilization seems to be a very common alternative in non-viral gene delivery systems due to the effectiveness and ease for automation of such nanoparticles [92]. In this regard, many different materials, such as cationic lipids or ionic liquids, proteins, and polycations, have been intensively studied [27, 29]. For example, Pandit et al. reported the functionalization of iron oxide microparticles with chitosan polymer for DNA purification [93]. In their article, the authors reported the capture of DNA at a pH optimal for PCR, enabling direct amplification from the microparticles. Classical adsorbents, such as silica and alkoxysilanes, have also been studied for use in DNA isolation [94, 95]. The advantages of these adsorbents are related to their biocompatibility, chemical stability, and nucleic acid affinity. Taking into consideration the same electrostatic principle, aminosilane-coated MNPs interact with the polyanionic DNA molecule due to the presence of phosphate groups in DNA and positive functional groups on the surface of nanoparticles. Generally, a silica coating is achieved through the sol–gel reaction (also known as the Stöber process), in which silica is synthesized via the hydrolysis and condensation of silicon orthoester [Si(OR)4], such as tetraethyl orthosilane (TEOS) and tetramethyl orthosilane (TMOS)] [50, 96]. A summary of the most important interactions of DNA with the surface of MNPs is given in Fig. 4. Since nitrogen-containing bases in DNA can strongly coordinate to the surface of ­Fe3O4 [97], the preparation of nanoparticles by coprecipitation onto DNA molecules is also considered to be a bioconjugation methodology. This procedure allows the design of one-dimensional (1D) nanostructured architectures due to the templating features of DNA. In this context, Byrne et al. studied the coprecipitation

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Fig. 4  DNA interactions with MNPs. a, b An electrostatic approach using unmodified (a) and functionalized (b) nanoparticles. c Coprecipitation of IONPs on DNA. d Formation of complementary hydrogen bonds between oligonucleotides covalently immobilized on MNPs and target DNA. e Noncovalent highspecific interactions

of nanoparticles on DNA and showed that denatured herring sperm DNA acts as a template for the preparation of magnetic nanowires [98]. Similarly, Hasan et  al. reported the use of the coprecipitation approach in the preparation of magnetic and conductive nanowires by DNA templating [99]. In this latter case, DNA proved to be a highly effective template for controlling the metal oxide formation, confining its growth in two dimensions to yield structurally well-defined, high-aspect-ratio nanowires with diameters of up to 30  nm. Such nanoplatforms could be useful in nanoelectronics, photonics, chemical sensors, and biological probes. The formation of hydrogen bonds between complementary DNA strands is a basic principle in the fabrication of nucleic acid–MNP hybrid nanocomposites by self-assembly. The complementary binding of an oligonucleotide (ODN) immobilized on MNPs and the target nucleic acid molecule (known as the hybridization process) underlies the operating principles of some diagnostic assays and biosensors (Fig.  5). However, the critical step during the preparation of ODN-modified MNPs is the conjugation to the nanoparticle surface. The use of covalent bonds is

Fig. 5  Schematic procedure of the hybridization process in nucleic acid–MNP hybrid nanocomposites and their applications in specific DNA sensing. ODN Oligonucleotide, QDs quantum dots Reprinted from the journal

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preferred to electrostatic interaction due to the high specific binding. Taking this fact into account, the manipulation of click-reactions, phosphoramidate bond formation, thiolated DNA, and 4-pyridyldithiol-derivatized peptide nucleic acid (PNA) are taken into consideration in the fabrication of DNA hybridization biosensors [23, 100–102]. According to Robinson et  al., many possibilities are derived by exploiting the chemistry of gold–sulfur (Au–S) complexes [23]. These authors reported the synthesis and characterization of Co–Au and ­Fe3O4@Au core–shell nanoparticles by reducing a gold (III) salt in a dispersion of such MNPs. The presence of the Au shell leads the functionalization of nanoparticles with thiolated single-stranded DNA (ssDNA) and subsequently its use for hybridization processes. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction has also been employed to achieve the attachment of DNA to ferrite nanoparticles. For example, the research group of Sreenivasulu have studied the self-assembly of multiferroic nanocomposites using DNA–DNA hybridization [100]. In this case, the azide-alkyne cycloaddition mediates the interaction between azide-functionalized barium titanate or nickel ferrite nanoparticles and alkyne-modified single-stranded oligonucleotide (ssODN). Such complex hybridized nanocomposites allow the combination of ferroelectric and ferromagnetic phases to study the mechanical strain of the related system. Along with the above-mentioned approaches, the covalent conjugation of DNA fragments to MNPs by forming a carbodiimide-mediated phosphoramidate bond is considered to be another useful route for developing hybridization biosensors. For example, Zhu et al. have investigated the application of such nanocomposites for electrochemical DNA hybridization [101], taking advantage of ssDNA immobilization on MNPs and using zinc sulfide nanoparticles as the oligonucleotide label. In most of the above-mentioned reports, oligonucleotides were used as conventional sequence-specific fragments. However, although Watson–Crick base pairing is remarkably specific, the mismatch discrimination of the ODN recognizer is not sufficiently selective and, in addition, it is susceptible to hydrolyzation by endogenous nucleases and proteases. To overcome such limitations during biomedical applications, the strategy of utilizing 4-pyridyldithiol-derivatized PNA as the sequence-specific gene recognizer can be considered. As a DNA analog, PNA comprises a polyamine instead of a sugar-phosphate backbone; as such, it is capable of binding DNA oligomers following Watson–Crick base pairing rules to form a PNA–DNA duplex that is significantly more stable than the corresponding DNA–DNA duplex. Wang et al. studied the use of PNA–MNPs biocomposites in gene recognition using surface-enhanced Raman scattering [102] and reported that PNA-modified MNPs can be easily prepared via a thiol-disulfide exchange reaction followed by the hybridization protocol. While Coulombic interactions of DNA with charged surfaces show a lack of specificity, the avidin–biotin complex is considered to be one of the most specific and stable noncovalent interactions. Since conjugations of biotin and its binding proteins (avidin and analogs such as streptavidin and neutravidin) are stable and highly specific and do not involve unstable intermediates, they could serve as a promising tool in biomedical and nanotechnological applications. Avidin is a basic tetrameric glycoprotein composed of four identical subunits that binds to biotin with

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high specificity and affinity (about 1­ 03- to 1­ 06-fold higher than an antigen–antibody interaction [103]). Biotin-based conjugates are also easy to synthesize and have less impact on the activity of the biomolecules. However, despite its enormous advantages and wide applicability, avidin has several limitations, including non-specific binding and possible immunogenicity. To avoid these limitations, concentrated efforts have been devoted to discovering and engineering superior variants of avidin. Information on the structure and physical–chemical properties of such variants are described in detail by de Freitas et al. [25, 104]. The specific binding of MNPs to DNA using high-affinity biotin–streptavidin noncovalent interactions requires preliminary modification of the surface of MNPs and nucleic acids with the appropriate molecules [17]. For example, Cannon et al. designed streptavidin-modified IONPs to bind biotinylated ssDNA-labeled with a Cy3 fluorescent dye [105] and thus enhance the immobilization process. The authors concluded that such nanocomposites are sufficiently specific to allow amplification-free detection of DNA and RNA molecules in drawn blood samples. Similarly, He et  al. reported the use of chemiluminescence detection of alkaline phosphatase–streptavidin capable of binding superparamagnetic IONPs modified with biotin-labeled hepatitis B virus DNA [106]. In this particular case, the functionalization of MNPs with (3-aminopropyl) triethoxysilane (APTES) allowed further treatment with succinic anhydride to efficiently bind the biotinylated DNA.

4 Biomedical and Technological Applications of MNPs 4.1 Magnetic Separation of DNA Separation technology is one of the most complex and important areas of biotechnology research [107]. It is considered to be the starting point for downstream processes and product development and comprises molecular routine biotechnological activities such as DNA sequencing, amplification, cloning, and bio-detection [108]. Generally, successful nucleic acid purification requires four important steps: (1) effective disruption of cells or tissue; (2) denaturation of nucleoprotein complexes; (3) inactivation of nucleases (e.g., DNase for DNA extraction); and (4) secure storage away from any possibility of contamination. Traditional extraction and DNA purification techniques can be divided into two fundamental categories, namely, those in which purification is mediated with organic solvents and those in which purification occurs by solid-phase methodologies. Among those techniques in which purification is mediated with organic solvents, the guanidinium thiocyanate–phenol–chloroform extraction technique is considered to be a conventional method that comprises the formation of a biphasic emulsion to purify DNA. In short, two layers are formed by centrifugation, with one layer, a mixture of phenol–chloroform, used to internalize proteins, carbohydrates, and cell debris, and the second layer, the aqueous phase, containing the purified DNA molecules. The DNA is then precipitated using ethanol or isopropanol in 2:1 or 1:1 ratio and a high salts concentration [107]. Similar techniques, such as alkaline extraction Reprinted from the journal

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[108] or cesium chloride gradient centrifugation [109], follow almost the same principles. In comparison to the above-mentioned convential methods, solid-phase isolation protocols allow a quick and efficient purification due to the prevention of incomplete phase separation in the liquid–liquid extraction and the use of toxic organic solvents. Solid-phase purification is most commonly performed using a spin column operated under centrifugal force. Silica matrices, glass particles, diatomaceous earth, and anion-exchange adsorbents are materials that have been employed as support in such systems [110]. The initial step in a solid-phase extraction process is to condition the column for sample adsorption. Column conditioning can be accomplished by using a buffer at a particular pH to convert the surface or functional groups on the solid column material into a particular chemical form. For the elution step, Tris–EDTA buffer or water is introduced to release the desired nucleic acid from the column so that it can be collected in a purified state [111]. As mentioned above, commonly used quick DNA isolation methods often contain chemicals that can lead to the degradation of DNA or be toxic to both humans and the environment [112, 113]. Moreover, they include time-consuming and laborintensive complex steps, such as centrifugation, precipitation, and filtration, all of which are able to compromise DNA integrity. A number of publications have reported in detail on DNA isolation techniques, emphasizing the special advantages of DNA magnetic separation [113, 114], which are a fast and simple handling of samples and the opportunity to deal with large volumes without the need for centrifugation steps. In addition, biomagnetic separation offers many benefits, including a high-quality product, simple treatment methodology, reduced need for chemicals, high-throughput system, and the potential for being used in automated processes [115]. The use of magnetic carriers such as IONPs functionalized with affinity ligands is preferred due to the high surface area and binding capacity of the IONPs and the ease manipulation [17]. Although many magnetic carriers are commercially available, the cost of using commercialized separation kits hinders the routine application of this facile technology for biochemical or clinical screening. In addition, new alternatives are developed almost every year in the continuing effort to improve separation efficiency. Such materials are MNPs modified with synthetic and natural polymers, porous glass, or material simply based on inorganic coatings, such as silica and organosilane precursors [17, 95, 116]. For example, Biao et al. reported the rapid purification of plasmid DNA from crude cell lysates using IONPs modified with silica [114]. These authors compared their method with a commercial kit as well as with a traditional phenol–chloroform technique, with their results demonstrating the advantages of their system. Tanaka et al. studied the adsorption and desorption behavior of DNA on aminosilane-modified MNPs for PCR analysis [117]. A comparison of some of the reported adsorbents in DNA isolation systems is given in Table 2. The successful application of silica-coated IONPs in DNA separation is associated with selective binding. Following the same principles as those for silica spin columns, such magnetic nanoplatforms require the use of a binding buffer to charge the surface of the nanoparticles. This surface charging creates a high affinity of the

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Reprinted from the journal

31

UV/VIS

UV/VIS 10 min

30 min

24 extractions in 40 min

10 min

60 min

3 min

3 min

3 min

Desorption time

~ 98

> 96

83.4

86.16

~ 90

~ 85

~ 84

~ 73

Desorption percentage (%)

[95]

[27]

[27]

[118]

[117]

[52]

[52]

[52]

References

 Some features and comparisons of commercially kits based on magnetic particles used for DNA, RNA, and pDNA separation are described in detail by Berensmeier et al. [116]

b

 1-Hexyl-3-methylimidazolium bromide

a

UV, Ultraviolet; VIS, visible light spectrum

Silica and chitosan

[C6MIM]-Br

NUCLISENS®; EASYMAG®b

UV/VIS

Agarose gel analysis

M-MSN

Dimercaptosuccinic acid

a

UV/VIS

Silica

Silica

UV/VIS

UV/VIS

Tris(hydroxymethyl)aminomethane

Chitosan

Method

Coating agent

Table 2  Adsorption-related information of functionalized iron oxide nanoparticles during DNA separation

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negatively charged DNA backbone towards the positively charged interface. Sodium also plays a role as a cation bridge that attracts the negatively charged oxygen in the phosphate backbone of nucleic acids. As a chaotropic agent, sodium cations at high concentrations also promote the disruption of ordered water molecules along the DNA [119]. Since the nucleic acid is tightly bound, washings remove all contamination, and the purified DNA molecules can subsequently be eluted under low ionic strength using TE buffer or distilled water. In all of these cases no centrifugation steps are necessary due to the magnetic properties of the nanoparticle cores, and this feature is precisely the advantage of the methodology depicted in Fig. 6. The above-mentioned electrostatic interactions between MNPs and DNA must be taken into account and, consequently, the isolation protocol should be carefully designed. In general, electrostatic interactions between positively charged adsorbents and DNA molecules are considered to be the best alternative in terms of time and resources [52]. This protocol is not only ascribed for silica but also for a number of other functional groups, such as amino, hydroxyl, among others. Therefore, the use of binding and elution buffer is central to the separation procedure. As represented in Fig.  6, the DNA adsorption and elution stages can be mediated with acid–base buffer solutions to manipulate DNA recovery via pH switching [120]. 4.2 Non‑Viral DNA Delivery Systems: Magnetofection and Preparation of DNA Vaccines The extensive study of the DNA molecule in past decades has provided not only a better understanding of the fundamental basis of human life but also marked the beginning of the development of a novel group of therapies and diagnostic models. The application of gene therapy (or transfection) is currently receiving much attention due to the vast potential of such therapies. Basically, the main principle of gene therapy relies on the use of DNA as a pro-drug that can lead to the expression of therapeutic proteins within specific cells. Such DNA-based therapeutics include plasmids containing transgenes, oligonucleotides for antisense and antigen applications, ribozymes, aptamers, and small interfering RNAs (siRNAs) [121, 122]. Most

Fig. 6  Schematic procedure for nucleic acid purification using magnetic nanoparticles (NPs) as support

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of these are considered to be promising candidates for the treatment of a wide range of diseases, including cancer, human immunodeficiency virus, neurological malfunctions such as Parkinson’s disease and Alzheimer’s disease, and cardiovascular disorders [123]. The efficiency of transfection depends on the delivery of therapeutic agents to cells, with the consequence of effecting alterations in gene expression by replacing or silencing defective genetic material. In this process, a DNA carrier, commonly called as “transfectant,” is needed for the transportation of genes to the cellular compartment. The use of novel nucleic acid delivery systems has not only improved the pharmacokinetics of DNA-based therapeutics but also achieved an efficiently targeted introduction of these molecules into desired tissues and cells. DNA delivery techniques are currently classified into three general types, with varying efficacy [121, 124]: (1) stimuli-mediated techniques; (2) mechanical transfection, (3) and vector-assisted delivery systems. The first two types involve introducing naked DNA into cells via microinjection [125], photoporation, particle bombardment, sonoporation, or electroporation [126, 127], all of which are considered to be invasive methodologies. Such techniques are very precise, but they are time-consuming and restricted to local delivery in specific areas; moreover, they are rapidly degraded by serum nucleases. In contrast, the application of vector-assisted delivery systems is a suitable option for use in clinical trials. Viral vectors are currently the most effective gene delivery methodology (80–90%), but they are associated with the potential risk of inserting viral nucleic acid sequences into the host genome and potentially causing unwelcome effects, such as the inappropriate expression of genes. Consequently, safety, and immunogenicity concerns limit their usage in the current clinical scenario [128]. Non-viral vectors have important advantages over viral approaches due to their demonstrated biosafety in reducing pathogenicity, low cost, and ease of production. However, this approach is hindered by a lack of efficiency [127]. Non-viral gene therapy, within its broader context, includes such nucleic acid delivery applications as, for example, anti-sense or siRNAs, but the techniques used for nucleic acid delivery do not fall within the scope of this review, which we have limited to a specific focus on other procedures and materials used as non-viral vectors. As early as around 1990, plasmid DNA (pDNA) has been recognized for having an enormous potential for applications in gene therapy. Compared to viral and RNAbased vectors, plasmids are easier and cheaper to produce and store, and they have a much longer shelf life [127–129]. At the molecular level, plasmids employ the DNA transcription and translation apparatus in the cell to biosynthesize the therapeutic entity, namely, the protein. Thus, they are able to correct genetic errors that basically produce functionally incompetent copies of a given protein. In addition to focusing on a high molecular weight double-stranded DNA structure, several research groups have studied plasmid design [130, 131], with a special focus on the choice of enhancer, which is the pDNA region(s) that improve production of the targeted gene. Plasmids have also powered a large number of clinical trials as part of gene therapy in monogenic and polygenic diseases, such as cystic fibrosis and cancer, and in infectious diseases [131]. However, the selection of pDNA carrier and the route to the cell nucleus are possibly the two most challenging issues during transfection. Reprinted from the journal

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Non-viral vector platforms or carriers should fulfill four important requirements: (1) capability to complex nucleic acids and protect them against nuclease enzymes at the extracellular compartment; (2) a positive net electric surface charge at physiological pH to overcome the negative potential of the cell membrane, since otherwise the cell membrane hinders the incorporation of negatively charged phosphate-containing DNA; (3) a mechanism to protect DNA from the acidic environment inside endosomes; and (4) chemical stability to maintain the integrity until the nucleus is reached [132]. Magnetofection techniques have been introduced in an attempt to fulfill these four important requirements and address the transient damage caused by the invasive methods mentioned above (i.e., microinjection, electroporation, among others). Magnetofection techniques are excellent alternative procedures that can significantly reduce the transfection time from several hours to < 60  min [28, 30, 132]. The association of superparamagnetic nanoparticles with gene vectors facilitates the transfection process into cells through the application of an external magnetic field that both targets and reduces the duration of the gene delivery, thereby enhancing the efficiency of the DNA vector (Fig. 7). The coating material is a key aspect of carrier design since these structures are responsible for DNA interaction as well as for DNA protection and chemical stabilization. Numerous materials have been used as coating agents for superparamagnetic IONPs, including cationic (bio)polymers, dendrimers, and cationic lipids (liposomal magnetofection). For example, Sohrabijam et  al. reported the use of chitosan-modified IONPs as a magnetofection carrier. Their results suggest a potentially enhanced magnetofection efficiency due to the cationic surface of the chitosan–IONPs [133]. Another example is the functionalization with polyethylenimine (PEI), which is considered to be one of the most interesting coating agents used in magnetofection due to its enormous stability [134]. The use of cationic lipids, such as N,N-di-n-hexadecyl-N,N-dihydroxyethylammonium chloride, has also been described to enhance DNA uptake in carcinogenic cells as

Fig. 7  Magnetofection process. Nuclear access is hampered first by the cell membrane, the cytoplasmic environment, and the nuclear membrane

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part of liposome formation [135]. Various examples of MNP applications in gene delivery that have been reported in the literature are shown in Table 3. Plasmids can be used not only as disease treatment, but also as a vaccination system for genetic immunization. A DNA vaccine is a third-generation vaccine that incorporates a vector with a eukaryotic cell promoter and a gene that encodes for an immunogenic protein. In contrast with protein-based traditional vaccines, DNA vaccination has the capacity to induce both cellular and humoral immune responses. The structure of plasmid DNA provides some advantages over other traditional protein-based or carbohydrate-based vaccines since plasmid DNA can encode many immunogenic proteins of the same virus and can also encode similar proteins belonging to different infective agents [145]. Other important advantages of DNA vaccines are their easy assembly, stability at room temperature, ease of manipulation, and low cost of plasmid production. However, the remaining challenges are to increase transfection efficiencies and facilitate intracellular uptake and to improve targeting to cells, as well as to perform these operations with small amounts of DNA. Various gene delivery and adjuvant systems at the nanoscale are used to overcome these problems. During the use of a nanotechnological adjuvant, the degradation of DNA is prevented, resulting in ultra-rapid delivery by targeting to the desired cells [146]. Adjuvants are generally grouped into two subtypes, namely, molecular adjuvants, which are immunostimulants, and carrier structures, which are systems that control release (e.g., mineral salts, liposomes, biodegradable polymers, and micro/nanoparticles). The use of cationic polymers or (polications) is associated with important advantages during transfection due to the possibility of electrostatic interactions with DNA molecules [93, 95, 133]. This property together with the superparamagnetic behavior of IONPs make these nanostructures excellent adjuvants for DNA vaccines. It has been reported that polymers bind with nucleic acid(s) to form complex structures known as polyplexes and that these polyplexes have increased transfection efficiency. Some of the examples reported in the literature include chitosan, PEI, poly(2-hydroxyethyl methacrylate) (pHEMA), polyamidoamine (PAMAM) dendrimers, polyethylene glycol (PEG), and poly-l-lysine [133, 145]. For example, Al-Deen et al. reported the use of IONPs/PEI/DNA polyplexes to enhance the delivery of a malaria DNA vaccine using magnetofection [147]. Their results indicate that in  vitro transfection efficiency into eukaryotic cells can be significantly enhanced under the application of an external magnetic field. Garu et  al. also described a novel DNA carrier based on lipoplexes of a model DNA vaccine using antibodylabeled MNPs [148]. This system revealed remarkable in vivo targeting properties of the described liposomal DNA vaccine carrier. Importantly, mice immunization induced a long-lasting anti-melanoma immune response. 4.3 Molecular Recognition Tools One of the advantages of using MNPs in molecular platform technologies is related to their easy manipulation due to a high separation efficiency with magnetic fields. The principal disadvantage is related to the aggregation process that could occur Reprinted from the journal

35

13

13

36

 PEG-block-poly(propylene glycol)-block-PEG

 Rat malignant glioma

 Human lung adenocarcinoma cell line

i

h

 Chinese hamster ovary cells

g

 Murine mammary adenocarcinoma

f

 Human umbilical vein endothelial cells

 Mouse embryonic carcinoma cells

e

d

 Human prostate carcinoma cells

c

b

 Poly(hexamethylene biguanide)

a

Plasmid

Plasmid

Poly(propyleneimine) dendrimers

Pluronic F-127b

Plasmid

Plasmid

Poly-l-Lysine

PEI (molecular weight: 25 K), chitosan

Plasmid

Polyacrylic acid and PEI siRNA

Plasmid

Hydroxyapatite

Branched PEI and ­PHMBGa

Plasmid

Deacylated polyethylenimine

H441i

Saos-2 osteoblasts

C6h

CHO-K1g and HeLa cells

Lung tissue

B16Ff

Rat marrow stromal cells

P19CL6e

37

12

45

80–90

60

47

60–70

80

80

23

HUVECd

DU145c

siRNA Plasmid

Polydopamine

Transfection efficiency (%)

Target cell

Vector

PEG, Branch PEI (molecular weight: 25 K)

Coating material

Table 3  Summary of some in situ magnetofection examples described in the literature using ion oxide nanoparticles as support

*

75

100

90

Not reported

Not reported

100

100

80

62.4

Cell viability (%)

[144]

[132]

[143]

[142]

[141]

[140]

[139]

[138]

[137]

[136]

References

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and consequently affect the sensitivity and specificity of the analysis. In this regard, molecular recognition involves specific noncovalent phenomena, such as hydrogen bonding, van der Waals, and hydrophobic forces, coordination to metals ions, π–π stacking, electrostatic or magnetic interactions, among others. These interactions play an important role in biological systems, as well as in the designing of biosensors for the early diagnosis of diseases and for therapeutic treatments by coupling with MNPs. For example, the double helix structure of DNA is found to be very stable due to some of these forces; specifically the Watson–Crick type of hydrogen bonds (guanine–cytosine and adenine–thymine). This type of interaction allows the development of specific nucleic acid probes, such as aptamers, for the molecular recognition of a wide range of targets comprising small molecules, proteins, and cells [26, 42, 90]. The development of new approaches for the selective detection of nucleic acids is currently one of the main challenges of the scientific community. Given the DNA sequence mismatches and structural folding of ssODN, strategies need to be developed that allow the detection of trace levels of specific sequences. The molecular recognition capacity of systems using ssODNs is a very sensitive and very specific compared with traditional recognition systems. In 1996, Tyagi and Kramer reported, for the first time, a new probe to detect specific nucleic acids in homogeneous solutions and also introduced the term ‘Molecular Beacon’ based on the fluorescence resonance energy transfer pair [149]. The single-stranded nucleic acid or hairpin molecules possess a stem-and-loop structure. The loop portion of the molecule is a probe sequence that binds a target nucleic acid sequence, while the stem is two complementary arm sequences that are annealed. The target and the arm sequences are not complementary. Fluorescent and non-fluorescent quenching moieties are attached to the end of both arms. When the target sequence is present, hybridization occurs and fluorescence is restored (Fig. 8). Consequently, the method is useful for detecting specific sequences of nucleic acids [149]. Molecular beacons can be applied in different fields, such as for the measurement of single nucleotide polymorphisms (genetic variations) [150–152], real-time

Fig. 8  Schematic representation of molecular beacon assembled to the core-shell IONPs@Au Reprinted from the journal

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PCR quantification [153], multiple PCR assays [154], and clinical diagnosis [153, 155]. Another probe is the TaqMan assay, which is used to quantify mRNA levels of selected genes. Two fluorescent moieties with different wavelength emissions appear in the system. Some recent reports have included the use of MNPs as platforms for TaqMan probes. For example, Liu et al. described a portable quantitative and selective DNA detection biosensor. In only one step, target recognition occurs as a consequence of the releasing of the invertase–DNA conjugate which can be collected with the help of a magnet. The released invertase–DNA was used to catalyze the hydrolysis of sucrose into glucose with highly efficient sequence selectivity [156]. DNA-assembled core–satellite superstructures are other platforms used in drug delivery, imaging, and biosensing. Tian et al. reported an on-particle rolling circle amplification process [157] that allows rapid microRNA detection. Once the targeted microRNA is detected, the long ssDNA produced acts as the scaffold of the core–satellite superstructure and it can be hydrolyzed by duplex-specific nuclease. Due to hydrolyzation, MNPs are released and subsequently quantified in an optomagnetic sensor. The high capacity to discriminate single-nucleotide mismatches opens new possibilities to use these structures in clinical applications. The development of nanotechnology and its applications in the field of biotechnology lead to an improvement in bioanalysis. The bar-code analysis, which involves the use of IONPs and gold nanoparticles, is a diagnostic tool used for the detection of nucleic acids and proteins. Both nanoparticles are modified with recognition units that interact with the analyte to form a sandwich-type structure. The magnetic properties of the designed system can then be used to separate the sandwich structures [158, 159]. Gold nanoparticles can also be functionalized with a shell of barcode consisting of hybridized oligonucleotides. After the separation of the sandwich structure, the strands of bar codes can be identified in the microarrays by PCR or another analytical tool. In addition, there has been a recent report of a method for the detection of gastric cancer in which DNA probes, magnetic nanoprobes, and silicon–gold nanoparticles are hybridized to form a sandwich structure; the conjugate is then magnetically separated and the Au–nanoparticle released [160]. The authors suggest that complementary and mismatched DNA can be clearly distinguished by using inductively coupled plasma mass spectrometry in the detection of DNA with high sensitivity and specificity.

5 Conclusions The systematic use of DNA-based magnetic nanoplatforms shows great potential in biotechnological fields due to the important advantages of these platforms in terms of time and resources. In this regard, relatively cheap and high-throughput DNA extraction procedures have overcome the main drawbacks associated with traditional methodologies. Compared with the well-known chemical recognition mechanisms, such as host–guest chemistry, the interaction of nucleic acids is universal and easily modified. As a consequence, several biosensors and diagnostic methods have been

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developed based on the magnetic behavior of MNPs and the special recognition properties of DNA. The appropriate selection of the delivery vector is a key factor in drug and gene delivery systems. DNA molecules and their interaction with the surface of MNPs should be carefully designed taking into acount the the final purpose and all the aspects related to the host cell environment. Future perspectives in vaccination routines will probably include DNA vaccine involving nanoparticles as a novel method to generate antigen-specific antibodies and cell-mediated immunity. However, many aspects still need to be optimized, such as the nanoparticle–DNA vaccine efficiency and cell viability, together with their complete clinical assays in human subjects to validate immunogenicity. Compliance with ethical standards  Conflict of interest  The authors declare no conflict of interest.

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Affiliations José Raúl Sosa‑Acosta1,2 · Claudia Iriarte‑Mesa1 · Greter A. Ortega1,3 · Alicia M. Díaz‑García1  1

Laboratory of Bioinorganic (LBI), Department of Inorganic and General Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba

2

Faculty of Chemistry and Pharmacy, Pontifical Catholic University of Chile, Santiago, Chile

3

Legaria Unit, Center for Applied Science and Advanced Technology of IPN, Mexico City, Mexico



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Topics in Current Chemistry (2020) 378:40 https://doi.org/10.1007/s41061-020-00302-w REVIEW

Magnetic Nanoparticles as MRI Contrast Agents Ashish Avasthi1 · Carlos Caro1 · Esther Pozo‑Torres2 · Manuel Pernia Leal2 · María Luisa García‑Martín1,3 Received: 31 December 2019 / Accepted: 18 March 2020 / Published online: 7 May 2020 © Springer Nature Switzerland AG 2020

Abstract Iron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models. Keywords  Magnetic nanoparticles · Iron oxide nanoparticles · Magnetic resonance imaging · Cancer · Diagnosis

Chapter 3 was originally published as Avasthi, A., Caro, C., Pozo‑Torres, E., Leal, M. P. & García‑Martín M. L. Topics in Current Chemistry (2020) 378: 40. https://doi.org/10.1007/s41061-020-00302-w. * Manuel Pernia Leal [email protected] * María Luisa García‑Martín [email protected] 1

BIONAND ‑ Centro Andaluz de Nanomedicina y Biotecnología, Junta de AndalucíaUniversidad de Málaga, C/Severo Ochoa, 35, 29590 Málaga, Spain

2

Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41012 Seville, Spain

3

Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Málaga, Spain



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1 Introduction Magnetic resonance imaging (MRI) is one of the main in vivo imaging modalities, along with positron emission tomography (PET), computed tomography (CT) and ultrasound imaging. MRI is the most versatile of all of these, being able to provide both anatomical and functional information with excellent image quality, and, most importantly, using non-ionizing radiation, which allows longitudinal studies to be performed without the risk of side effects. The MRI signal comes from the radiofrequency signal of protons magnetized by an external magnetic field. These protons originate mainly from water molecules. The application of radiofrequency pulses is used to excite the magnetization, and magnetic field gradients are used to provide spatial localization. Contrast in MRI reflects differences in signal intensity, which depends on the concentration of water molecules within the tissue, the relaxation times, ­T1 and ­T2, of the water protons and the mobility of the water molecules (diffusion, flow) [1]. Additionally, image contrast can be further enhanced using contrast agents (CAs), with Gd-chelates being used most commonly in clinical practice. However, CAs lack specificity and have recently been related to toxicity issues caused by the unexpected release of free Gd. Magnetic nanoparticles have emerged as a promising alterative with improved properties in terms of specificity and biocompatibility. Over the past two decades, many studies have aimed at the development of new magnetic nanomaterials that can serve to improve the diagnosis and treatment of many different diseases. Among these nanomaterials, iron oxide nanoparticles (IONPs) have been investigated most extensively as CAs for MRI due to their magnetic properties, that is, the superparamagnetism that leads to very high relaxivity, their high biocompatibility, since they can be incorporated into iron metabolism, and also the easy functionalization of their surfaces with target molecules for molecular imaging purposes [2]. The first step in the development of IONPs is synthesis of the magnetic core, for which many different methods have been proposed, all aiming at strict control of the size, shape and magnetic properties, so that the synthesis process can be performed under highly reproducible conditions, which is one of the essential requirements for the potential clinical translation of these new nanomaterials [3]. Functionalization of magnetic nanoparticles is then needed to make them soluble in aqueous media and to provide them with stability and biocompatibility [4]. Further functionalization may include the addition of different molecules to target specific tissues or cells [5]. The most relevant functionalization strategies will be discussed in detail in this review. Finally, the in vivo characterization of IONPs is the most critical aspect in the development of IONPs for biomedical applications. Although many new nanomaterials show excellent in vitro properties, most of them fail when tested in vivo. Thus, around 6500 studies (PubMed database) on magnetic nanoparticles have been published since 2010, in which IONPs often appear as promising new CAs for MRI. However, up to now, extremely low clinical translation has been achieved [6]. Therefore, comprehensive studies with appropriate in  vivo experimental models are of paramount importance for the successful development and eventual clinical translation of these nanomaterials.

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In this review, we describe the recent advances in regard to the synthesis, functionalization and in  vivo applications of IONPs as MRI CAs for the diagnosis of several pathologies, with special emphasis on cancer diagnosis.

2 Methods for the Synthesis of IONPs Over the past few decades, various procedures to synthesize IONPs have come to fruition. The ultimate goal of these procedures is to gain complete control over the properties of IONPs, such as size, shape, saturation magnetization, etc. However, this has not yet been achieved completely. The main hindrance behind this failure is the inability to fully determine the science behind the processes and their mutual interactions, but it is not so distant in the future that we will be successful. Figure 1 shows different methods to synthesize IONPs, which are described in detail below, along with their pros and cons. 2.1 Coprecipitation Coprecipitation is the method most commonly used for the synthesis of IONPs due to its facile nature. Massart [7] pioneered the existing scientific knowledge established by Le Fort [8] and Elmore [9] regarding the synthesis of magnetic colloids, and stressed the importance of the stoichiometric ratio between Fe(II):Fe(III) being 1:2. The synthesis process described by Massart requires the addition of alkaline medium (pH ~ 11, slowly or rapidly) into the iron salts solution at room temperature or at elevated temperature. This mixture requires an inert atmosphere to prevent nanoparticles from oxidizing. It was later established that the synthesis of particles follows the LaMer’s model of nucleation and growth [10]  (Fig.  2). The synthesis process has been described to occur in two steps, as shown below [11–14]

Fe2+ + 2Fe3+ + 8OH− ⇆Fe(OH)2 + 2Fe(OH)3 → Fe3 O4 ↓ + 4H2 O. However, Lagrow et  al. [15] recently challenged this mechanism of synthesis. They claimed that while increasing the pH via sodium carbonate, two intermediate phases are formed, one poorly crystalline ferrihydrite and another crystalline iron hydroxide carbonate. This ferrihydrite eventually grows into iron oxide at the cost of iron hydroxy carbonate. Even though Lagrow’s proposed mechanism seems to answer a few loopholes undescribed by Massart, improving the homogeneity and reproducibility of the nanoparticles, it fails to ascertain if the same mechanism is followed when ammonia or ammonium hydroxide is used. Irrespective of the mechanism followed, nucleation is judged as the sizedetermining step and is exploited to modulate the size of particles [14–16]. The nature of particles depends on various other factors, such as the type of salts used (e.g. chlorides, sulfates, nitrates, perchlorates, etc.), the ­Fe2+ and ­Fe3+ ratio, pH and the ionic strength of the media, along with the reaction environment [17–30]. Jiang et al. [24] showed that the particle size distribution is narrowed Reprinted from the journal

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Fig. 1  Methods used in the synthesis of iron oxide nanoparticles (IONPs)

if the homogeneity of pH within the solution is improved by adding urea to the reaction mixture. There are also reports suggesting that particle size decreases with increasing pH [17]. A similar trend is observed between particle stability and iron concentration, but substantial studies are lacking to support this observation [23]. Particles with different morphologies, such as nanodots, ellipsoid,

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Fig. 2  LaMer’s model depicting the nucleation and growth process of the nanoparticles. Adapted with permission from [10]. Copyright (1950) American Chemical Society

spherical, clusters or necklace like, can be synthesized by varying their aging conditions [25–27]. Itoh et al. [26] synthesized ellipsoidal and spherical hematite nanoparticles by aging them in phosphate ions and nitriloacetic acid (NTA), respectively. The relationship between shape/size and the electrostatic surface density of particles is linked to the interfacial tension between the oxide and the solution, which causes a decrease in the surface energy, thus modulating shape and size [28]. If a modern method like ultrasonication is used with coprecipitation, it can yield narrowly distributed particles, as shown by Bui et  al. [31], who compared their modified version of the coprecipitation method (using ultrasonication instead of stirring) to the solvothermal method, and found the former to yield more homogeneous and small sized nanoparticles. However, the comparison between their method and the conventional coprecipitation method (with stirring) is missing. The major advantages of the coprecipitation method are its time saving facile nature, with no requirement of high temperature or pressure, and the production of particles with high yield and easily scalable to large quantities. However, the particles synthesized with this method generally lack homogeneity and form single and also multicore nanoparticles. Particles thus synthesized also tend to form aggregates, which leads to an undesired assortment of blocking temperatures. Another disadvantage of this method is that the pH of the resultant solution is too high, thus requiring neutralization before they can be used for biological applications.

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2.2 Thermal Decomposition In this method of synthesis, high temperatures are exploited to break down the precursor to yield nuclei as well as their further growth into nanoparticles (Fig. 3). It started as a way to ease the study of properties of systems with narrow size distribution [32]. Smith and Wychlk were among the first researchers who utilized this method to synthesize colloidal dispersions of iron using iron pentacarbonyl [Fe(CO)5] as a precursor, along with different solvents and the addition of different polymers. They concluded that the polymers added during the reaction not only coated the dispersions forming stable particles, but also acted as catalysts for the decomposition [33, 34]. They suggested that the decomposition takes place at 140–160 ℃ in the presence of butadiene polymers while gathering support from the mechanistic studies conducted by Bergman and coworkers [35]. Later, their hypothesis was verified experimentally, showing the presence of an intermediate carbonyl complex formed after decomposition of Fe(CO)5 [36]. The reaction takes place in two main steps: nucleation and growth. This separation of stages can be used advantageously to alter the size and shape of nanoparticles as demonstrated by Hyeon et al. [37] and Jana et al. [38]. They used iron oleate as precursor and proposed that nucleation starts at 200–240 ℃, initiated by dissociation of one of the three oleates available in one molecule of iron oleate [Fe-(oleate)3], while the growth begins at 300 ℃ with the subsequent dissociation of the remaining two oleates. The complete mechanism of the reaction is not fully understood even though it has been widely studied, both experimentally and computationally [39–41]. Nonetheless, these studies led to the discovery of “polyiron oxo clusters” species as the actual precursor for the formation of nanoparticles, as initially suggested by Wells [36]. More recent studies have reported the synthesis of a new precursor by synthesizing an intermediate between Fe(CO)x and oleylamine (OLA), and achieved controllable size of 2.3–10 nm [42]. To date, different precursors have been reported in the literature: iron acetylacetonate [Fe(acac)3] [43], iron cupferron [Fe(cup)] [44], iron chloride (­FeCl3) [45], iron pentacarbonyl [Fe(CO)5] [46], along with different iron complexes such as iron oleate [45], iron stearate [38] and iron eruciate [47]. Depending on the process involved and the size required, it becomes important to select the right

Fig. 3  Different stages during the synthesis of IONPs in the thermal decomposition method. Adapted and modified with permission from [41]. Copyright (2013) American Chemical Society

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precursor as the reaction proceeds differently depending on the way the precursor is broken down [48]. There are several other factors that could affect the size and morphology of particles, such as temperature, nature of the solvent, reactants ratio, reflux time, and seed concentration [45, 49, 50]. Thus, Hyeon found that the heating rate of the reaction, along with the boiling point  of the solvent used, is also a crucial factor to adjust the size of the nanoparticles [45], and Pellegrino’s group concluded that there is an inverse relationship between the size of the nanoparticles and the heating rate [49]. However, controversy still exists regarding the role of the temperature ramp in the synthesis of IONPs, and, therefore, comprehensive and deeper studies are still needed to properly elucidate the mechanism involved. Kovalenko et al. [51] showed the importance of surfactants, not only to prevent aggregation, but also to modulate shape and size. They displayed the use of fatty acids, such as oleic acid (OA) or salts of OA, to synthesize spheres and cubic nanoparticles, respectively. Later, several groups have tried to shed light on the role of OA as well as other fatty acids regarding the size and shape of IONPs, but up to now, a fully elucidated theory is still lacking [52–59]. Quality of particles can be further improved by the controlled addition of water and oxygen in the inert environment to decrease crystal defects, and improve magnetic properties and homogeneity [60, 61]. In summary, thermal decomposition, albeit a bit complex and time-consuming, yields very homogenous and monodisperse nanoparticles, making it one of the most used methods to synthesize nanoparticles for biological applications. The shape and size of nanoparticles can be controlled by tuning the parameters described above. Major drawbacks of this method include the inability to properly scale up and the lack of dispersibility of the particles in aqueous solvents, although this can be remedied by surface modifications in situ, as described by Li et al. [56, 62], or using post preparative methods, as explained in greater detail in later sections of this review. 2.3 Hydrothermal and Solvothermal Synthesis In this method, the hydrolysis and oxidation (or neutralization) reaction takes place in a reactor or autoclave at high temperature and pressure. Depending on the reaction solvent, it is either referred to as hydrothermal (if the solvent is water) or solvothermal (any other solvent or combination). Both reactions follow the aforementioned model of nucleation and growth [63, 64]. There have been several reports [4, 37, 65–68] on the use of this method to synthesize magnetic nanoparticles as well as its comparison with other methods [69]. The reaction parameters, such as temperature, reactor size, time, concentration of the reactants, and the nature of the solvent and capping agents, affect the size, shape and other properties of the final product. Out of all these parameters, the effect of the solvent has been studied the most [70, 71], closely followed by that of the surfactant [72, 73]. The particles show a preferential surface binding towards the carboxylate from the OA rather than the amine from the oleylamine [72], which very likely is the case for every method described in this article, although it still needs verification.

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This preferential binding was recently used by Brewster et al. [73] to present a new way to control the particle size and crystal phase. They varied the carbon chain length in the iron carboxylate, which was used as the precursor, and showcased the effect of two different ligands, amine and carboxylic acid, which were added to the reaction [73]. They demonstrated that the size of the particles decreased as the carboxylate chain length increased in the presence of amine ligands, while no definite trend was observed when varying the carboxylate free ligands. The hydrothermal/solvothermal method has also been used to synthesize other ferrites [74]. Kim et  al. [75] recently demonstrated a gram scale yield of magnetite nanoclusters by modifying the procedure and utilizing trisodium dihydrate, but, to the best of our knowledge, this is the only report for large scale synthesis using this method. To further exploit the particles thus formed for biological applications, surface coating becomes necessary, as will be discussed in detail in the subsequent section. Polymers such as polyvinylpyrrolidone (PVP), polyacrylic acid (PAA) and polyethanolimine (PEI), have been shown to improve the magnetic properties when used in the synthesis of monodispersed clusters [76]. Recently, Köçkar et  al. [77] explained a way to get in-situ capping of IONPs with tartaric acid/ascorbic acid/ mixture of two, which led to the synthesis of uniform, un-agglomerated, biocompatible particles of less than 8 nm with good saturation magnetization. The hydrothermal/solvothermal method is, therefore, an ideal method for the synthesis of iron oxide nanoparticles, mainly nanoclusters. However, the main disadvantage of this method is that, due to the lack of stirring inside the autoclave, monodispersity, as well as scalability, can sometimes be hindered. 2.4 Polyol Method This method is an iteration of the solvothermal method, with polyols being used as solvents to synthesize nanoparticles by dissolving the precursor, solubilizing in the diol at high temperatures, and eventually leading to the formation of metal nuclei and particles. Following previous works pertaining to synthesis of metallic powders [78–84], Caruntu et  al. described this method to synthesize nanocrystalline metal oxide nanoparticles by synthesizing magnetite nanoparticles [85]. They explained the mechanism stating that reduction starts from the liquid state rather than the solid, and the nanoparticles are formed in two steps: hydroxides are formed first and then metal centers are chelated. Heterogeneous nucleation performs better than homogeneous nucleation as it has been studied to provide a better separation between nucleation and growth, thus giving better control over the size, shape and crystallinity [78]. Polyols play multiple roles, acting as reducing agent, stabilizer and solvent [86], modulating the process to yield large and small clusters [87], nanoparticles [88] or single-core/multicore nanoparticles [89]. Different polyols have been exploited for the synthesis of iron oxide nanoparticles, such as diethylene glycol, giving 3  nm particles [90], or triethylene glycol, giving 10  nm particles [91]. However, Cai et al. [92] reported that only triethylene glycol gives nonaggregated nanoparticles. To our knowledge, there are no reports on the use of tetra or penta ethylene glycol, which could have ameliorated the agglomeration problem

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even more, if the trend described holds to be true. Other parameters that have been identified to modulate the size, shape, crystallinity and saturation magnetization are temperature, time, precursor concentration, and surfactant. The role of water was studied by Hemery et al. [93], when its importance was revealed by inability of the anhydrous iron chloride to produce magnetic particles [93]. The impact of stoichiometry in polyol synthesis has been studied by Wetegrove et al. [94], showing that the increase in F ­ e3+ concentration forms larger crystallites and the increase in F ­ e2+ content promotes nucleation [94]. As stated above, hydrophilicity is important, which is generally lacking in particles synthesized using the polyol method. However, there are reports of the synthesis of hydrophilic nanoparticles using this method [88, 95] but their limitations include the lack of a surface functionality for bioconjugation. This problem has further been remedied by the use of polyamines [96], polyimine with polyol [97], polyamine with polyol [98] and PAA [99]. The research done by Babić-Stojić et al. [100], wherein they esterified 3 nm IONPs in situ, implied the importance of the surface layer in the properties of nanoparticles. The morphology of the particles is of equal importance as size in in vivo applications and has been shown to be altered by the addition of halide ions [101]. There have also been advancements in solvents, such as the thermostable ionic solvent [P6,6,6,14][Tf2N], which has been shown to be capable of synthesizing quasi spherical magnetite nanoparticles of around 14 nm [102]. In conclusion, the method described herein has the advantage of being environment friendly, scalable, and good for synthesizing both single and multicore particles. However, it has the drawback that the particles thus formed lack homogeneity. 2.5 Sol–Gel Method This is a two-step chemical method, with the first step being the synthesis of the sol (particles in a solution) via hydroxylation of the precursors, and the second step, the formation of a gel by condensation and polymerization. Eventually, heat treatments are used to achieve a proper crystalline state. Costa et  al. [19] were among the first to synthesize magnetic nanoparticles using this method, but they failed to identify the correct mechanism. Subsequently, the work of Portugal et  al. [103], made the mechanism a bit clearer upon finding signatures of iron hydroxide, but the exact mechanism is still unknown. Like in the polyol method, the solvent is shown to affect the ferrite grain as well, but changes in grain size have been attributed to a different growth model with two different solvents [104]. Water concentration is also shown to improve hardness and structural defects [105]. Size and shape are also affected by other parameters such as solvent ratio, time, pH, stirring, gelating agent and, temperature. Liu et al. [106] used different calcination temperatures to synthesize different phases of IONPs, and this transformation has been attributed to two separate mechanisms, crystal regrowth and chemisorption, depending on the temperature. Akbar et al. claimed to have synthesized three different phases of iron oxide (α-Fe2O3, γ-Fe2O3, and F ­ e3O4) simply by varying the precursor to solvent ratio, thus suggesting the importance of that ratio [107]. The

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particles were shown to possess higher saturation magnetization. They also observed differences in hematite particle size and morphology when using different precursors, with iron acetate giving rise to smaller spherical particles, while iron nitrate led to larger, quasi cubic particles. These differences were due to the water content as well as the presence of nitrate and carboxylate in the precursors [108]. More recently, Hu et al. [109] reported a new explosion-assisted sol–gel method in which they used ferric nitrate as precursor and citric acid as chelating agent to form a gel. The gel was then homogenized and heated with picric acid to attain highly pure, well dispersed and crystallized magnetite nanoparticles ranging from 3 to 20  nm. The synthesis was proposed to be resulting from the combined action of the complexing of citric acid with metal ions, and the explosion, thus explaining the important role of citric acid, not only as a carbon source, but also to allow the combustion and reduction of the dried gel simultaneously. The chemistry of the sol–gel method is vast, with the involvement of different precursors, gelators as well as chelators, but it is beyond the scope of this review. It is, however, nicely explained by Danks et al. [110]. This method is more recommended for synthesizing thin films [111] and nanocomposites [112, 113] since it can form thin films in just 2 min if the heating source is changed to microwaves, and pure phases can be formed by using high microwave power (600–800 W). 2.6 Microemulsion Method The microemulsion method is a form of coprecipitation performed in a confined space such as micelles. It generally involves two immiscible liquids with surfactants forming the interfacial layer [114], and is classified as either the water-in-oil method or oil-in-water method [115]. Inouye et al. [116] were the first to report the synthesis of magnetic particles using this method, exploiting the faster oxidation of ferrous ions in micelles. In water-in-oil microemulsion, a hydrophobic phase is used with aqueous droplets separated by a surfactant [117]. The most common surfactants used are PVP and cetyltrimethylammonium bromide (CTAB). In this method, particles generally collide and coalesce, and break again, leading to the growth of particles, the particle size being determined by the size of the droplets. In a final step, particles are centrifuged and lyophilized to get pure nanoparticles [118–120]. Many articles have been published on the use of this method to synthesize iron oxide nanoparticles [121–124]. Although surfactant concentration is not shown to affect the size, precursor concentration and temperature are important influencers, together with pH [125] and the choice of surfactant [126, 127]. Recently, Singh et al. [128] showed the importance of ionic concentration and temperature on the morphology, size and crystallinity by claiming that, in order to obtain monophasic particles, ­[Fe2+] and ­[Fe3+] should be ≤ 0.09  M and ≤ 0.184  M, respectively, with a temperature range of 65–72 ℃. They also observed changes in the morphology of the particles, from cubes to pentagons to spheres, when increasing the concentration of the surfactant (CTAB) between 0.01 and 0.1  M, but they did not describe

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the mechanism, or explain why the shape of the CTAB nanodroplets changes upon varying concentration. Nor did they explain why particle size changed with concentration [128]. Bonachhi et al. [129] achieved ultra-small magnetic nanoparticles by using γ-cyclodextrin by hydrolyzing F ­ e2+ ions in aqueous solution, while Lee et al. [130] varied the ratios of the precursor and solvent from 3.6 to 8.1, and achieved 2 to 10 nm magnetite particles. Vidal et al. showed the importance of oleylamine as surfactant to prevent aggregation [131], while Pileni et al. explained the importance of using functionalized surfactants and pH to improve the crystallinity and morphology of the nanoparticles [132]. Following a similar approach, Han et al. used a nonionic surfactant, ­C16E15, to synthesize nanoparticles with high saturation magnetization (74.8  emu/g) [133]. It is worth mentioning that if the surfactant described in this method is replaced by a phospholipidic molecule to form particles within liposomes, they are termed magnetoliposomes, which show significantly higher blood half-life [134–136]. However, if the particles are formed within the aqueous compartment, they are known as magnetovesicles. These special particles can be synthesized using film hydration and extrusion [137], sonication [66], phase evaporation [138] and nanoreactor [139], and are very promising for biomedical applications. Recently, even metallosurfactants have been used as precursors to synthesize particles of around 3 nm [140]. This method has also been utilized in exchanging the capping of iron oxide nanoparticles to improve solubility [141–143]. Similarly, oil-in-water has a hydrophilic solution with oil droplets used as a reactor. Recently, spinel ferrites have been shown to be synthesized using this method, with metal ethylhexanoates as precursors and a pseudo ternary solvent system, which includes oil, surfactant and water in the ratios of 20:20:60 [144]. The oil in water method has also been used as a strategy to cap nanoparticles [145]. The microemulsion method has several advantages, such as providing a narrow range of particles with relative ease, good morphology and without the need for high temperatures. But it also has disadvantages, including scalability, the toxicity of some surfactants, the amount of surfactant used, as well as the need for ligand exchange. 2.7 Aerosol Method This is also a chemical method, which leads to high production of particles. This method can be subdivided in two categories. The first is spray pyrolysis, in which precursor salts are sprayed into the reactors, where they are condensed and solvent is evaporated, which in turn also means that the size of the particles depends on the droplets [146]. Serna’s group [147] were among the first to synthesize ­Fe2O3 nanoparticles using this method. Their study claimed that if small size is the most important feature for the application, iron acetylacetonate should be used because of its exothermic decomposition reaction; however, if crystallinity is to be considered, then iron chloride is favored due to solvent elimination at higher temperature. This leaves other precursor benefits open for exploration. The importance of intraparticle reactions in controlling the size of particles was established later, along with the solvent, rate Reprinted from the journal

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of evaporation, time spent in the reactor, and temperature. These studies concluded that the heating time and temperature, along with the type of evaporation or reaction taking place during the drying stage, will conform the particle structure as hollow, dense, foam-like, etc. [148, 149]. Zheng et al. [150] recently reported that chloride ions prevent phase transition from γ-Fe2O3 to α-Fe2O3 at higher temperatures, leading to higher magnetization, which highlights the importance of chloride ions in the reaction. Das et al. proposed a new strategy to decrease size with high crystallinity by adding ethanol to the ultrasonic pyrolysis [151]. It was explained that the faster evaporation rate of ethanol compared to water, as well as a decrease in surface tension of the water–ethanol solution, led to the formation of smaller droplets and eventually smaller particles. Since the rate of evaporation of the solvent has been stressed and linked to particle size, it might be interesting to see how methanol, or any other solvent with a boiling point lower than that of ethanol, affects the size and crystallinity of particles. The second category is Laser pyrolysis, a gas phase method that utilizes the heat generated by a laser to heat the precursors and the flow of a gas or a mixture of gases to produce nanoparticles. The sizes of the particles can be controlled by modulating the power of the laser since a direct relationship exists between the two [152, 153]. Zhao et al. [154] were the first to improve on the TEA laser using a cw C ­ O2 laser, which yielded particles with higher purity. There have also been reports on use of this method to synthesize hybrid silica-iron oxide composites [155]. Laser pyrolysis has a new iteration, flame spray pyrolysis (FSP), which uses a flame to heat the precursor [156]; the size of the nanoparticles can be controlled by varying the flame length or the oxidant flow rate, and the precursor/fuel composition. Lower flow rate of the oxidant leads to reduced flame length, with higher temperatures thus forming smaller particles and vice versa [157]. The main advantage of this method is that it helps in achieving very high homogeneity and monodispersity irrespective of the complexity of particles, including hybrid silica-iron oxide composites [155]. 2.8 Sonochemical Method This method utilizes acoustic cavitation, which means the formation, growth and collapse of bubbles generated by ultrasound, to synthesize nanoparticles. Instead of using high temperature or pressure directly, this method creates them indirectly by using bubbles or cavities formed in the liquid by the acoustic waves. Further oscillation of such waves helps them gather and store ultrasonic energy, creating a hot spot (~ 5000  K) and leading to the synthesis of particles of different shapes and sizes. This method works for both volatile and non-volatile solvents [158–160]. The reaction medium was already considered the most important factor in controlling the properties of nanoparticles by Suslick et al. [160] when they proposed the method, since the bubbles formed will depend on the vapor pressure of the media. The nature of the particles can also be altered by changing the ultrasonic frequencies based on the inverse relationship between oxidation of F ­ e2+ to ­Fe3+ and ultrasonic frequencies

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[161]. The synthesis of particles in the presence of different ligands has also been performed, giving rise to particles between 5 and 16 nm [162]. Vijayakumar et al. [163] used a similar route to synthesize IONPs. They proposed a mechanism stating that ultrasonic waves produce the vaporization of water and further pyrolyzation into H and OH radicals due to prolonged temperature and pressure, which leads to the formation of hydrogen ­(H2) and hydrogen peroxide ­(H2O2) from the reaction between ­H2 and hydroxyl radicals, respectively. Meanwhile, the same energy also breaks down iron acetate into Fe(II) ions. These Fe(II) ions are later oxidized to Fe(III) using H ­ 2O2 as oxidant and forming F ­ e3O4 by using OH radicals [163]. There are several studies showing the effect of surfactants on the particles. Mukh-Qasim et  al. [164] used SDS as stabilizer to get around 8.5  nm amorphous but water dispersible ­Fe3O4 particles, while Rahamwati et al. used iron sands along with different concentrations of PEG-6000. This latter group showed that, as PEG concentrations increased, the crystallite size of the particles increased [165]. They also showed that the morphology of the particles shifted from flower-like to cubes to spheres with increasing PEG concentrations. Kim et  al. [166] synthesized OA-capped IONPs, which form a ferrofluid when dispersed in chitosan, with a hydrodynamic diameter of 65  nm, thus being potential MRI CAs. This method can also be used to synthesize composite nanoparticles [167] or other ferrites [168, 169].This method has also been used for surface functionalization in very short time [170]. The main advantage of this method is its accelerated nature to produce nanoparticles with good yield, but it falls short when it comes to phase homogeneity. 2.9 Microwave Synthesis This is a modern-day hydrothermal method of synthesizing nanoparticles and one of the most used in recent days due to its much-improved kinetics of crystallization. It requires as low as 10 s and yields small and monodisperse particles due to homogenous heating [171]. Palchik et al. were among the first to use this method in a domestic microwave oven and suggested that the synthesis of particles was happening due to thermal breakdown of Fe(CO)5, which in turn was taking place due to heating of chlorobenzene, since Fe(CO)5 is a microwave resistant compound [172]. This indirectly marks the importance of the solvent. On the other hand, Liu et al. demonstrated the importance of water in maintaining a stable heating environment, along with the role of stoichiometry [173]. Another important parameter that have been studied extensively is the nature of the surfactant, with studies reporting the use of different concentrations of OA [174], amino acids [175], polyethylene glycol (PEG) [176], and different ratios of OA and oleylamine (OLA) [177]. OA is shown to increase saturation magnetization with increasing concentration, with no definite trend in size. However, concentrations beyond 0.35 mmol/dm3 led to agglomeration and the product became difficult to isolate. Recently, amino acids such as glycine have been shown to reduce the crystallite size of IONPs, opening the path to explore other amino acids [175]. The presence of PEG in the reaction has also been shown to lead to smaller IONPs,

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as compared to the reaction in its absence. When the reaction is performed in the presence of PEG, it tends to favor the formation of magnetite instead of maghemite. This happens due to PEG being sacrificial in nature and thus preventing oxidation. High microwave power and low synthesis time also favors the formation of maghemite [176]. Other studies have shown that the presence of OA during the synthesis, along with OLA, reduces aggregation among particles [177]. Temperature has also been shown to transform phases in IONPs [178]. Blanco-Andujar et  al. proposed a facile method to synthesize citric acid coated IONPs and potentially scale them up [179]. The importance of aging temperature on crystallinity can be seen when ­Fe2O3 nanocubes are synthesized by decomposing iron oleate in a microwave and aging it in an autoclave at 180 ℃ for different time intervals [180]. Particles aged for 20 h showed cubic shape and higher saturation magnetization. Hu et al. [181] argued that the precursor is the most important parameter by synthesizing three phases of iron oxide, hematite, magnetite and maghemite, using ­FeCl3 alone or in combination with ­FeCl2. Literature suggests that the morphology and composition of the particles can also be controlled using this method. Different morphologies, such as lamellar sheets [182], octahedrons [182] and hexagonal plates [183] are synthesized by slight changes in salts. Cu-doped IONPs with good colloidal stability are obtained in 10 min [184] using the microwave method. In fact, even using a domestic microwave, sizes of 8–10 nm can be easily achieved [185]. This method has been shown to be better than hydrothermal [186] or thermal decomposition [187] in terms of size, crystallinity and saturation magnetization. However, particles thus synthesized display lower surface reactivity than those synthesized using the thermal decomposition method, although with more ease of stabilization. The versatility of this method is acknowledged by its association with different methods: coprecipitation [179], thermal decomposition, [177] polyol [188] and sol–gel methods [189]. The particle size can be varied by modulating the power and hence the temperature, the time spent in the reactor, the cooling rate, etc. This method has become more popular recently due to its multiple advantages. 2.10 Biosynthesis This is an eco-friendly method as most of the constituents needed are available from nature directly or indirectly. It generally involves the use of microbes [190] or plant extracts [191] to synthesize nanoparticles. Lovely et  al. [192] were the first to use a microbe, GS-15, to form magnetite nanoparticles. Thereafter, many different magnetic bacterial strains were found and studied in order to produce IONPs [193–197].These nanoparticles are formed by the reduction/hydrolyzing capabilities of these biological entities. However, when a bacterium is used, its nature as well as its incubation time becomes an important parameter since it allows changes in size and morphology [198, 199]. Even fungi such as Fusarium oxysporum and Verticillium sp., have been shown to possess hydrolyzing capabilities to form different sizes and shapes of nanoparticles [200]. Viruses such as tobacco mosaic virus (TMV) have also been used as templates to synthesize nanotubes [201]. Iron oxides formed by microbial reduction have been

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shown to lead to phase transformation with better crystallinity, although decreasing their reducibility [202].The scalability issue has also been answered by using a 30-l reactor, although there is only one report of such nature [203]. Plants or plants extracts have been used for the synthesis of nanoparticles [204]. Most recently, IONPs have been synthesized using figs, Ficuscarica and Plantago major extracts, which, apart from reducing precursors, also cap and stabilize the particles. These reactions have been concluded to take place due to the presence of phenols, and normally lead to sizes ranging from 2 to 50 nm [205, 206]. The main advantages of this method are that it is energy saving and non-toxic. Also, there is an unlimited supply of reducing agents, making it economically viable. On the other hand, its major disadvantage is unpredictability regarding the nature of the particles, with less control over the shape and size, along with uncertainty of yielding monodisperse particles when scaled up. 2.11 Other Methods Several different methods for the synthesis of IONPs have not been described above due to a dearth of information in the literature. Alvarez et al. [207] developed a novel flow injection synthesis (FIS) method to fabricate magnetite nanoparticles in a capillary reactor, and produced homogenous particles of 2–7 nm with high reproducibility. There have been reports of the use of metal rods as anodes and electrochemical deposition in the presence of surfactants to yield 3–8 nm particles [208–210]. Chemical vapor deposition (CVD) [211, 212] has been used to fabricate thin films and morphologycontrolled nanoparticles. Other methods, such as synthesis in a reactor [213], the solution combustion method [214], and the use of microfluidic channels on a chip [215, 216], have also been introduced. All the methods described above have their own pros and cons, and the choice of one or the other depends on the application for which the nanoparticles are being developed. Thus, for nanoparticles to be used as MRI CAs, the most suitable methods appear to be the thermal decomposition or microwave methods, since they provide a very narrow size distribution, high saturation magnetization and good morphology control.

3 Functionalization of IONPs One of the most important topics in the design of IONPs for in  vivo applications is functionalization, which provides NPs with high stability in physiological media, stealth and vector targeting properties. In this section, we summarize the most relevant methods to functionalize IONPs for clinical purposes. 3.1 Organic Supra‑structures In recent decades, a class of highly branched and monodispersed macromolecules with well-defined three-dimensional (3D) architectures, such as nanomicelles,

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dendrimers, liposomes and nanogels, have been developed to create hybrid nanoscale materials for imaging and therapeutic applications. 3.1.1 Nanomicelles Nanomicelles are formed by the self-assembly of surfactant molecules or copolymers that adopt a core–shell like structure, thus entrapping in their inner core hydrophobic materials, such as drugs, dyes or inorganic nanoparticles (Fig. 4). The small size is another advantage of the micelles, which can be synthesized between 5 and 100 nm. This provides nanomicelles with long blood circulation times, which favor their active or passive accumulation in the target sites. Consequently, nanomicelles are generating great interest in the development of promising payload nanocarriers for theranostics [217–219]. Particularly interesting are the results obtained with hybrid nanosystems using polymer micelles loaded with IONPs. For instance, Jianping Bin and coworkers described the synthesis of a tumor-targeted MRI vehicle through the encapsulation of IONPs in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan micelles [220]. In vitro and in vivo studies demonstrated the efficacy of folate-conjugated superparamagnetic iron oxide nanoparticle (SPION)micelles in targeting and visualization by MRI of folate receptor overexpressed tumor cells. Torchilin et  al. [221] created a diagnostic and therapeutic agent for in  vivo use based on poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE) micelles loaded with Paclitaxel (PTX), a poorly water soluble anticancer drug, and IONPs. The combination of both multi-modal cargos inside the micelles showed no property changes, either in the relaxivity of the IONPs or in the apoptotic antitumour activity of PTX. 3.1.2 Dendrimers Dendrimers are a class of well-defined nanostructured macromolecules consisting of three critical architectural domains: the multivalent surface, the interior shells surrounding the core, and the core. These domains can be tailored for a specific

Fig. 4  Synthesis of chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) [308]

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purpose, such as a dendritic sensor [222, 223] or a payload carrier, the encapsulation of molecules in their interior shell being the most used application of dendrimers [224, 225]. One of the most common dendrimers is based on the chemical structure poly (amidoamine) (PAMAM), which has a large number of reactive amine groups on the periphery, making them an excellent platform to construct nanomaterials for biomedical applications [226–228]. Luong et al. [229] designed a promising theranostic agent based on the combination of IONPs and a hydrophobic anticancer drug loaded in a PAMAM dendrimer decorated with folic acid (FA). The design of this hybrid theranostic agent starts with functionalization of the SPIONs with activated carboxyl groups that bind folic acid-PAMAM dendrimers. The engineered SPIONs@FA-PAMAM showed great potential as MRI diagnostic agents, with increased internalization in cancer cells and better image contrast. Moreover, the encapsulation of hydrophobic anticancer drugs, such as 3,4-difluorobenzylidenecurcumin (CDF), in the dendrimers of the SPIONs@FA-PAMAM, enhances their anticancer activity by delivering a higher dose of CDF with high specificity to target cancer cells expressing folate receptors. Dendrimers could also be used in gene therapy as gene delivery platforms. Xiao et al. [220] synthesized a nanohybrid dendrimer based on the combination of PAMAM dendrimers and IONPs through electrostatic interactions. First, the IONPs were functionalized with negatively charged polystyrene sulfonate (PSS), and then positively charged PAMAM dendrimers decorated with plasmid DNA were deposited onto the PSS-functionalized NPs, resulting in a nanohybrid material, PAMAM dendrimer/pDNA-coated MNPs. The results demonstrated that the efficiency of this hybrid system to transfect NIH 3T3 cells is strongly dependent on the dendrimer generation, the amine/phosphate groups ratio and the plasmid DNA concentration. 3.1.3 Liposomes Liposomes comprise a lipid bilayer surrounding an aqueous core. They can be made from different lipid formulation and present different sizes depending on the method of preparation. Similarly to the organic macro-structures mentioned above, liposomes are able to encapsulate payloads in their hydrophobic or hydrophilic inner, which makes them excellent nanocarriers for therapeutic and imaging applications. Liposomes based on phospholipids are the most common vesicles for in vivo applications due to their great advantages, such as biocompatibility, biodegradability and reduced toxicity [230–232]. The incorporation of IONPs into liposomes is gaining increased attention of researchers as a way to synthetize more effective magnetic nanocarriers for in  vivo applications. Di Corato et  al. [233] designed a liposome formulation based on phosphatidylcholine lipids that entraps magnetic NPs and a photosensitizer in its interior. In a single synthesis method, higher concentrations of hydrophilic IONPs were encapsulated in the core, and a hydrophobic photosynthesizer, Temoporfin (marketed as Foscan), was incorporated into the lipid bilayer. The resulting magnetic liposome presented double functionality, magnetic hyperthermia and photodynamic therapy, which led to complete death of cancer cells in vitro and total ablation of solid-tumor in vivo. Reprinted from the journal

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Zheng et al. [234] synthetized a tumor-specific peptide-decorated liposome containing payloads of IONPs and an anti-cancer drug in their inner core and lipid bilayer, respectively. Like the protocol described above, the combination in a single pot reaction of egg phosphatidylcholine, cholesterol, paclitaxel (PTX), different 1,2-distearoyl-snglycero-3-phosphoethanolamine (DSPE) phospholipids, such as DSPE-PEG and cell penentrating peptide-modified DSPE-PEG, and hydrophilic SPION, generated a theranostic liposome. The results confirmed the effectiveness for tumor targeting and antitumor activity through MRI in vivo experiments. 3.1.4 Nanogels Nanogels (NGs) are nanosized water-soluble particles formed by crosslinked polymer networks with loading capacity of therapeutics. Stimuli-responsive NGs are a class of smart particles that respond to external physical changes, such as pH, temperature or redox agents [235, 236]. This behavior allows the controlled-release of payloads from NGs, minimizing possible side effects and avoiding the use of high doses. NGs can also be loaded with diagnostic agents, such as magnetic NPs, enabling their visualization and follow-up by MRI. These characteristics, together with the ease of uptake by cancer cells and tumor tissues due to their softness and fluidity, make NG-based nanosystems a high potential theranostic material [237, 238]. Qian et al. [239] prepared a hybrid NG system based on a thermo-responsive copolymer [N-isopropylacrylamide, methacrylic acid and poly (ethylene glycol) methacrylate] that stabilizes hydrophobic IONPs and 10-hydroxy camptothecin (HCPT) in its inner compartment. The obtained IONP/HCPT-NG generated an increase in reactive oxygen species (ROS), allowed the enrichment of NG at the tumor site by applying an external magnetic field, and offered the possibility of being used as nanocarrier for photothermal therapy due to its absorption in the near infrared (NIR) range. In vivo results demonstrated that the combination of PTT and chemotherapy with external magnetic fields on IONP/HCPT-NGs, reduced the growth of primary tumors and prevented metastasis [239]. Alginate (AG) is a natural polysaccharide that has been gaining attraction in recent years for the synthesis of polymeric nanomaterials with biomedical applications thanks to its biocompatibility, biodegradability and ease of gelation [240]. For instance, Hao et  al. [241] designed alginate NGs loaded with IONPs and bone mesenchymal stem cells (BMSCs) for enhanced tumour MR imaging (Fig. 5). The potential advantage of using BMSCs as tumor delivery vehicles is that they are not tumorigenic and minimally immunogenic. In this way, polyethilenimine (PEI)-functionalized IONPs were crosslinked to AG NGs previously synthesized by a double emulsion method. The resulting AG/PEI-NP NGs were taken up by BMSCs without affecting cell characteristics. BSMC-AG/PEI-NP NGs were then used successfully for the in vivo diagnosis of different tumor models [241].

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Fig. 5  Schematic illustration of alginate/polyethilenimine-iron (III) oxide (AG/PEI-Fe3O4) and stem-cellmediated delivery of nanogels (NGs) for enhanced breast or glioma tumor molecular resonance (MR) imaging. Reprinted with permission from [241]. Copyright (2019) Royal Society of Chemistry

3.2 Inorganic Coverage Mesoporous silica is the most important inorganic coating material for IONPs due to the ease of functionalization, high stability, and vast surface area and pore volume to host large number molecules. These characteristics make hybrid mesoporous silicaIONPs excellent nanocarriers for controlled drug release therapies [242, 243]. Based on this, Vallet-Regí et al. [244] designed a responsive silica matrix nanocarrier for tumor therapy based on magnetic NPs that combine the heat release mediated by magnetic hyperthermia and doxorubicin release through a thermoresponsive polymer. The as-prepared OA-capped IONPs are transferred into aqueous solution with CTAB, which helps the growth of the silica matrix by addition of tetraethyl orthosilicate (TEOS) as a silica precursor. Then, the silica-matrix-coated IONPs are functionalized with a methacrylate molecule as a polymer precursor to perform, using N-isopropylacrylamide (NIPAM), N-(hydroxymethyl)acrylamide (NHMA), and N,N′-methylenebis(acrylamide) (MBA) monomers, the synthesis of a thermoresponsive polymer surrounding the mesoporous silica-coated IONP (Fig. 6). Direct injection into the tumor site of Doxo-loaded mesoporous silica NPs, together with the application of amplified magnetic fields, provoked a synergistic effect between magnetic hyperthermia and chemotherapy that led to significant tumor growth inhibition and low toxicity [244]. Hurley et al. [245] demonstrated that the inclusion of functionalized mesoporous silica coating in IONPs cores results in stable NPs with high heat capacity and high MRI contrast. The anionic surfactants capped IONPs (a commercially available IONP called EMG-308) required pre-functionalization with polyvinylpyrrolidone (PVP) prior to silica condensation with the TEOS precursor. Finally, the functionalization with PEG and trimethyl silane derivates yields colloidal stable NPs with the same magnetic character that un-functionalized IONPs and minimal toxicity toward human skin fibroblasts. Furthermore, a direct injection into LNCaP prostate cancer tumours implanted in nude mice showed that these hybrid mesoporous silica-IONPs can improve the heating and imaging contrast of IONPs [245]. Reprinted from the journal

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Fig. 6  Synthesis of mesoporous silica-coated (ms)-IONPs. Polyvinylpyrrolidone (PVP)-10 was added to IONPs prior to cetyltrimethylammonium bromide (CTAB) addition and silica condensation to allow for CTAB colocalization with IONPs and to maintain a spacer layer between the silica shell and IONP core. Reprinted with permission from [245]. Copyright (2016) American Chemical Society

3.3 Ligand Exchange Ligand exchange is a very complicated coating strategy that involves multiple interactions potencials/forces. It requires the use of reactive binding molecules that enable the replacement of capping agents attached to the nanoparticle surfaces. This binding between the iron atoms of the IONP and the anchor group of the ligand molecules is mediated by electrostatic interactions. Therefore, the nature of the anchor group is determinant in the search for highly stable ligand molecules at the IONP surfaces. In addition to anchor groups, the hydrophilic balance of the ligand is also important to render water-soluble NPs [236, 246, 247]. In our group, we have developed different ligand formulations to functionalize IONPs to obtain soluble and stable NPs in physiological media for in vivo MRI applications. These ligands are based on a gallol group as a strong binder and PEG chains as hydrophilic tunable spacers, which also minimize plasma protein adsorption. In this manner, we have demonstrated that selection of the right molecular weight of PEG chain and the outermost charged group of the ligand plays a fundamental role in the fate and bioavailability of intravenously injected IONPs. Thus, a ligand with a PEG chain between 1500 and 3000  Da and neutral outermost groups showed the best stealth properties, resulting in longer blood circulation times and higher bioavailability without increased toxicity [248–250].

4 Applications of IONPs in MRI Among the main clinical diagnostic techniques, MRI stands out for its unique combination of qualities, such as its non-invasive character, the absence of ionizing radiation, excellent image quality, and its ability to provide both anatomical and functional information [251]. The MRI signal comes mainly from the protons of the water molecules, while the image contrast is generated from differences in the intensity of this signal among different tissues, which depends on the concentration, relaxation times ­(T1 and ­T2) and mobility of the water molecules within each tissue [252, 253]. Additionally, image contrast can be further enhanced using CAs. Although there are several mechanisms that can produce MRI contrast, such as

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chemical exchange saturation transfer (CEST) or hyperpolarization, most MRI CAs produce contrast by altering the relaxation times of the surrounding water protons [254, 255]. The capacity of a CA to decrease the relaxation times ­(T1 or ­T2) is given by a parameter known as relaxivity ­(r1 or ­r2), which is expressed in ­mM−1·s−1. In MRI, among the most commonly used CA are chelates of paramagnetic gadolinium(III) ions ­(Gd3+). However, conventional Gd-chelates have some important limitations, such as the lack of diagnostic specificity and the toxicity associated with their use as a result of the unexpected release of free Gd ions [256, 257]. Magnetic NPs have emerged as a promising alternative to overcome these limitations [258]. 4.1 IONPs in Tumor Diagnosis 4.1.1 Untargeted IONPs The evaluation of IONPs as CAs in cancer research is performed mainly in rodent models, called ‘indirect xenografts’ [259]. Cancer cells can be implanted either into a tissue unrelated to the original tumor site (heterotopic model) or into the corresponding anatomical position (orthotopic model) [260] (Fig. 7). The route of administration of magnetic NPs is also relevant as it influences the biodistribution and pharmacokinetics of the CA. Several administration routes have been used in preclinical studies, mainly intratumoral, intraperitoneal or intravenous injection; for obvious reasons, the latter is the most interesting for clinical applications. After intravenous administration, IONPs have been described to accumulate in tumors due to the EPR (Enhanced Permeability and Retention) effect. This passive transport is determined by the high vascularization of tumors, and therefore increased blood flow, together with increased vascular permeability and poor lymphatic drainage [261]. Efremova et al. [262] developed IONPs for diagnosis of breast cancer in a heterotopic model. They observed that IONPs accumulated passively inside the tumor 24 h after intravenous injection using T ­ 2-weighted MR images. Similar studies have been conducted using orthotopic models of breast cancer [263, 264], pancreatic cancer [265] and glioblastoma multiforme (GBM) [266]. All these studies conclude that IONPs accumulated in the tumor due to the EPR effect; however, most of them lack quantitative analyses, which are necessary to determine the amount of IONPs that actually reach the tumor. Intratumoral administration could be an alternative for tumor therapy when the CA is not able to reach the tumor by a venous route. However, this approach has serious limitations for diagnostic applications since, in most cases, it would not add any useful information to that already provided by the MR images without CA. Furthermore, intratumoral administration makes no sense when it comes to very early diagnosis, detection of metastasis or in the case of inaccessible tumors. Nevertheless, several preclinical studies have been conducted using intratumoral injection of IONPs [267–269]. The authors used qualitative MRI to evaluate the distribution of IONPs throughout the tumor, which showed that IONPs spread slowly and inefficiently. Therefore, in these studies the information provided by MRI after the Reprinted from the journal

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Fig. 7  C6 brain tumor model implanted orthotopically (upper panels) and heterotopically (lower panels). Left) ­T2-weighted MR images before the injection of IONPs; right) ­T2-weighted MR images 1 h after the injection of IONPs

intratumoral injection of IONPs serves as proof of concept, but, as we have just mentioned, it is of no practical value for potential clinical applications. In conclusion, up to now, untargeted IONPs have not proven to be a good alternative to conventional MRI CAs for cancer diagnosis. 4.1.2 Targeted IONPs To improve the accumulation of IONPs in tumors, a promising strategy is conjugation with targeting segments [5]. In principle, this functionalization would allow not only the visualization of IONPs by MRI, but would also offer the possibility of visualizing cellular and subcellular functions and processes in living organisms without perturbing them, giving rise to so-called molecular MRI (mMRI) [270], which was first described by Richard Klausner [271, 272] (Fig. 8).

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Fig. 8  Scheme of the non-targeted (top) and targeted IONPs (bottom)

It is worth mentioning that the targeted strategy for cancer diagnosis was described before the untargeted strategy. Reimer et al. [273] described in 1990 the diagnosis of liver cancer after the intravenous administration of IONPs-arabinogalactan conjugates, in both heterotopic and orthotopic models. IONPs have been functionalized with epithelial growth factor (EGFR) antibodies for the diagnosis of breast cancer [274], pancreatic/stomach cancer [275] and brain cancer [276]. Because there is an established relationship between mutations involving overexpression or overactivity of EGFR and various types of cancer, this receptor is currently one of the most important targets in cancer research [277–279]. Similarly, PSCA (prostate stem cell antigen) antibody was bound to IONPs for diagnosis of prostate cancer [280]. Integrins receptor, especially α5β3, has been found to be differentially overexpressed in tumors, playing a vital role in tumor angiogenesis [281–283]. Integrins are recognized mainly by short peptide sequences, such as Arg–Gly–Asp (RGD). Therefore, some NPs functionalized with RGD have been proposed for the diagnosis of brain cancer [284], colon cancer [285] or fibrosarcoma [286], among others. Among other functionalization molecules for targeted diagnosis, it is worth highlighting the use of aptamers for kidney [287] and liver cancer [288], peptides for prostate and liver cancer [289, 290], and flavin adenine dinucleotide (FAD) for prostate cancer [291].

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Fig. 9  a In vivo MR images of a NCr nude mouse at different time points after intravenous injection of IONPs. b Quantification of liver contrast collected at different time points after accumulation of IONPs in NCr nude mice. c In  vivo MR images of liver tumor orthotopic xenographs at different time points after intravenous injection of IONPs. d Quantification of contrast-to-noise ratio (CNR) of tumor-to-liver contrast at different time points. e, f Histopathological analysis of mouse liver 1 h after the intravenous injection of IONPs. Reprinted with permission from [292]. Copyright (2018) American Chemical Society

Recently, Chee et al. published an interesting study in which they described the design of a library of short peptides and ligands to functionalize IONPs. From this library, they selected the ligand that provided IONPs with the best characteristics for in  vivo use, namely, long term stability, non-specific binding to live cells and absence of cytotoxicity at high concentrations. IONPs functionalized with this ligand showed a significant increase in contrast between the liver tumor and the healthy liver tissue, as compared with commercial MRI CAs [292] (Fig. 9). Finally, it is worth mentioning that, in clinical diagnosis, positive contrast is generally preferred over negative contrast because it avoids the potential confusion of signal decay caused by negative CAs with signal voids caused by magnetic field inhomogeneities induced by air, metal prosthesis, etc. Thus, a very recent study described the use of Cu as a dopant agent that enhances the positive contrast of IONPs functionalized with RGD for targeted diagnosis of breast cancer [184]. Even though many IONPs show dual contrast potential, that is, ­r2/r1 ratio  between 3 and 10, their use in vivo as positive CAs is limited by the acquisition conditions of conventional ­T1-weighted MRI sequences, which are usually based on the spin-echo acquisition scheme and therefore require relatively long echo times. However, the introduction of new MRI acquisition sequences, such as ultra-short echo time (UTE) sequences, is making it possible to detect IONPs as positive contrast [293].

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4.2 IONPs as CA in Other Pathologies Although most research in IONPs designed to serve as MRI CAs is focused on cancer diagnosis, there are many other pathologies that can benefit from advances in this field of research, as discussed henceforth. Recent investigations have demonstrated that an acetylcholine-sensitive mMRI nanosensor can be used for measuring the endogenous release of acetylcholine in the rat brain after its intracerebral administration [294]. Similarly, after intracerebral administration of alginate-coated IONPs, changes in C ­ a2+ levels have been monitored following a quinolinic acid-induced striatal lesion [295]. Other magnetic nanostructures have been used for the detection of brain inflammation [296]. These particular nanostructures are based on IONPs coupled covalently through peptide linkers that have been designed to be cleaved by the intracellular macrophage cathepsin, which results in microparticles of iron oxide (MPIO) and allows the fate of magnetic NPs to be tracked. This is because the MPIO, once sequestered by macrophages in the liver, decrease their relaxivity, while particles that associate with their target tissue in the brain remain unaltered and functional. Thrombosis is a major clinical problem whose incidence has not decreased over the last 20  years and is involved in several pathological disorders such as myocardial infarction, ischemic stroke or pulmonary embolism, among others [297]. Early detection is essential for effective treatment, but it remains challenging in practice. P-selectin is an adhesion molecule, overexpressed at the surface of endothelial cells and platelets upon activation, which plays a fundamental role in thrombus formation [298]. Based on this fact, Suzuki et  al. [299] innovated a fucoidan (a natural sulfated polysaccharide with high affinity for activated platelets through P-selectin)-coated USPIONs to visualize by MRI arterial thrombi in the early stage of the disease. Other investigations used PLGA-coated IONs, functionalized with EWVDV peptide, which has a high affinity and specificity for P-selectin, to target thrombi for both diagnosis and treatment through the induction of thrombolysis [300]. 4.3 Other Applications IONPs have also been used in combination with MRI for many other in vivo applications, such as imaging of activated microglia during brain inflammation [301], tracking of stem cells [302–304], image-guided treatment of anemia using bacteria loaded with IONPs [305], or to carry out vascular imaging [306, 307], among others.

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5 Conclusions Recent advances in nanotechnology applied to biomedical research have made possible the development of a new generation of magnetic nanomaterials with great potential as MRI CAs. IONPs stand out due to their excellent combination of properties for in vivo applications, that is, their superparamagnetism along with their high biocompatibility. Also, advanced functionalization strategies have allowed these IONPs to be specifically targeted to different tissues or cells to perform molecular imaging. However, in spite of all these advances, and the large number of studies carried out in this field, very little clinical translation has been achieved so far. The main reasons behind this relative failure are very likely related to reproducibility and scalability issues during the synthesis process, which must be further improved. Also, in vivo studies must be thoroughly designed to include comprehensive toxicity assays and preclinical imaging studies using appropriate animal models. Acknowledgements  Ashish Avasthi thanks the Marie Curie COFUND program for her PhD scholarship (NanoMedPhD, Grant agreement 713721). Financial support was provided by the Spanish Ministry of Science, Innovation and Universities (CTQ2017-86655-R) to María Luisa García-Martín and Manuel Pernia Leal. Manuel Pernia Leal also thanks the “V Plan Propio” of the University of Seville for his Postdoctoral Fellowship.

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Topics in Current Chemistry (2020) 378:12 https://doi.org/10.1007/s41061-019-0275-y REVIEW

Gold, Silver and Iron Oxide Nanoparticles: Synthesis and Bionanoconjugation Strategies Aimed at Electrochemical Applications Claudia Iriarte‑Mesa1 · Yeisy C. López1,2 · Yasser Matos‑Peralta1 · Karen de la Vega‑Hernández3 · Manuel Antuch4  Received: 31 July 2019 / Accepted: 13 December 2019 / Published online: 7 January 2020 © Springer Nature Switzerland AG 2020

Abstract Nanomaterials have revolutionized the sensing and biosensing fields, with the development of more sensitive and selective devices for multiple applications. Gold, silver and iron oxide nanoparticles have played a particularly major role in this development. In this review, we provide a general overview of the synthesis and characteristics of gold, silver and iron oxide nanoparticles, along with the main strategies for their surface functionalization with ligands and biomolecules. Finally, different architectures suitable for electrochemical applications are reviewed, as well as their main fabrication procedures. We conclude with some considerations from the authors’ perspective regarding the promising use of these materials and the challenges to be faced in the near future. Keywords  Gold nanoparticles · Silver nanoparticles · Iron oxide nanoparticles · Nanobioconjugation · Immobilization strategies · Biomolecules · Biosensors Abbreviations AFP Alpha-fetoprotein Chapter 4 was originally published as Iriarte‑Mesa, C.,·López, Y. C., Matos‑Peralta, Y., Vega‑Hernández, K. de la & Antuch, M. Topics in Current Chemistry (2020) 378: 12. https://doi.org/10.1007/s41061-0190275-y. * Manuel Antuch manuel.antuch‑cubillas@ensta‑paris.fr; [email protected] 1

Laboratorio de Química Bioinorgánica, Departamento de Química General e Inorgánica, Facultad de Química, Universidad de La Habana, Zapata y G, Vedado, Plaza de la Revolución, 10 400 La Habana, Cuba

2

Instituto Politécnico Nacional, Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada, Calzada Legaria 694, Col. Irrigación, 11 500 Ciudad de México, Mexico

3

Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, 75005 Paris, France

4

Unité de Chimie et Procédés, École Nationale Supérieure de Techniques Avancées (ENSTA), Institut Polytechnique de Paris, 828 Boulevard des Maréchaux, 91120 Palaiseau, France





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AgNPs Silver nanoparticles Apt Aptamer APTES (3-Aminopropyl)triethoxysilane AuNPs Gold nanoparticles CEA Carcinoembryonic antigen CFP-10 Culture filtrate protein CFU Colony forming unit CMX Carboxymethyl dextran CNT Carbon nanotubes CP Carbon paste CQDs Carbon quantum dots CS Chitosan CuAAC​ Cu(I)-catalyzed alkyne-azide cycloaddition DDT 1-Dodecanethiol DET Direct electron transfer DHEAS Dehydroepiandrosterone sulfate DMSO Dimethylsulphoxide DNA Deoxyribonucleic acid DPV Differential pulse voltammetry DTA/TG Differential thermal analysis/thermogravimetry EDC 1-Ethyl-3-(dimethylaminopropyl) carbodiimide EIS Electrochemical impedance spectroscopy EtOH Ethanol Fe3O4 NPs Magnetite nanoparticles GCE Glassy carbon electrode GC–MS Gas chromatography and mass spectrometry GO Graphene oxide GOx Glucose oxidase GPC-3 Glypican-3 GQD Graphene quantum dots Hc Coercitivity HCC Hepatocellular carcinoma HER2 Human Epidermal growth factor Receptor 2 HOBt  N-hydroxybenzotriazole HRP Horseradish peroxidase Ig Immunoglobulin IL Ionic liquid IONPs Iron oxide nanoparticles ITO Indium tin oxide LBL Layer by layer LOD Limit of detection microRNA Microribonucleic acid MNPs Magnetic nanoparticles Ms Saturation magnetization Mr Remanent magnetization MWCNT Multi-walled carbon nanotubes

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NHS  N-hydroxysuccinimide NPs Nanoparticles OA Octanoic acid pACC​ Pediatric adrenocortical carcinoma PDVB Polydivinylbenzene PEDOT:PSS Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate PEG Polyethylene glycol PEI Polyethyleneimine PPy Polypyrrole PSA Prostate-specific antigen PVA Polyvinylalcohol PVP Polyvinylpyrrolidone RGO Reduced graphene oxide RIL Rilpivirine RSD Relative standard deviation SAM Self-assembled monolayer SPR Surface plasmon resonance tB Brownian relaxation time tN Neel relaxation time TOAB Tetraoctylammonium bromide TOPO Tri-n-octyl phosphine oxide Tris Tris(hydroxymethyl)aminomethane WP Whatman filter paper ZnONRs Zinc oxide nanorods ΔG Variation of Gibbs free energy

1 Introduction Nanoscience and nanotechnology have allowed major breakthroughs in the development and use of new devices. Nanoparticles (NPs) have played an important role in the design of new materials for application in areas related to medicine [1, 2], water treatment [3, 4], electrochemical and optical sensing [5], catalysis [6–11] and electrocatalysis [12, 13]. Their outstanding position in current chemistry is due to the numerous advantages they confer, including biocompatibility and ease of functionalization [14], along with the possibility to make biosensors with increased sensitivity, reproducibility and reduced assay times [15, 16]. Among the many nanosystems now available, gold and silver NPs are the most well known, and possess a wide variety of interesting optical and electrochemical properties [17–20]. Likewise, iron oxide NPs have become widely employed because of their magnetic and electrochemical properties [21–24]. The excellent properties of NPs can be boosted by conjugation with biomolecules, allowing exploitation of the natural specificity of the biological component, while the NP scaffold provides increased stability and frequently improves the biological properties of the biomolecule as compared to its native state [25–29]. The wide variety of methodologies used to conjugate biomolecules to NPs guarantees innumerable applications of the bioconjugates obtained. Reprinted from the journal

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Hence, selection of the most appropriate strategy constitutes a crucial aspect in the design and construction of functional nanobioconjugates [30, 31]. This contribution aims to highlight the virtues of conjugating diverse biomolecules with NPs. Herein, we focus on gold, silver and iron oxide NPs. Other nanometric systems such as quantum dots, carbon nanotubes, fullerenes, graphene, reduced graphene oxide (RGO), Janus and core–shell NPs are outside the scope of this review. The purpose of this contribution is to provide a pedagogic overview of the topic, with emphasis on the progressive presentation of the contents. Accordingly, we begin with simpler and more general concepts, such as the preparation, structural description and physicochemical characterization of the three kinds of NPs, later on covering the most advanced and up-to-date bioelectrochemical applications of NP–biomolecule conjugates. Our intention was to review the most recent advances in nanobioconjugation chemistry; consequently, 70% of the work reviewed here comes from the last 3  years (2017–2019), 86% from the last 5  years (2015–2019) and 93% from the last decade (2009–2019), thus assuring a current view of the most recent developments in the field. This review is organized into five sections in addition to this Introduction. The following section presents the general properties of gold, silver and iron oxide NPs. Thereafter, a section on  synthetic routes summarizes the main methods used to obtain these nanomaterials. We then discuss stabilization and surface functionalization of NPs with different functional groups, which allows their further bioconjugation to diverse biomolecules, as described in the next section, Conjugation of biomolecules to NPs: the main key to further application. Finally, Nanobioconjugates and their electrochemical application offers a review of the most recent trends in the design of electrochemical biosensors based on the conjugation of gold, silver, and iron oxide NPs with biomolecules. The use of different electrode architectures, and preparation protocols and biosensor performances are discussed, in order to provide a contemporary outline of current trends in the utilization of bioconjugated nanosystems in bioelectrochemical applications.

2 General Properties of Gold, Silver and Iron Oxide NPs 2.1 Gold and Silver NPs NPs are atomic aggregates with a diameter between 1 and 100 nm [32]. Such dimensions determine their unique properties, which differ from individual atoms and bulk materials. These differences are explained by their high surface to volume ratio and quantum size effects [33]. Both gold and silver NPs (herein referred to as AuNPs and AgNPs, respectively) present unique colors that have made them attractive for developing new analytical assays [34]. The colors of these colloids are caused by a phenomenon known as surface plasmon resonance (SPR) [35, 36]. This is a feature typical of many metallic NPs, including AuNPs and AgNPs. SPR consists of the collective oscillation of conduction electrons across the NP due to the resonance that occurs with incident radiation (Fig. 1).

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Fig. 1  Schematic representation of surface plasmon resonance (SPR) in metallic nanoparticles (NPs). The sinusoidal line represents the visible electromagnetic wave

In 1908, Gustav Mie provided the explanation for the visible-light absorption of colloidal gold suspensions. Mie assumed small spherical and homogenous NPs interacting with an electromagnetic field in order to solve Maxwell’s equations [37]. For NPs with a diameter comparable to the excitation wavelength, the extinction coefficient Cext is governed by the dipolar absorption term in Mie’s equation. This case is known as the quasi-static or dipolar approximation (Eq. 1) [38].

Cext

3∕ 𝜀i 24𝜋 2 R3 𝜀m 2 = ( )2 𝜆 𝜀r + 2𝜀m + 𝜀2i

(1)

where R is the radius of the spherical NP, 𝜆 is the wavelength, 𝜀m is the dielectric constant of the medium related to the refraction index through the expression 𝜀m = 𝜂m2 . The terms 𝜀r (𝜔) and 𝜀i (𝜔) represent the real and imaginary component of the dielectric function of the nanoparticle (Eq. 2). [ ] 𝜀(𝜔) = 𝜀r (𝜔) + i𝜀i (𝜔) . (2) Resonance is produced when 𝜀i (𝜔) is small, or depends poorly on the oscillation frequency 𝜔 and, therefore, Eq. 3 holds.

𝜀r (𝜔) = −2𝜀m

(3)

The previous analysis describes the SPR maximum behavior only for NPs below 10 nm. However, the size of the NPs influences the position of the SPR due to the dependence of the dielectric constant of the metal on NP size. The dielectric constant of the material may be adjusted for different sizes by introducing a relaxation frequency parameter. Amendola et  al. [39] developed a procedure to fit UV–Vis spectra for AuNPs using Gans’ model (an extension of Mie’s theory for nonspherical particles [40]) considering only the average radius of the NPs (R), a standard deviation with a Gaussian distribution, and the fraction of spherical to spheroidal AuNPs. The method allows the size, concentration, and aggregation level of AuNPs to be estimated with an accuracy of 6% for AuNPs between 4 and 25 nm. This procedure Reprinted from the journal

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may be extended to other nanometric systems such as AgNPs and noble metal alloys [40]. For AuNPs and AgNPs, the resonance condition is satisfied at visible wavelengths. Thus, AuNPs of around 10 nm are red, possessing a maximum at approximately 510  nm; whereas AgNPs of similar size are yellow, corresponding to an absorption maximum at around 400  nm. Multiple factors influence the maximum of the SPR, including metal type [41], NP size [42], shape [43], functionality of the nanostructure [44], composition [45], interparticle distance [46], ligand–NP interactions [47], the refractive index of the medium [48], pressure [49] and temperature [50]. 2.2 Iron Oxide NPs Among metal oxides NPs, iron oxide NPs (IONPs) have attracted special interest due to their attractive magnetic properties as well as their high biocompatibility and low toxicity [51]. Magnetic materials are classified as ferromagnetic, ferrimagnetic, antiferromagnetic and superparamagnetic (Fig. 2). Ferromagnetic materials present multiple magnetic domains, where the electron spins are oriented in the same direction and therefore display a remanent macroscopic magnetization. In ferrimagnetic materials, a portion of the magnetic moments inside the domains are oriented in one direction and the rest in the opposite direction. Thus, in each domain, there is a magnetic dipole. These materials show remanent magnetization after the removal of an external magnetic field, but smaller than that observed for ferromagnetic materials. When the number of magnetic moments oriented in opposite directions is equal, the net magnetic moment is null, and, as a consequence, the material is antiferromagnetic. Finally, in a superparamagnetic material, the magnetic dipoles align themselves in the direction of an external magnetic field. By withdrawing the external

Fig. 2  a Representation of the domain structure of ferromagnetic, antiferromagnetic and ferromagnetic solids. b Spin orientation inside the magnetic domain at Ms and Hc = 0 for a superparamagnetic solid. c Coercivity (Hc) as particle diameter (D) function

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field, thermal fluctuations cause disordered movement of the magnetic moments, which causes a null magnetic moment. The superparamagnetic behavior of a material is the result of magnetic anisotropy. Two main contributions to anisotropy exist, related to (1) crystal anisotropy and (2) particle shape and morphology. Crystal anisotropy is associated with the existence of different crystallographic directions along which the spins of the electrons are aligned faster, and, therefore, the substance is easily magnetized. The other anisotropic contribution is related to the size and morphology of the particles; for example, spherical particles are prone to present smaller coercivity than elongated particles [52]. If the material size decreases toward the nanoscale, the number of spins that can be oriented by an external magnetic field is increased. In this case, a tendency toward superparamagnetic behavior is produced. It is known that IONPs can adopt a superparamagnetic behavior above a critical diameter (Fig. 2c), i.e., the NPs are attracted to the magnet but when the magnetic field is removed they lose magnetization [53]. The critical diameter where superparamagnetic behavior is observed is around 15–20 nm for magnetite NPs [54]. Key magnetic parameters used to assess the potential application of those systems are (1) saturation magnetization (Ms), (2) remanent magnetization (Mr), (3) the coercivity (Hc) and (4) the Neel and Brownian relaxation time of nanoparticles (­tN and ­tB, respectively) as illustrated in Fig. 3. The saturation magnetization (Ms) can be defined as the highest value of magnetization reached by the material. This value corresponds to the parallel alignment of all magnetic moments of the system. When the magnetic field is diminished, the magnetization (M) at H = 0 is not equal to zero, and this is called remanent magnetization (Mr). On the other hand, the value of the magnetic field at which the magnetization becomes zero is known as coercivity (Hc). In the case of nanoparticles, superparamagnetic behavior is characterized by nearly zero Hc and Mr. Another distinguishing feature of magnetic NPs (MNPs) is their capacity to generate heat when the NPs are exposed to a high-frequency magnetic field. Under these conditions, the monodomain nanoparticles generate heat through the oscillation of their magnetic moment. This heat may be dissipated via two different processes, (1) Brownian relaxation, produced by the rotation of the entire magnetic particle within a surrounding liquid, and (2) Néel relaxation, which is the rotation of the magnetic

Fig. 3  a Magnetization curve (M vs. H) for a magnetic solid, showing Ms, Mr and Hc. b Magnetization curve for superparamagnetic nanoparticles showing nearly zero Mr and Hc Reprinted from the journal

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moment within the magnetic core. In most cases, the heating power is governed by the fastest regime of relaxation [52]. The ability of IONPs to generate heat in the presence of an alternating magnetic field [55] has made them the base for the development of hyperthermia applications, employed mainly to induced death in tumor cells [56]. In order to produce hyperthermia, energy dissipation phenomena must be involved, according to Néel or Brown relaxation [57], although in most cases is difficult to distinguish which process is actually taking place. The most studied iron oxides at the nanoscale are hematite (α-Fe2O3), magnetite ­(Fe3O4) and maghemite (γ-Fe2O3). Hematite presents a hexagonal unit cell with a = 0.5034 nm and c = 1.375 nm, and six formula units per cell. Hematite may also appear in the rhombohedral system with a = 0.5427 nm and α = 55.3º, and two formula units per cell. The structure consists in an hcp array of oxygen ions along the [001] direction and two-thirds of the sites are occupied by Fe(III) arranged regularly, with two filled sites followed by one vacant site in the (001) plane. At bulk scale, hematite behaves as a weak ferromagnetic material or antiferromagnetic. On the other hand, magnetite and maghemite present a cubic unit cell, and, and at bulk scale behave as a ferrimagnet. The structure of magnetite is typical of an inverse spinel containing iron(II) and iron(III) distributed in its structure. Fe(III) ions are located in both tetrahedral and octahedral sites, while Fe(II) ions occupy only octahedral sites due to the higher ferrous crystal field stabilization energy. The cubic unit cell has an edge length a = 0.839 nm, presenting eight formula units per cell. Magnetite is non-stoichiometric, with cation deficiency in the Fe(III) sublattice. Maghemite is isostructural to ­Fe3O4, but the majority of Fe ions are trivalent, and cation vacancies compensate the oxidation of Fe(II). Maghemite has a cubic unit cell with a = 0.834 nm. In the cell, eight cations occupy tetrahedral sites and the rest are distributed randomly in octahedral sites. The vacancies are limited to octahedral sites [58].

3 Synthetic Routes 3.1 Synthesis of AuNPs There are numerous reports on the different methodologies for the synthesis of AuNPs with a wide variety of sizes and morphologies (reviewed in [59, 60]). Herein, we will describe only the most important. The chemical synthesis of AuNPs is based on the reduction of a gold salt and the stabilization of the NPs. The two conventional chemical methods for obtaining AuNPs are the Turkevich and the Brust-Schiffrin methods. In 1951, Turkevich reported an easy pathway to obtain spherical AuNPs by reducing hydrogen tetrachloroaurate(III) ­(HAuCl4) using trisodium citrate as both reducing agent and stabilizer [61]. This method involves the use of water as a solvent, and the citrate is added once the solution is boiling. The NPs obtained are in a range from 10 to 150 mn in size. The Turkevich method is still used widely due to its simplicity and reproducibility. Recent studies show that citrate can be further substituted for α and

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β-hydroxy carboxylates as stabilizers in order to prepare nanoparticles of various sizes, size distribution, and shape [62]. The Brust-Schiffrin approach [63] was reported in 1994 and presented a new procedure for the synthesis of spherical NPs somewhat similar to the Turkevich method, but the size of the particles obtained was below 10  nm. In this method, metallic clusters are grown at the same time as a self-assembled thiol monolayer is attached to the growing nuclei. In order to achieve both processes simultaneously, the reaction occurs in two phases (water and toluene). Sodium borohydride (­ NaBH4) is used as a reducing agent and tetraoctylammonium bromide (TOAB) as a phase-transfer catalyst. The gold complex anion, [­ AuCl4]−, is transferred from the aqueous phase to the organic phase by electrostatic interactions between the positively charged TOAB and the negative gold ion. Seed-mediated growth method is another strategy to obtain AuNPs. Unlike the above-mentioned methodologies, seed-mediated growth is one of the easiest ways to effectively control the size of the NPs [64, 65]. It was first reported by Wiesner in 1989 [66] and consists of obtaining gold seeds via reduction of ­HAuCl4, and then adding more H ­ AuCl4, which is reduced using phosphorus. This methodology has evolved, and is currently used for the preparation of AuNPs with narrow size distribution [67]. Other strategies report the use of fungi [68] and plant extracts [69] as reducing agents; photosynthesis [70], and laser ablation [71] are additional approaches for preparing colloidal gold, as illustrated in Fig. 4. 3.2 Synthesis of AgNPs AgNPs can be synthesized by reducing silver ions in aqueous or non-aqueous solutions through chemical methods. For example, chemical reduction with sodium citrate [72], sodium borohydride [73], and calcium ascorbate [74], have been used as

Fig. 4  Most common synthetic routes for preparing gold NPs (AuNPs) and silver NPs (AgNPs) Reprinted from the journal

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reducing and stabilizing agents. Green synthesis of AgNPs has become very trendy in the past few years [75]. This methodology has gained increasing attention due to its eco-friendliness and low cost [76]. There is a great variety of plants that have been reported as agents for AgNPs synthesis under mild conditions [75, 77]. Some of the most common plant extracts that can behave as reducing agents and stabilizers are from Polyalthia longifolia [78] or Moringa oleifera [79]. Some families of bacteria, for example Pseudomonas [80], have been used for the preparation of colloidal silver. Other methodologies for obtaining AgNPs (common to AuNPs) are based on microemulsion techniques [81], microwave heating [82], and laser ablation [83] (Fig. 4). 3.3 Synthesis of IONPs As described for AuNPs and AgNPs, IONPs can be synthesized through a large diversity of methods, and these can be categorized into physical, chemical and green syntheses. Chemical methods are most often used, particularly chemical co-precipitation and thermal decomposition. In 1981, Massart first reported the preparation of magnetite NPs in alkaline media using ­FeCl3 and ­FeCl2 as precursors in a molar ratio 1:2 ­(Fe2+/Fe3+) under inert atmosphere (Eq. 4) [84].

Fe2+ (ac) + 2Fe3+ (ac) + 8OH− (ac) → Fe3 O4 (s) + 4H2 O.

(4)

This procedure allows a large mass of NPs to be obtained but with broad size distribution and low crystallinity. Unlike chemical coprecipitation, thermal decomposition of organic complexes produces NPs with narrow size distributions and high crystallinity, which makes it the most attractive method to prepare IONPs for biomedical applications [85, 86]. This method is based on the thermal decomposition of organic complexes of iron, such as iron oleate [87], pentacarbonyliron(0) [88], Fe(acac)3 [89] or ferrocene [90]. Other chemical strategies are sol–gel [91], oxidation [92], and solvothermal reactions [93]. The laser ablation technique allows preparation of NPs with various sizes and compositions by modifying the wavelength, pulse duration, and power of the laser [94]. On the other hand, green synthesis of IONPs has gained much attention recently due to their good reproducibility, low cost, high yields, mild reactions conditions and biocompatibility [95].

4 Stabilization and Surface Functionalization 4.1 Functional Groups Relevant for NP Modification In the case of noble metal NPs (e.g., Au and Ag), thiolated ligands are essentially used to cover the surface due to the strong Au–S and Ag–S interaction (approximately 200 kJ mol−1 [96]). In the case of IONPs, the most employed coating agents are carboxylates, phosphates, hydroxyls, and in some cases thiols, although oxygenated groups are preferred for modifying IONPs [97] (Fig. 5). The choice of the

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Fig. 5a–k  Functional groups with high affinity to the surfaces of NPs. a Thioesters, b thiols, c dithiocarbamates, d thioureas, e phosphine oxides, f amines, g phosphates, h catechins, i trimethoxysilane, j carboxylic acids, k alcohols

strategy to stabilize and functionalize NPs depends strongly on the envisaged application. Certainly, if the final application of the NPs is a biosensor, the preferred ligand will be a biomolecule capable of specifically recognizing a molecule of interest. If the aim is to provide biocompatibility, ligands with biological significance are preferred, such as polyethylenimine (PEI), carboxymethyl dextran (CMX) or polyethylene glycol (PEG) [98]. 4.2 Ligand Exchange Ligand exchange consists of replacing the coating agent of the NP with another coating agent presenting higher affinity toward the NP surface. This process may be performed right after the synthesis of the NPs. Kluenker and co-workers conducted a study for the thiol exchange process on AuNPs coated with oleylamine [99]. The ligand exchange process was followed by solution NMR. When oleylamine was replaced by 1-octadecanethiol, the tests showed that the procedure corresponded to an equilibrium reaction. This study reveals how complex the ligand exchange process is, and that efficient surface coverage depends on the repeated exchange reactions with large ligand excess, the size of NPs, and the size of the ligand. The authors found that a more effective ligand replacement is achieved after repeated functionalization reactions using high ligand concentration or by reducing NP size [99]. Moreover, the cellular uptake of AuNPs through ligand exchange has been reported recently; 12 different ligands (small thiolated molecules, thiolated Reprinted from the journal

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polymers, thiolated and non thiolated biomolecules) were tested, showing that cell uptake is influenced by the effect of the exchangeable ligand and thus the NPs can aggregate within the lipid bilayers. These results represent a step forward in our understanding of the cellular uptake and cell integrity once NPs are incorporated into the cell [100]. For biological applications, it is crucial to know the composition of the surface precisely. Locardi et  al. [101] prepared 1-dodecanethiol-coated AuNPs for a posterior ligand exchange using 11-mercaptoundecanoic acid. The latter authors achieved partial substitution of the hydrophobic coating for a more hydrophilic one, thus improving the water stability of the NPs for further biological applications. The layer composition of the NPs obtained by these researchers was determined by differential thermal analysis/thermogravimetry (DTA/TGA) coupled with gas chromatography and mass spectrometry (GC–MS) [101]. AgNPs coated with polyvinylpyrrolidone (PVP) were prepared by Sang Cho and co-workers [102]. Afterward, the capping agent was replaced using propanethiol. These authors obtained NPs with very low aggregation tendency and high thermal stability. The final purpose was to incorporate more stable AgNPs inside perovskites for solar cell applications [102]. The effect of ligand exchange on the crystallite size of AgNPs coated with oleic acid was further evaluated by Okada [103]. In this latter work, three ligands were tested: tri-n-octyl phosphine oxide (TOPO), octanoic acid (OA), and 1-dodecanethiol (DDT). The highest increase in crystallite size of AgNPs was observed for TOPO as the exchangeable ligand [103]. Likewise, to modify the surface, IONP ligand exchange may also be carried out. A new and precise synthetic route to obtain magnetite NPs (­Fe3O4 NPs) functionalized with polymeric ligands through ligand exchange has been reported recently [104]; this produced NPs with different surface charges, allowing evaluating their interaction with cells.

5 Conjugation of Biomolecules to NPs: the Main Key to Further Applications The application of NPs requires the stabilization of colloidal systems in a polar medium, especially water, and the subsequent conjugation of biomolecules. Several biomolecules, such as proteins [105], polypeptides [106] and antibodies [107] have been conjugated to the surface of nanomaterials. Conjugation allows to combine the biological functionality of the biomolecule with the chemical and mechanical stability of the support, it guarantees the increase in operational stability, facilitates the separation and purification of biomolecules and increases their reusability [108, 109]. However, conjugation also causes alteration of the conformation of the biomolecule, which may cause the loss of biological activity and the presence of fractions of immobilized macromolecules with a different number of junctions to the support [110, 111]. In the case of immobilized enzymes, despite the fact that conjugation methodologies are expensive, the possibility of recovering biocatalysts from the reaction medium and the development of continuous operations reduce the overall costs of the process [112].

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The crucial parameters to consider during the design of functional bioconjugates are (1) the dispersion of the colloidal system in an aqueous medium, (2) the stability of the association of the biomolecule with the support, and (3) the orientation and functionality of the conjugated biomolecule [113, 114]. The most commonly used strategies for bioconjugation include physical adsorption [115], covalent binding [116], inclusion inside polymeric matrices [117] and conjugation through supramolecular interactions based on molecular recognition [118] (Fig. 6). 5.1 Physical Adsorption Physical adsorption occurs through the interaction between the biomolecule and the nanometric support via multivalent interactions, including van der Waals forces, the formation of hydrogen bonds, hydrophobic interactions and electrostatic interactions, depending on the traits of the biomolecule and the coating of the NPs [119]. Bioconjugation through physical interactions is highly versatile, since it offers the possibility to separate the biomolecule from the NPs by changing the conditions of the medium, which has allowed the use of these methods in the design of composites for drug delivery and controlled release of drugs [120]. However, this strategy lacks control of the spatial orientation of the immobilized biomolecules, which may lead to the decrease or loss of their biological activity [121]. Due to the reversible

Fig. 6  Strategies of bionanoconjugation Reprinted from the journal

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character of the physical interactions, variations in pH [122], temperature [123] or polarity of the medium [124] may promote the desorption of the immobilized component. For electrostatic adsorption, the conjugation of biomolecules to NPs relies on the attraction due to opposite charges in both species. The surface of NPs can be engineered to have a specific charge in order to promote the interaction with biomolecules. For example, the reversible immobilization of trypsin has been reported through the direct immobilization of the enzyme via the electrostatic interactions between the positively charged trypsin and the negatively charged citric acid coating ­Fe3O4 NPs [125]. The adsorption of proteins onto inorganic supports, such as noble metal and metal oxide NPs, and the influence of electrostatic interactions in the conjugation, have been described in several reports [126–128]. These interactions have proved to be particularly useful in the assembly of plasmid deoxyribonucleic acid (DNA) onto the surface of MNPs. Bioconjugation is promoted by the strong interaction between the negative charge associated with the phosphate backbone of most nucleic acids and the positively charged F ­ e3O4 NPs coated with a layer of silicon dioxide [129]. This effect may be achieved with other ligands possessing amino groups, such as (3-aminopropyl)triethoxysilane (APTES), chitosan and tris(hydroxymethyl)aminomethane (Tris) [130]. Despite the simplicity and efficiency of this strategy of conjugation, it is highly sensitive to the pH and the ionic strength of the medium [131]. On the other hand, hydrophobic interactions are commonly used to adsorb hydrophobic drugs onto nanometric supports. In this case, the surface of the NPs is modified with hydrophobic molecules to allow the absorption of the drugs, which are then triggered and released inside cells when the coatings of the NPs are degraded. Wu et  al. [132] described the synthesis of Janus nanoparticles comprised of Au nanorods and a polydivinylbenzene (PDVB) matrix, as a promising biomedical material for cancer treatment. The hydrophobic components of PDVB were used as carriers of curcumin for chemotherapy. This anticancer drug was loaded into the Janus nanoparticles due to strong hydrophobic interactions between curcumin and PDVB. The UV–Vis extinction of Janus NPs in the near infrared region also makes them an ideal candidate for photothermal therapy, guaranteeing significant decrease of cell viability, migration, and invasion as a result of combined chemo- and photothermal-effects [132]. 5.2 Supramolecular Conjugation Supramolecular conjugation is based on the molecular recognition between a ligand and a receptor, in which both the ligand and the receptor accommodate each other in a dynamic process based on chemical complementarity, without the actual formation of covalent bonds. When NPs are involved, the receptor is generally located at the surface of the NP, and immobilization occurs by means of a reaction via host–guest self-assembly [133]. Supramolecular interactions are also reversible, but possess the advantage of directing the orientation of biomolecules, which is the main advantage of the supramolecular strategy as compared to

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covalent immobilization or physical adsorption. Several reports demonstrate that the conformation of enzymes is not heavily harmed when supramolecular methodologies are used [134, 135]. Due to its importance, we highlight in this revision the supramolecular immobilization using the biotin-avidin interactions. Certainly, avidin is a glycoprotein having four identical subunits that have high specificity and affinity for biotin, resulting in a strong interaction (Kaff ~ 1015 [136]). Streptavidin, a non-glycosylated tetramer protein, is the most commonly used avidin analog for immobilization through supramolecular interactions [137]. Biotinylated proteins [138], oligonucleotides [139], antibodies [140], and single-stranded DNA [141] have been immobilized on AuNPs and nanohybrids functionalized with streptavidin to obtain biosensors (Fig. 7). This methodology has also been used to conjugate gold/iron oxide core–shell nanoparticles with both chloroperoxidase and glucose oxidase (GOx) through layer-by-layer assembly using the specific avidin–biotin interactions. The bienzymatic nanoreactor obtained combined the generation of H ­ 2O2 in situ from glucose and oxygen, with facile separation using a magnetic field. The latter had a positive impact on the reusability of the obtained system. The combination of both enzymes also enhanced considerably the operational stability of the bioconjugate [142]. Other molecules, such as the family of cyclodextrins, also behave as hosts, and therefore allow the supramolecular conjugation of NPs caped with cyclodextrins with adamantane-functionalized biomolecules via inclusion complexes [143]. Other molecules such as ferrocene have also been used as cyclodextrin guests for the functionalization of modified biomolecules [144]. Assembly of a thiolated cyclodextrin and a ferrocene derivative has also been reported. The NPs obtained were used for controlled drug delivery. The noncovalent complex formed between cyclodextrin and an amphiphilic ferrocene derivative allowed encapsulation of doxorubicin; the drug may be rapidly released at low pH [145].

Fig. 7  Schematic representation of the supramolecular interaction between biotinylated biomolecules with NPs capped with streptavidin or avidin Reprinted from the journal

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In addition, enzymes such as laccases have been immobilized in AuNPs by supramolecular interactions between the aromatic amino acids of the side chains of the enzyme and functionalized ferrocene molecules as a coating on the NPs. The results were compared with an analogous covalent coupling, demonstrating the advantages of supramolecular conjugations [146, 147]. Antibody–antigen interactions have also been used for bionanoconjugaion. In several cases, immobilization is beneficial to increase the nanoparticle-antibodyantigen association constant, relative to the free antibody [148, 149]. The immobilization of antibodies on nanomaterials has found several applications in diagnosis [150], biosensing [151], magnetic separation [152], purification of analytes [153] and cell labeling [154]. 5.3 Encapsulation Encapsulation on nanometric supports occurs when NPs coated with hydrophobic ligands are overcoated with amphiphilic ligands. The process at the surface of the NPs is achieved by intercalating the hydrophobic portions of ligands (or biomolecules) of the solution with the hydrophobic coatings of the NPs. Thus, the hydrophilic portion of the immobilized component (ligand or biomolecule) is oriented towards the solution. This methodology allows the stabilization of colloidal systems in hydrophilic media due to the head groups within the hydrophilic portion of the coating. In addition, the functional group may also allow further bioconjugation of the NPs, as previously reported [155]. This methodology allows the immobilization of drugs inside polymeric nanoparticles to develop controlled release agents and nanodelivery systems in cancer therapy [156]. Encapsulation of essential oils in poly(ɛ-caprolactone) nanocapsules has been reported to enhance the antimicrobial activity against food-borne pathogens. This is promising for food preservation [157]. Essential oils have also been encapsulated using several supports with different designs including NPs [158], nanocapsules [159], nanoemulsions [160], micelles [161], and liposomes [162]. In these cases, the formation of polymer-based and lipid-based nanosystems avoids the drawbacks of essential oils related to their volatility and low solubility, and also enhances antioxidant, anti-inflammatory and antibacterial activities of the encapsulated compounds. Nanoencapsulation has been also used to enable the production of “healthy” foods and drugs, through delivering specific substances such as vitamins [163], antibiotics [164], flavors [165], antioxidants [166], omega-3 fatty acids [167], proteins [168], and nucleic acids [169] in an easily absorbable nanometric form. The operational lifetime of enzymes for environmental applications may be enhanced through encapsulation. As an example, laccase encapsulated within chitosan NPs showed temperature and pH activity profiles similar to those of free enzyme, but the procedure of encapsulation ensured its stability against microbial degradation, allowing clear applications in industrial bioremediation [170]. Encapsulation has also extended the use of enzymes in conditions where these biocatalysts are neither stable nor active. For instance, GOx has been encapsulated within polymeric nanocapsules with a hydrophilic core via inverse miniemulsion periphery

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RAFT polymerization. The encapsulated enzyme showed high enzymatic activity and stability in a mixture of toluene/t-BuOH, in which the free enzyme undergoes denaturation [171]. 5.4 Chemical Conjugation Chemical bioconjugation allows the immobilization of biomolecules at the surfaces of nanoparticles by forming covalent bonds. This method guarantees stable anchoring between the support and the biomolecule. Several works report that supramolecular conjugation, encapsulation or adsorption, are simpler and more economical methods to immobilize enzymes onto NPs, but show long-term loss of activity since the enzyme-support binding is weak compared to covalent methods [172, 173]. Covalent immobilization ensures that the number of immobilized molecules remains constant after conjugation with a small probability of losing the biomolecule during operation of the nanobioconjugate. For conjugates obtained by covalent immobilization of enzymes, greater resistance to deactivation due to the effects of temperature, organic solvents or pH has been reported [174, 175]. Although the formation of covalent bonds can affect the active conformation of enzymes, several reports describe the covalent coupling of these biocatalysts onto metal oxide NPs as a method for ensuring the increase in the enzymatic activity and stability of the immobilized biomolecule [176, 177]. The coupling protocol is based on reactions involving amino (–NH2) [178], carboxyl (–COOH) [179], hydroxyl (–OH) [180], azide ­(N3−) [181] or thiols (–SH) [182]—functional groups present on the surface of the support as well as in the side chains of the biomolecule. Of the 20 amino acids, the ones used most often for the formation of covalent bonds with the support are those that present ionizable groups in their side chain of biomolecules, such as lysine [183], cysteine [184], tyrosine [185], histidine [186], arginine [187], and aspartic [188] and glutamic acids [189]. One of the most widely used protocols for the chemical immobilization is known as the Steglich reaction, or the carbodiimide method, which is based on peptide coupling between a carboxyl group and a primary amine [107, 190]. During the chemical reaction, the carboxylic acid is activated in the presence of a coupling agent such as 1-ethyl-3-(dimethylaminopropyl) carbodiimide (EDC), forming an activated ester. Frequently, additives such as N-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (NHS) are added to increase yields and decrease side reactions. Finally, the amine reacts with the activated ester to form an amide, with excellent yields (> 90%) (Scheme 1) [191]. The described methodology should be optimized carefully to avoid any irreversible damage to the biological function of the immobilized component. If the covalent immobilization is properly designed, the spatial disposition of the biomolecule can be controlled [192]. Alternatively, it is possible to use the high reactivity and selectivity of the isothiocyanate group towards primary amines to form thioureas [193]. This protocol has been used in biochemistry for the conjugation of antibodies [194], as well as in the labeling of nanoparticles coated with amino groups using fluorescent isothiocyanates for

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Scheme 1  Formation of an amide by covalent coupling with the 1-ethyl-3-(dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (Steglich) reaction

biomedical applications [195]. The reaction is practically quantitative, and it is possible to use dimethylsulphoxide (DMSO) or ethanol (EtOH) as solvents (Scheme 2) [196]. Another route commonly used in bionanoconjugation is the alkylated azide cycloaddition catalyzed by Cu (I), which is based on the concept of “click chemistry”. Cu(I)catalyzed azide/alkyne 1,3-dipolar cycloadditions, also known as “CuAAC’’, involve the cycloaddition of an alkyne and an azide to form a 1,2,3-triazole ring, which is a strong linker between the NP and the biofunctional agent (Scheme 3) [197]. Although bonds formed by click chemistry are electronically similar to amide bonds, triazols are highly stable whereas amide bonds, and also disulfide linkages formed by other direct conjugation strategies, are prone to cleavage by hydrolysis and reduction, respectively [198]. The reaction has demonstrated high versatility and suitability for the conjugation of several chemical compounds, from small molecules to proteins [199]. This methodology is characterized by specific conjugation, as azide and alkyne reactive groups are highly specific to each other and do not react with most other functional groups. “CuAAC’’ reactions are commonly used despite the fact that neither alkynes nor azides are present as functional groups in naturally occurring biomolecules. This guarantees highly oriented linkages, and control of the disposition of the immobilized biomolecule [200]. Click chemistry has been implemented with gold nanoparticles functionalized with a synthetic functional copolymer consisting of a backbone of polydimethylacrylamide (DMA) functionalized with an alkyne monomer. The polymeric coating guaranteed the stabilization and functionalization of the colloidal system, as well as the alkyne functionalities for the interaction with azido groups from modified anti-mouse IgG antibody. NPs functionalized with antibodies were applied to the development of gold labels for biosensing applications [201].

Scheme 2  Formation of thioureas by the reaction of the isothiocyanate group with a primary amine

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Scheme 3  Mechanism of formation a 1,2,3-triazole by a click chemistry reaction

Overall, it becomes clear that the conjugation of NPs with macromolecules is extensive. Several possibilities have been explored, including polymers, surfactants, organic ligands, biological ligands, amino acids, peptides, DNA strains, antibodies, aptamers, and proteins, with multiple inorganic NPs, aiming for a wide range of applications as depicted in Fig.  8. Among these multiple applications, we have selected those related to bioelectrochemistry to illustrate the use of the nanobioconjugation strategies described so far in practical cases.

6 Nanobioconjugates and their Electrochemical Applications In general, metal NPs have excellent conductivity and catalytic properties, which make them suitable for acting as “electronic wires” to enhance electron transfer between redox centers in proteins and electrode surfaces [202]. Electrodes modified with NPs show electrochemical responses that depend on the size of the NPs, the space between the particles and the particle density [203, 204]. Furthermore, the molecular components of NPs have a strong influence Reprinted from the journal

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Fig. 8  Surface functionalization of NPs with different biomolecules

on the electron transfer rate as a consequence of interfacial changes resulting in electron tunneling through NP–NP and NP–electrode junctions [204]. It is convenient to highlight that the electrochemical interpretation of bionanoconjugated systems is delicate, and results may be misinterpreted. Bartlett et al. [205] argue that the vast majority of articles reporting biosensors with direct electron transfer (DET) between native GOx and nanostructured electrodes are incorrect. This is due to the lack of a critical and deep analysis of experimental evidence. Bartlett and coauthors demonstrate their hypotheses by an exhaustive study of experimental results, and suggest evidence that should be fulfilled in order to support any serious claim of DET for GOx. Several architectures are reported in the literature to conjugate biomolecules with nanoparticles, such as a totally random distribution [206], a self-assembled monolayer (SAM) [147] or a layer-by-layer (LBL) assembly [174] (Fig. 9). The main methods summarized in the section  Conjugation of Biomolecules to NPs: the Main Key to Further Applications are also employed for the preparation of electrochemical biosensors, viz. adsorption [207], encapsulation [208], covalent binding [209], cross-linking [210] and supramolecular associations [211]. Herein, we will focus on major issues regarding bioconjugates of AuNPs, AgNPs and IONPs for bioelectrochemical applications.

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Fig. 9  Possible architectures obtained when the surface of the electrode is modified with biomolecules

6.1 Electrochemical Applications of Bioconjugates Based on AuNPs AuNPs are attractive scaffolds due to their compatibility with the immobilization of biomolecules while maintaining catalytic activity and providing a large specific surface area and good electrocatalytic properties [212, 213]. For instance, the use of AuNPs for the development of glucose biosensors has been exploited extensively due to good electrical communication between the transducer and the active redox site of the enzyme [214]. Rassas et al. [212] recently reported the development of a nanobiosensor for glucose detection capable of detecting concentrations of the order 5 µM and a dynamic range between 10 µM and 7 μM. Here, the presence of AuNPs improved the performance of biosensor based on a mixed polysaccharide/GOx composite. This biosensor established improvements such as avoiding loss of selectivity, high sensitivity (283.9 µA/log[glucose]), allowing the application to real biological samples such as saliva and serum [212]. Zou et al. [215] developed an electrochemical immunosensor for enzyme-free detection of E.coli K12 by employing as nanocomposite AuNPs attached to the polypyrrole (PPy)-RGO) surface through electrostatic adsorption. This serves as

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a platform for the immobilization of a capture antibody, which was conjugated onto a composite made of ferrocene and doped polypyrrole-AuNPs. The fabricated immunosensor showed a linear range from 1.0 × 101 to 1.0 × 107  colony forming unit (CFU) ­mL−1 and a low detection limit of 10 CFU mL−1. Hoo et  al. [216] recently reported the construction of an electrochemical glucose biosensor based on a nanocomposite of zinc oxide nanorods (ZnONRs) and AuNps. In another example, AuNPs were then drop-casted on ZnONR/ITO substrates, while the GOx enzyme was immobilized with a matrix of Nafion onto the modified electrode. The results suggest direct electron transfer from GOx enzymes to the modified electrode. Moreover, the use of AuNPs can provide an additional pathway that facilitates electron transfer. The optimized conditions for this bioelectrode were Nafion/60 µL GOx/80 µL 30 nm AuNP/ZnONR/ITO, exhibiting high sensitivity of 14.53 and 2.54 µA ­mM−1 ­cm−2 for a wide working range of 0.05–1.0 and 1.0–20 mM and a low limit of detection (LOD) of 0.18 mM [216]. Buk and co-workers [217] reported a nanohybrid system based on carbon quantum dots (CQDs) and AuNPs for the design of enzymatic electrochemical biosensors using the CQDs/AuNPs as an immobilization matrix for a large surface area microfabricated gold electrode. As a proof of concept, the GOx enzyme was chosen as a model system, and immobilized onto the microfabricated gold electrode surface. GOx was conjugated a CQDs/AuNPs nanohybrid by cross-linking with glutaraldehyde. The biosensor exhibited high electrocatalytic activity, a good sensitivity of 47.24 µA ­mM−1 ­cm−2, reproducibility (5.4% relative standard deviation, RSD, n = 5) and selectivity toward glucose, even in the presence of possible interfering species. In continuation with the previous work, Buk et al. [218] developed an electrochemical biosensor from the system CDQs/AuNPs and gold microdisk array electrodes. The biosensor presented an improved analytical performance and a sensitivity of 626.06 mA mM−1 ­cm−2 with a linear range from 0.16 mM to 4.32 mM. AuNPs coated with horseradish peroxidase (HRP) have been used to obtain an electrochemical aptasensor for the detection of kanamycin, based on streptavidin–biotin supramolecular interactions (see Fig. 7). After a biotinylated aptamer of kanamycin interacts with its complementary oligonucleotide strand modifying the electrode, NPs coated with HRP and streptavidin are added to probe the formation of the double-stranded DNA. Methylene blue is intercalated in the helical structure obtained as electron mediator [219]. Another attractive application of AuNPs is their compatibility to conjugate antigenic carbohydrates [220]. Zhang et  al. [221] described the design of a thioninebridged multiwalled carbon nanotube (MWCNT)/AuNP composite to detect a glycan on living cancer cells using enzyme catalysis. In such work, thionine allowed negatively charged AuNPs to bind to the MWCNT surface. This biosensing platform was used to quantify the amount of mannose at the surface of the cells, which corresponded to 3.39 × ­1010 molecules per human liver cancer cells, and 1.84 × 1­ 010 molecules for prostate cancer cells. Compared to other reported methods, this biosensor provided a useful protocol for the glycan assay, facilitating early medical diagnosis. In this regard, the field of biosensors has achieved remarkable advances in the detection of cancer biomarkers [222]. Recently, Nguyen et  al. [223] demonstrated a simple microfluidic device for the capture of A549 human lung adenocarcinoma

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cells using a specific aptamer and the SAM of AuNPs. Lima et  al. [224] have recently prepared the first electrochemical immunosensor to detect dehydroepiandrosterone sulfate (DHEAS) by electrochemical impedance spectroscopy (EIS), in order to provide an alternative method for the early diagnosis of pediatric adrenocortical carcinoma (pACC). The fabrication of this immunosensor consisted in the modification of an oxidized glassy carbon electrode (GCE) with arginine-functionalized AuNPs (AuNPs-ARG) and anti-DHEA IgM antibodies (ox-GCE/AuNPs-ARG/ IgM). The AuNP-based immunosensor showed good sensitivity, accuracy, stability, selectivity, and feasibility to detect DHEAS with a linear range from 10.0 to 110.0 µg ­dL−1, with a LOD of 7.4 µg ­dL−1. 6.2 Electrochemical Applications of Bioconjugates Based on AgNPs AgNPs are also important nanomaterials in electroanalysis due to their physicochemical properties. Many efforts have been made to improve the analytical methods that allow quantification of different biomarkers, metabolites and infectious agents based on AgNPs or nanocomposites [225]. Abbaspour and co-workers described a highly selective sandwich immunosensor based on a dual-aptamer for the detection of Staphylococcus aureus [226]. In this latter study, the authors first immobilized a biotinylated anti-S. aureus aptamer on streptavidin-coated magnetic beads via biotin-streptavidin affinity reaction (see section Iron oxide NPs and Fig. 7). Subsequently, the AgNPs conjugated with antiS. aureus aptamer (Apt-AgNP) were incorporated, thus completing the sandwich design. Here, the AgNPs were assembled to the aptamer through their thiol groups (see section Gold and silver nanoparticles and Fig. 5). The biosensor presented high sensitivity and an extended dynamic range from 10 to 1 × ­106 CFU/mL with a low detection limit of 1.0  CFU/mL (S/N = 3). AgNPs are also useful for the detection of pharmaceutical drugs. In this regard, AgNPs play an important role as electrode modifiers due to their ability to increase the conductivity in the biosensor [225]. Ashrafi et  al. [227] developed a novel, unique and sensitive biosensor to determine benzodiazepines, i.e., alprazolam, chlordiazepoxide, diazepam, oxazepam, and clonazepam. To prepare the biosensor, the authors synthesized a nano-ink based on AgNPs plus N-doped graphene quantum dots (Ag/N-GQD) and then electrodeposited it at the surface of a gold electrode modified with chitosan (CS), using LBL strategy. The obtained CS-Ag/N-GQD film combined the advantages of CS, and Ag/N-GQD with excellent electrical conductivity, biocompatibility and abundant active sites for the electro-oxidation of the species of interest within standard and plasma samples. Another fine example has been reported by Roushani and Shahdost-fard [228]. These authors developed a selective electrochemical aptasensor for the ultrasensitive detection of cocaine. The aptasensor was constructed by the covalent immobilization of aptamer-functionalized AgNPs as biorecognition element, on top of a nanocomposite made of MWCNTs, an ionic liquid (IL) and CS (MWCNTs/IL/ CS). Riboflavin was used as the redox probe in the electrochemical aptasensor for the diagnosis of the target. The biosensor showed high sensitivity, specificity, and

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selectivity with a detection limit of 0.15 nM. Likewise, Aftab et al. [229] recently published a sensitive voltammetric nanosensor for the detection of Rilpivirine (RIL) based on amine group functionalized MWCNT, CQDs and AgNPs (CQDs/NH2fMWCNT/AgNPs). The nanosensor allowed detection of RIL in biological samples with LOD of 1.79 × 10−10 M, 4.47 × 10−10 M in serum sample and 5.26 × 10−10 M, 8.23 × 10−10 M. There is a significant interest in the early detection of different types of cancer. Meng et al. [230] developed an electrochemical biosensor for the sensitive analysis of prostate-specific antigen (PSA) based on a specific peptide as a molecular recognition element. The peptide was immobilized onto a gold electrode surface. In the absence of PSA, GO is immobilized on the peptide-modified electrode. In turn, it allows the silver ions to be absorbed onto GO through electrostatic interactions. GO acts as a reducing and dispersing agent, facilitating the formation of AgNPs, which contributes to better electronic transport and hence to the analytical signal. In the presence of PSA, the peptide is specifically recognized and cleaved at the surface of the electrode. The biosensor displayed high sensitivity, selectivity and a linear range from 5 to 2 × 104 pg/mL, with a LOD of 0.33 pg/mL. Elhakim et al. [231] designed a novel sensitive electrochemical sensor for microribonucleic acid (microRNA) detection in normal serum samples, hepatocellular carcinoma patients and human liver cancer cells. The biosensor constructed consisted in a carbon paste (CP) decorated with AgNPs and extracted propolis (bee glue). The porous structure of propolis allowed the AgNPs to be adsorbed, increasing the surface area of the sensor, facilitating the charge transfer process. The microRNA was also immobilized on the surface of the electrode through trapping with propoleos. The biosensor presented high selectivity and sensitivity, and a very low detection limit of ­10−3 femtomolar. Chen and co-authors reported the fabrication of inexpensive and flexible electronic and electrochemical sensors for a wide range of biochemical and biomedical applications [232]. The electrochemical biosensor was fabricated by a simple method involving wax patterning on plastic, hand painting of AgNPs to lay down a conducting layer, and simple drop casting of carbon nanotubes (CNT) to improve the electrochemical performance of the sensor. The nanosensor was applied for the amperometric detection of carcinoembryonic antigen (CEA) by monitoring an electroactive product released from a magnetic-bead based immunoassay. The limit of detection for CEA found to be 0.46 ng/mL, which is 10 times lower than the clinical cutoff value. The results of this work show that the improvement in electrochemical performance can be achieved by simple drop casting of CNT onto working AgNP electrodes. 6.3 Electrochemical Applications of Bioconjugates Based on IONPs MNPs are also used widely in the development of biosensors. In this sense, magnetic IONPs have been studied intensively due to their strong magnetic properties, electrocatalytic activity, biocompatibility with biomolecules, inexpensive synthesis and low toxicity [108, 130]. For example, electrocatalytic processes on the electrode

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surfaces can be switched by means of functionalized IONPs in the presence of an external magnet [233]. In addition, the F ­ e3O4 NPs possesses peroxidase-like activity that could catalyze the electrochemical oxidation–reduction of ­H2O2, similar to HRP [234]. It is worth noting that both the oxidation reaction and the reduction of ­H2O2, depending on the applied potential, can be used as a transduction reaction in a biosensor [235]. Tian et  al. [236] have designed an ultrasensitive electrochemical cytosensor to detect MCF-7 CTCs—a tumor marker in human breast carcinoma. The electrochemical cytosensor was developed based on magnetic field-induced, targeted separation, and enrichment, and RGO/molybdenum disulfide (RGO/MoS2) composites and ­Fe3O4 NPs with a synergistic effect on the catalysis of H ­ 2O2. The proposed cytosensor exhibited a linear range from 15 to 45 cells ­mL−1 with a lower detection limit of 6 cells ­mL−1 for MCF-7 detection. Pakapongpan and Poo-arporn [211] describe a novel strategy for obtaining an enzyme biosensor based on direct electrochemistry. In this case, nanomaterials such as RGO and ­Fe3O4 NPs were used to increase the specific area of the electrode, to create a favorable environment to immobilize the enzyme GOx and to facilitate electron transfer between the enzyme and the surface of the electrode. Initially, the authors obtained the RGO-Fe3O4 nanocomposite by means of covalent bonding through the coupling agent, EDC, and NHS (see Scheme  1), while for immobilization of the enzyme they used electrostatic interactions since GOx is negatively charged at pH 7 and on the surface of the F ­ e3O4 NPs there is a positive environment of amino groups. Recently, ­Fe3O4/graphene composites have attracted great interest in the manufacture of biosensors. Teymourian et al. [237] established a novel label-free nanocomposite, using an indicator-free strategy of electrochemical DNA sensor based on ­Fe3O4 NPs/RGO ­(Fe3O4/RGO) nanocomposite. In the functioning of the sensor, ­Fe3O4/RGO nanocomposite was used as a substrate to immobilize probe DNA and hybridization with the target sequence to form dsDNA, which achieved a better analytical signal through measuring changes in the differential pulse voltammetric (DPV) peak current of the underlying Fe(II)/Fe(III) redox system. ­ e3O4, Tufa et al. [238] described an electrochemical immunosensor using GQD, F and AgNPs for the detection of Mycobacterium tuberculosis. In this device, the synergic effect of three nanomaterials is used to achieve better electrochemical performance. A core–shell ­Fe3O4@Ag/GQDs nanotriplex was synthesised for immobilization of Ab1, and by means of the Ab2-AuNPs conjugate as the label for detection of the culture filtrate protein (CFP-10). ­Fe3O4 NPs were used to improve mass transport and increase the surface to volume ratio, while AgNPs enhanced electrical conductivity, helping prevent ­Fe3O4 NPs from aggregating and helping GQD load more of the anti-CFP-10 antibody onto the electrode. The immunosensor showed a wide linear range (0.005–500 μg/mL) with a limit of detection (signal/noise  =  3) reaching 0.33 ng/mL, resulting in a reliable and robust performance with high selectivity toward CFP-10. An electrochemical biosensor based on ­Fe3O4 NPs–PVA nanocomposite for glucose detection has also been reported by Sanaeifar et al. [207]. The polyvinyl alcohol-Fe3O4 nanocomposite acted as a modifier of the surface of an Sn electrode and Reprinted from the journal

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allowed GOx to be immobilized via physical adsorption. Also, F ­ e3O4 NPs dispersed in the PVA matrix promoted electron transfer between the enzyme and electrode. The GOx/PVA-Fe3O4/Sn bioelectrode detected glucose in the range from 5 × 10−3 to 30 mM with a sensitivity of 9.36 μA ­mM−1, and exhibited a lower detection limit of 8 μM at a signal-to-noise ratio of 3. Shamsipur et  al. [239] described a sandwich-type immunoassay for the detection of human epidermal growth factor receptor 2 (HER2)—a key prognostic tumor marker allowing diagnosis of breast cancer at early stages. The electrochemical immunosensor employed the synergistic effect of a nanomagnetic platform and a bioconjugate for the determination of HER2. ­Fe3O4 nanoparticles were synthesized by a simple chemical co-precipitation method. The magnetite nanoparticles coated with 3-aminopropyltrimethoxysilane and conjugated to the antibody were then immobilized on a GCE. The biosensor showed a linear relationship between the DPV stripping signal of silver and the logarithm of HER2 concentrations was obtained in the range of 5.0 × 10−4–50.0 ng/mL (R2 = 0.9906) with a detection limit of 2.0 × 10−5 ng/mL. Kumar et  al. [240] presented an easy method for the fabrication of an electrochemical paper biosensor to detect CEA biomarker using ­Fe3O4 NPs decorated poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). Whatman filter paper (WP) was chosen for preparation of the paper electrode. The incorporation of F ­ e3O4 NPs into PEDOT:PSS/WP improved electrochemical performance and signal stability. The nanostructured paper-based electrode was used to immobilize anti-CEA monoclonal antibodies. The proposed immunoelectrode exhibited efficient linear detection range (4–25 ng/mL), high sensitivity (10.2 µA ­ng−1 mL cm−2) and long shelf life (34 days). Chikhaliwala et  al. [241] constructed an electrochemical immunoassay for the simultaneous determination of alpha-fetoprotein (AFP) and glypican-3 (GPC-3), both constitute important biomarkers for early detection of hepatocellular carcinoma (HCC). The GCE was modified through drop-casting with F ­ e3O4 NPs decorated ­ e3O4 NPs facilitated with hyperbranched amino functionalized dendrimers. The F magnetic separation of analytes as well as enhanced the electroanalytical effect in synergy with a large surface area of dendrimers. This sensor exhibited a linear range from 0.02 to 10  ng/mL for both biomarkers, and a low detection limit of 50 and 70 pg/mL, respectively.

7 Conclusions This review is dedicated to gold, silver, and iron oxide nanoparticles, their main physical and chemical characteristics, synthetic routes, and surface modification with ligands and biomolecules aimed at electrochemical applications. We have provided an overview of the multiple designs and architectures, along with experimental procedures to obtain functional bioconjugates and their use for electrochemical applications. A generalized view of the contents of this review shows that no one bionanoconjugation strategy is better than others. Indeed, selection of the methodology to

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follow depends strongly on the proposed application, but the outcome results are difficult to predict a priori. However, some general guidelines may be followed. For certain applications, the orientation of the biomolecule on a support is not essential; when purifying a biomolecule over a (nanostructured) inorganic support, electrostatic interactions may be used for retention of the biomolecule, which may be further liberated after a change of pH or ionic strength. Conversely, antigen–antibody and enzyme-based systems often require that the biomolecule be orientated optimally so as not to block their recognition sites. Regarding the chemical modifications used to obtain nanobioconjugates, current methods are effective but the range of experimental conditions in which they works appropriately are essentially narrow, i.e., temperature, incubation and reaction times, reagents, pH and ionic strength are some of the factors to consider very carefully. It is also worth highlighting that, although nanoparticles modified with biomolecules have demonstrated high efficiency in diverse fields, many of the current systems exist only at the laboratory scale. With an eye on future developments in this field, we foresee scaling-up to gram-scale production as the next challenge in order to widen the use of nanobioconjugates in point-of-care diagnostic devices, thus increasing their impact in everyday life. Undeniably, this is a dynamic research field that will continue to grow exponentially in the near future.

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Topics in Current Chemistry (2020) 378:35 https://doi.org/10.1007/s41061-020-0296-6 REVIEW

Quantum Dot Bioconjugates for Diagnostic Applications María Díaz‑González1 · Alfredo de la Escosura‑Muñiz1 · Maria Teresa Fernandez‑Argüelles2 · Francisco Javier García Alonso3 · Jose Manuel Costa‑Fernandez2  Received: 30 December 2019 / Accepted: 29 February 2020 / Published online: 26 March 2020 © Springer Nature Switzerland AG 2020

Abstract Quantum dots (QDs) are a special type of engineered nanomaterials with outstanding optoelectronic properties that make them as a very promising alternative to conventional luminescent dyes in biomedical applications, including biomolecule (BM) targeting, luminescence imaging and drug delivery. A key parameter to ensure successful biomedical applications of QDs is the appropriate surface modification, i.e. the surface of the nanomaterials should be modified with the appropriate functional groups to ensure stability in aqueous solutions and it should be conjugated with recognition elements capable of ensuring an efficient tagging of the BMs of interest. In this review we summarize the most relevant strategies used for surface modification of QDs and for their conjugation to BMs in preparation of their application in nanoplatforms for luminescent BM sensing and imaging-guided targeting. The applications of conjugations of photoluminescent QDs with different BMs in both in vitro and in vivo chemical sensing, immunoassays or luminescence imaging are reviewed. Recent progress in the application of functionalized QDs in ultrasensitive detection in bioanalysis, diagnostics and imaging strategies are reported. Finally, some key future research goals in the progress of bioconjugation of QDs for diagnosis are identified, including novel synthetic approaches, the need for exhaustive characterization of bioconjugates and the design of signal amplification schemes. Keywords  Biosensing · Diagnostics · Luminescence · Nanoparticles · Quantum dots · Surface functionalization

Chapter 5 was originally published as Díaz‑González, M., Escosura‑Muñiz, A. de la, Fernandez‑Argüelles, M. T., Alonso, F. J. G. & Costa‑Fernandez, J. M. Topics in Current Chemistry (2020) 378: 35. https://doi.org/10.1007/s41061-020-0296-6. * Jose Manuel Costa‑Fernandez [email protected] Extended author information available on the last page of the article Reprinted from the journal

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1 Introduction Nanotechnology encompasses the fabrication, characterization, manipulation and application of materials that have at least one dimension within the range 1–100  nm. When the size of the material is below this threshold, the material behaves differently from the same material with macroscopic dimensions due to the quantum confinement of the electrons when the dimensions are smaller than the Bohr radius, giving rise to unique and extraordinary physicochemical properties [1]. Nanomaterials can be classified according to different criteria, with the most frequent criterion based on the dimensions of the nanomaterial. Three-dimensional (3-D) nanomaterials are those with three dimensions larger than the nanometer scale, but which are composed of individual building blocks that are within the nanometer scale range, such as nanocomposites. Two-dimensional (2-D) nanomaterials are those that present one dimension in the nanometer scale and include, for example, thin films or nanocoatings. One-dimensional (1-D) nanomaterials possess two dimensions within the range of 1–100  nm and only one dimension larger than the nanometer scale; these nanomaterials include, among others, nanotubes, nanorods and nanowires. Finally, zero-dimensional (0-D) nanomaterials are those with three dimensions within the range 1–100 nm, including nanoparticles (NPs) such as metal NPs, semiconductor quantum dots (QDs), and carbon-based QDs (CQDs) [2]. The development of novel nanomaterials has gained increasing interest in recent decades due to their fascinating physicochemical properties, which have a a great potential for application in different research areas and industries, such as (bio)analytical chemistry [3, 4], water treatment systems [5], catalysis, electrocatalysis [6–9], cancer treatment [10], energy storage devices [11], among others. Although little information is currently available on the production of QDs, it was possible to estimate worldwide and Europe-wide production and use of ten different nanomaterials, including QDs, from a 2012 survey sent to companies producing and using engineered nanomaterials, with the results indicating that the estimated production of QDs was about 10 t/year or lower [12]. Inorganic semiconductor nanocrystals, or QDs, have demonstrated a range of unique optoelectronic properties and represent novel, attractive options in many biomedical applications [13–16]. For example, QDs have been widely employed for fluorescence sensing and bioimaging due to their exceptional photoluminescent characteristics, including the capability to tune the emission wavelength just by controlling the size of the NP. Although conventional organic fluorescent molecules are widely used in bioimaging applications, QDs are superior luminescence tags in terms of their photophysical properties, namely, QDs have broad excitation spectra and narrow and sharp emission spectra and large Stokes shifts (> 100  nm). Such optoelectronic properties are of great value in multiplexed applications [17, 18] as by using a single light source it is possible to simultaneously excite multiple QDs of different sizes (multiple emission peaks). Additionally, QDs have very high molar adsorption coefficients, as well as higher

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quantum yields than organic fluorophores. Consequently, fluorescent NPs are nearly 20-fold brighter and many thousand-fold more stable against photobleaching than conventional organic dyes [19, 20]. Such exceptional optical behavior justifies the rapid emergence of QDs as valuable photoluminescent probes in many analytical applications. In particular, the use of NPs for diagnostic purposes is increasing exponentially due to their highly valuable optoelectronic properties and small size. Additionally, recent advances in such areas as surface modification and functionalization have given rise to the improved colloidal stability of NPs in complex media and biological buffers and biocompatibility, while allowing the NPs to bond to recognition elements [21]. In this context, especially relevant are the developments in the synthesis of NPs with interesting optical properties that overcome the limitations of traditional organic dyes, including the synthesis of gold NPs (AuNPs), semiconductor QDs, gold nanoclusters, silver nanoclusters, rare-earth-based NPs, carbon dots and dyeloaded NPs [22]. However, despite the exceptional properties demonstrated by QDs developed to date, their applications in clinical analysis, especially during the first decades of development, can still be considered to be somehow limited, in part due to their low targeting efficiency and eventual high toxicity, both of which could hinder their application in in vivo imaging. These limitations underlie the many research efforts to develop QDs exhibiting low biological toxicity (e.g. those based on an A ­ g2S core) [23]. Additionally, in the absence of any molecular moiety being attached to the NP surface, QDs generally show nonselective distribution acros different organisms, thus failing to satisfy the minimum requirements for appropriate molecular imaging. Clearly, the development of QD-based nanoprobes requires a previous surface functionalization of the NPs to facilitate the various approaches used in targeting-guided imaging techniques. In addition, to ensure the required biocompatibility of the nanoprobes to be used in in vivo imaging or sensing, an appropriate surface functionalization of the NPs is required. The aim of this review is to highlight advances in the use of QDs in diagnostic applications. In the following sections, we first introduce and briefly describe the main types of QDs used in bioanalysis. This is followed by a section that focuses on the strategies of solubilization and stabilization of QDs in aqueous solutions under physiological conditions and then by a section in which approaches used for the functionalization of QDs with biological molecules are summarized. The functionalization of QDs is a key aspect of their use and a requirement before they can be employed for the detection of analytes in biological matrices. Thereafter, we describe some of the most relevant applications of QD bioconjugates in the optical imaging of biomarkers, including a review of the in  vitro applications of QDs in medicine in which different detection schemes based on the bioconjugation of QDs to antibodies, aptamers, peptides or other types of recognition elements. In this context, we provide an overview of recent advances in the development of lowcost, portable and easy-to-use QD-based biosensing devices for clinical applications (point-of-care). The final section discusses future prospects with the intention to indicate the direction that research on the use of QDs in diagnostic applications is heading. Reprinted from the journal

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2 QDs: Nature and Types Despite the many problems encountered in the initial attempts to synthesize colloidal fluorescent semiconductor NPs, such as lack of reproducibility and reduced optical quality, important advances have been achieved in this field. In pioneer studies on the routine preparation of colloidal QDs, the core of the QDs was usually capped with an organic layer that coordinates with core-metal sites and stabilizes the QD surface, thereby preventing an irreversible flocculation (aggregation) of the nanocrystals [24]. Unfortunately, these protective ligands are also hydrophobic, and thus nanocrystals capped with such coatings are not compatible with bioanalytical assay conditions. Consequently, the QD surface should be further modified by attaching the appropriate hydrophilic functional groups to allow dispersion of the QDs in aqueous solutions while maintaining their high photoluminescence quantum yield. Although fluorescence emission is the most exploited property of QDs, doping the core of the nanocrystals with transition elements has been a strategy adopted to provide the QDs with new improved multimodal characteristics for biomedical applications. Additionally, during recent years, many research groups have tried to overcome the problem of eventual cytotoxicity of the more conventional heavymetal based QDs. Approaches based on carbon-based nanomaterials are one of the most promising strategies. In this section, we briefly review the nature and characteristics of QDs typically used in clinical and biomedical applications. 2.1 Semiconductor QDs Quantum dots are spherical semiconductor photoluminescent NPs with a diameter ranging between 2 and 10 nm. Since the dimensions of the NP are smaller than the Bohr radius, the energy levels are quantized. As a consequence, the optoelectronic properties of QDs depend on their size due to quantum confinement effects and differ from the properties observed for the same bulk material [25]. In fact, due to the quantized energy levels, QDs generate an intense emission of photoluminescence: when the semiconductor QD is irradiated with a light source, the absorption causes an electron to move from the lower energy valence band to a higher energy conduction band, following which an electron–hole pair is generated, and its recombination gives rise to the emission of intense photoluminescence. Other optical features that make QDs very appealing for use in analytical applications include broad absorption spectra, narrow and symmetric emission bands that can be tuned by changing the composition and size of the NP (see Fig. 1), large Stoke shifts and high photostability [26, 27]. The energy band gap decreases with increases in QD diameter, and as a result the emission wavelength shifts to longer wavelengths. Hence, for QDs with the same composition, the emission can be tuned by just modifying the size of the NP (referred to as size-dependent emission). In addition, the QD can be synthesized with different semiconductors, such as CdS, CdSe, CdTe, ZnS, ZnSe,

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PbS, InP, among others, all of which also affect their spectral properties. Such features of QDs are very attractive because emission in a wide range of spectra, from the ultraviolet (UV) up to the near-infrared (NIR), can be obtained by simpley changing the composition and size of the QD. Additionally, all QDs generate broad absorption bands, meaning that a single excitation source can be used to efficiently excite QDs with different emission wavelengths, a characteristic which, in addition to their high luminescent quantum yields and long photostability (e.g.: CdS/ZnS QDs are nearly 20-fold brighter and 100-fold more stable than the widely used Rhodamine 6G [19]), is of great interest in multianalyte detection [16, 29]. The synthesis of semiconductor QDs can be performed in both organic hydrophobic solvent and aqueous media, although the synthetic routes that generate QDs with the best optoelectronic properties are those carried out in nonpolar solvents and using hydrophobic ligands. As a result, while the QDs obtained through these routes present outstanding photoluminescent properties, they tend to aggregate and precipitate in aqueous solutions. This renders it necessary to modify their surface with molecules that present hydrophilic groups oriented towards the medium, a configuration which bestows the QDs with good colloidal stability in aqueous media. The most common strategies to transfer QDs from hydrophobic organic media to aqueous solution are summarized in section Stabilization Strategies for QDs in Aqueous Media. Reprinted from the journal

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2.2 Metal‑Doped QDs In recent years, advances made in the rational design of nanomaterials have contributed to the development of hybrid NPs that combine the interesting size- and shape-dependent properties of semiconductor QDs with a long-lived phosphorescence-type emission. In this context, the incorporation of suitable atoms or ions into host lattices has generated a novel type of QDs that are very promising for use in bioanalytical applications [30]. ZnS, ZnO, ZnSe, CdS and CdSe QDs can be used as host lattices into which other transition-metal and lanthanide ions, including ­Mn2+, ­Cu2+, ­Co2+, ­Ni2+, ­Ag+, ­Pb2+, ­Cr3+, ­Eu3+, ­Tb3+, ­Sm3+ and ­Er3+, are incorporated as dopant agents, giving rise to luminescent QDs with novel properties [31]. Consequently, host lattices such as as ZnS and ZnO are being widely studied because, first, they do not contain toxic metals and thus potentially have a lower toxicity and, second, they are characterized by a larger energy band gap, which allows the incorporation of more doping agents, which is very attractive in terms of developing dual-doped QDs [32, 33]. The introduction of the dopant typically increases the photoluminescence lifetime of the QD (see Fig. 2), producing a phosphorescence-like emission that overcomes the limitations of fluorescent NPs or dyes due to the removal of the fluorescence background commonly found in biosensing and bioimaging applications [14]. Most of the synthetic routes described to incorporate the doping agent into the host structure are based on wet chemistry procedures carried out in organic media, typically under high temperatures, or in aqueous media, through precipitation or microemulsion methods in order to control the size and shape of the nanocrystal as well as obtain a homogeneous distribution of the dopant in the host matrix.

Fig. 2  a Excitation and emission spectra of colloidal Mn:ZnS QDs (solid line) and of colloidal ZnS QDs (broken line), b decay curve of luminescence emission of colloidal Mn:ZnS QDs with a first lifetime component in the range of 0.3 ms and a second longer lifetime component of around 2.1 ms Reprinted from [34], copyright 2012, with permission from Elsevier

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2.3 Carbon‑Based QDs (C‑dots) Inorganic semiconductor QDs have been intensely evaluated as luminescent nanomaterials for bioanalytical applications, but carbon-based NPs, such as CQDs and graphene QDs (GQDs), have also drawn attention as attractive alternatives due to their high photoluminescence quantum yields, low photobleaching effects, high biocompatibility and low toxicity, while avoiding the use of heavy metals commonly found in semiconductor QDs [35]. Additionally, carbon-based NPs possess an exceptional colloidal stability in aqueous media as a consequence of their small size, since Brownian motion provides sufficient energy to inhibit aggregation between them [36, 37]. The most remarkable property of CQDs is most likely their excitation wavelength-dependent fluorescence emission (see Fig.  3), which makes them excellent alternative NPs for optical imaging applications [38]. The principle of such characteristic emission is not fully understood, and the origin of the fluorescence emission of CQDs remains a topic of heated discussion. In this context, CQDs obtained through different synthetic routes or using different precursors present different optical behaviors, suggesting that CQDs are quite complex. In fact, the scientific community has yet to agree on an explanation of the optical properties of CQDs, which have been variously attributed to surface state emission, intrinsic band emission, triple ground state emission, dipole emission involving electron–phonon coupling, transition from surface electrons to valence holes, selftrapped excitons and even to the presence of small organic molecules [39, 40]. The synthesis of CQDs has typically employed graphite as the carbon source, and a surface passivation of the CQDs is frequently necessary in order to obtain better fluorescence properties. However, green methods for the synthesis of CQDs based on the use of natural precursors are gaining in importance, as in addition to these synthesis methods being cost effective and environmentally friendly, the CQDs obtained do not require any surface modification, present high photoluminescence and have excellent stability in aqueous media [41].

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The potential of CQDs for use in diagnostic applications has increased recently with the metal doping of NPs with N and lanthanides (e.g. Gd and Yb), resulting in co-doped nanomaterials exhibiting not only strong fluorescence but also high constrast capabilities in magnetic resonance imaging (MRI) and computed tomography (CT) [42]. This simple approach has enabled the design of multimodal QDs for bioimaging applications. However, studies on the surface modification of these co-doped NPs with appropriate recognition biomolecules (BMs) for targeted bioimaging are still needed.

3 Stabilization Strategies for QDs in Aqueous Media As mentioned in a previous section, conventional high-quality fluorescent QDs are commonly synthesized in organic solvents at high temperature. However, the QDs must be made water-compatible (stable in aqueous and biological media so that they maintain their optoelectronic properties) if the intenstion is to use them in bioanalytical applications. To this end, surface modification of the QDs after synthesis is a must; as well, QDs should have functional groups available on their surface for further bioconjugation to BMs. The appropriate QD surface passivation also can solve some of the problems typically affecting these NPs. First, crystalline NPs can easily form surface defects that quench the fluorescence properties of naked QDs [43]. Second, naked QDs can suffer from surface oxidation, photochemical degradation and/or the leaching of metal ions from the NP core after exposure to ionic or biological media, which affects their optoelectronic properties and produces undesirable cytotoxicity [44]. Thus, modification of the QD surface with the appropriate ligands is essential not only to stabilize the NPs in physiological media (particularly important if they are going to be used in clinical applications) but also to reduce nanocrystal surface defects, thereby minimizing QD reactivity and toxicity. Moreover, despite the significant progress achieved in the synthesis of QDs, biological uses of QDs require that such NPs be modified into biocompatible probes. In this context, the availability of robust and versatile NP surface chemistries are invaluable strategies to achieve stabilization of the QDs in biological buffers while preserving their original photophysical properties and providing adequate reactive groups for further bioconjugations. The three main strategies employed for hydrophilization of QDs (based on the attachment of polar functional groups to the surface of the QD) are summarized in Fig. 4. As shown in Fig. 4, a universal and simple approach is based on ligand exchange of the original hydrophobic coating of the QDs (e.g. trioctylphosphine oxide [TOPO] chains). In this method, the original coating is removed and replaced with bifunctional molecules that often bind to the QD surface (e.g. through a thiol end) and which have a hydrophilic functional group on the other end (such as carboxyl or sulfonic acids) that provides the required NP solubility in aqueous and polar media and is also available for further bioconjugation [19]. Bidentate ligands, such as dithiothreitol (DTT) or dihydrolipoic acid (DHLA), as well as oligomeric phosphines, peptides and crosslinked dendrons are widely used to obtain QDs that are stable in an aqueous environment [45].

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Fig. 4  The three QD phase-transfer approaches commonly used for aqueous stabilization of bare nanoparticles (NPs): the ligand or cap exchange process; bonding of amphiphilic polymers and phospholipids to hydrophobic groups on the surface of the QDs; and surface silanization of the core NP. Reprinted from Karakoti et al. [46], copyright 2015, with permission from Elsevier

Another method commonly used to achieve QD stability in an aqueous environment is based on the well-known silica chemistry used for inorganic encapsulation of the hydrophilic structures (e.g. surface silanization) of the QDs through the generation of a silica shell around the NP surface [46]. This is a very attractive approach to achieve water stabilization of QDs as the silica surface is non-toxic, chemically inert and optically transparent. In this method, typically a precursor molecule, such as mercaptopropyltrimethoxysilane (MPTMOS), is added to the QDs (which replaces the hydrophobic surface chains of the QD). The thiol groups of the MPTMOS react with the inorganic surface of the QD, and the methoxysilane groups polymerize through the formation of siloxane bonds, thus generating a highly crosslinked protective shell around the QD. An additional advantage of this approach is that silica exhibits a high degree of biocompatibility, and it is a simple process to functionalize its surface with appropriate (bio)analyte recognition BMs. Consequently, QDs encapsulated in a silica layer are highly suitable for further bioanalytical applications [47]. The third common approach to achieve water stabilization of QDs is to transfer the nonpolar QDs into an aqueous media combined with the use of amphiphilic polymers. Here, the hydrophobic shell of QDs (e.g. TOP [trioctylphosphine]/ TOPO) interacts with the hydrophobic alkyl chains of the amphiphilic polymeric structures through hydrophobic or electronic interactions. The hydrophilic groups of the amphiphilic polymer used will then remain oriented to the external part of the QD surface, thereby providing the required water stability [48]. A large number of amphiphilic copolymers are available for use in this approach, such as polymaleic anhydride [49]) and polyelectrolytes (poly-acrylamide [50], or biopolymers such as DNA [51]). Application of a polyethylene glycol (PEG)-based coating to QDs is another alternative often used to provide stability and biocompatibility to the NPs, Reprinted from the journal

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although QDs coated with PEG spacers have reduced nonspecific protein binding, which may often limit the applicability of these NPs in bioanalytical methodologies. For such uses, PEG molecules should be previously activated with appropriate functional groups (e.g. amine, thiols or carboxyls) to provide hydrophilic bridges between the QD surface and the PEG chains [52]. A variant of this third stabilization approach consists of the encapsulation of the hydrophobic QDs in appropriate hydrophilic vehicles, such as liposomes [53]. The hollow spherical structure of liposomes and the high loading capacity makes them attractive carriers for hydrophobic QDs. Moreover, the surface of liposomes can be easily modified with the appropriate functional groups so as to allow a simple further bioconjugation with proteins, thereby minimizing nonspecific interactions of water-soluble and water-insoluble QDs with surface material and amplifying the analytical signal due to the possibility to incorporate several QDs in a single nanoliposome. In this context, a signal amplification platform based on the measurement of fluorescence from QDs encapsulated in liposomes has been recently proposed for the highly sensitive detection of human telomerase activity [54]. In the approach described, similar to a typical hybridization bioassay, biotinylated liposomes containing the QDs were recognized by a capture probe conjugated with streptavidin. In a final step, the QD-encapsulated liposomes were disrupted by the controlled addition of Triton X-100, and the fluorescence intensity of the released QDs was measured to detect telomerase activity [54]. Liposomes containing hydrophobic QDs have also been employed for tumor imaging applications through the specific recognition of aptamers conjugated to the surface of the liposomes (see Fig. 5) [55]. However, a significant drawback of liposomes is their low stability when entering in  vivo media. Additionally, QDs stabilized by this approach have a substantially increased hydrodynamic diameter, which could limit their application in bioimaging and targeting procedures. It must also be taken into account that the procedure selected for hydrophilization of the QDs likely affects their suitability in subsequent bioconjugation and future bioanalytical applications. For example, some approaches can significantly increase the hydrodynamic ratios of the NPs, which in turn can lead to non-specific binding or reduced accessibility to some targets. In this context, ligand exchange provides QDs with a small hydrodynamic diameter but also with lower photoluminescence quantum yields, while encapsulation results in larger nanoprobes sizes with higher quantum yields [56].

4 QD Bioconjugation Strategies One of the main challenge to the use of QDs in biomedical applications can be considered to be the generation of robust bonding between the appropriate target recognition molecule and the surface of the NP, as this bonding will be a key parameter affecting the direct application of the QDs in biological media. In this section, we summarize some of the most relevant physicochemical processes used to attach BMs to the QD surface, a process referred to as bioconjugation.

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Fig. 5  a Schematic illustration of the synthesis of aptamer-conjugated liposomes containing QDs and an aptamer (Apt-QLs) against the epidermal growth factor receptor. b Liposomes containing QDs were visualized by transmission electron microscopy. c Fluorescence emission was verified (excitation wavelength [λex]  550  nm, emission wavelength [λem]  620  nm). d Dynamic light scattering revealed generation of 165-nm-diameter liposomes. Reprinted from Kim et al. [55]

All NPs have a very high surface-to-volume ratio; consequently, the role of the NP surface is of paramount importance [57]. The properties of the NP surface are determined not only by their own chemical nature, but also by the layer of capping molecules, referred to as ligands because they bind to the QD surface metals in a similar way as ligands do to the central atom in the metal complexes. Thus, ligands “stop particles aggregating, resist nonspecific adsorption of surrounding molecules, and provide a conjugation point for functional biomolecules” [58]. The synthetic method utilized to prepare QDs determines not only the size, shape and chemical nature of the QDs, but also the ligands that cap their surface. In fact, these ligands are chosen mainly because they have to control the size, shape and polydispersity of the QDs during the synthesis and to maintain their homogeneous dispersion in the solvent post synthesis. Ligand exchange reactions extend the versatility of QD material.

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The main elements of the bioconjugation process requiring attention have been described in a comprehensive article written by Sapsford et al. [56] and comprise: (1) Control over the BM/QD ratio. The desirable ratio varies with the type of the application. It should be noted that QDs are usually larger than BMs, with the possible exception of some large proteins. It should also be noted that the reactions are interfacial in nature and that such interfaces inherently polydisperse across a population of QDs (2) Control over the orientation of the BM on the QD. Optimal activity of both the QD and the BM should be maintained. (3) Control over the separation between QD and BM. This point is crucial if the platform QD–BM is to be used in a Förster resonance energy transfer (FRET) experiment [59] (4) Control over the strength of the QD–BM bond. Most clinical or in vivo experiments require permanent and, therefore, strong linkage. Many different approaches can be used to immobilize BMs onto the QD surface, with the simplest method to link a BM to a QD surface being adsorption. However, in adsorption, the attachment of a BM is rather tenuous and maintained by weak interactions only, such as hydrogen bonding, London dispersion and Coulombic forces and lone-pair electrons [60]. As an example, the proteins present in the human body tend to bind nonspecifically onto the surface of QDs, a process which is to be avoided. A closely related approach is based on pure electrostatic interactions between the BM and the QD [61]. However, while this method of functionalization is generally straightforward and fast, electrostatic interaction, similar to simple adsorption, suffers from serious disadvantages, including instability, lack of orientation control on the BM and on the BM/QD ratio [62, 63]. Therefore, the most common routes to achieve bioconjugation consist of the four shown in Fig. 6 [56]. 4.1 Direct Union of BMs BMs can be joined to a semiconductor QD surface through the direct covalent union of the BMs to the surface of the QD semiconductor (route 1 in Fig. 6). Thus, proteins, peptides and nucleic acids can be bonded to the QD surface metal atoms (especially Zn) through their (cysteine) thiol and (histidine) imidazole groups [56]. Thiol and histidine motifs could eventually be added to the “natural” BMs and, occasionally, thiol groups are created, reducing peripheral S–S bonds. Occasionally, BMs are bonded directly to the QD in the synthesis processes (biological templating) [56]. 4.2 BMs Bonded to a Ligand A more general method to join BMs to a QD surface is to bind covalently the BM to a ligand that has been previously attached to the QD surface (route 2 in Fig. 6). It should be pointed out that GQDs usually contain carboxyl, hydroxyl, carbonyl and epoxide external groups [64] and that carbon-based QDs (CQDs) can be synthesized

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Topics in Current Chemistry (2020) 378:35 Native ligands L

BM BM

L 4

bioconjugated QD

native QD

3 L

1

L

The four main routes to bioconjugugation

BM 1: 2: 3: 4:

2 L

BM

direct union BM bonded to a ligand L BM bonded to an encapsulating shell BM bonded through Biotin/Sreptavidin

Fig. 6  The four main routes to join a biomolecule (BM) to a semiconductor QD surface. (1) Through a direct covalent bond, (2) through a covalent bond between the BM and a ligand (L) that was previously anchored onto the QD surface, (3) covalent binding of the BM to a terminal functional group integrated in an encapsulating shell; (4) taking advantage of the specific union biotin/streptavidin

to have selectively carboxylic, amine or other groups in their surface [65]. On the contrary, native semiconductor QDs, with some exceptions being those prepared in water [66, 67], do not have the appropriate ligands able to be robustly bonded to a BM. However, this is not a problem because, as seen in the preceding section, the original ligands can be replaced by others. The new ligands could be monodentate or bidentate simple molecules, such as 3-mercaptopropionic acid (MPA) or dihydrolipoic acid (DHLA), respectively [68], that are attachable to the QD surface through the thiol group(s) and which possess a free terminal carboxylic group to join the BM. However, the new ligands are usually complex molecules with an anchoring group(s) (e.g. polythiol), a spacer chain (frequently a hydrophilic segment) and a terminal functional group (carboxylic or amine groups among others) [69]. Very often, the spacer chain is PEG, that is the whole ligand is a bifunctional PEG molecule [67] because PEG is biocompatible and highly soluble in water and stabilizes QDs against aggregation. 4.3 BMs Bonded to an Encapsulating Shell The native ligand exchange method is associated with a number of problems, such as a relatively weaker bond between the thiol group and the metal of the QD surface, reduced photoluminescent quantum yield, among others [61, 63]. An alternative is the encapsulation of the QDs (route 3 in Fig. 6), either with a layer of amorphous silica or with a copolymer. The formation of a silica outer sphere (silanization) increases the solubility and stability of the QDs and retains most of the emission properties [63]. A variety of silanization processes have been described [63, 67, 70, 71]. In general, all are laborious and require several steps [63], including bonding of the silica layer onto the QD surface through an anchoring group. The most commonly used anchoring groups are Reprinted from the journal

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thiol or amino groups (A in Fig. 7a). The silica layer which also possess functional groups at the periphery, such as thiol and amino, among others (F in Fig. 7a). The encapsulation of a semiconductor QD with an amphiphilic copolymer is possible due to the ability of the latter’s long hydrophobic tails to interact and interdigitate with the pristine QD ligands (such as TOP, TOPO, hexadecylamine, stearic acid, etc.) [67], thereby leaving the hydrophilic and functionalized segments in contact with the water molecules of the solvent [61, 63, 70]. Although the copolymers of maleic anhydride or acrylic acid are the most popular [61, 63, 70, 72, 73], there are many others (e.g. phospholipid–PEG copolymers, which possess a terminal functional group [74]) (see Fig. 7b). Some authors consider the envelopment of several QDs inside a polyethylenimine coat [75] or inside the bilayer of a liposome [76, 77], as specific cases of QD encapsulation. Although these examples are not strictly comparable to those described in Fig.  7, in which every QD is singularly encapsulated, there is certainly some similarity. 4.4 BMs Bonded Through Biotin/Streptavidin Another method used very frequently to join BMs to the QD surface is based on the strong interaction between biotin and avidin, with a dissociation constant of ­10−15 M [78]. Avidin, a protein found in egg white, contains four identical subunits, each with a single biotin-binding site. Biotin is vitamin H. In this method (route 4 in Fig. 6), it is considered advantageous to substitute avidin with deglycosylated avidin derivatives, such as streptavidin or neutravidin [56, 62]. There are a variety of biotin

(a)

(b)

SILICA SHELL

COPOLYMER ENCAPSULATION COOH

COOH

Phospholipides F-PEG

QUANTUM DOT

Si O Si O O A Si O Si O O Si O Si

F

COOH

QUANTUM DOT

F

COOH

COOH PAA and PMA copolymers

F F

native ligands

Fig. 7  Encapsulation of a semiconductor QD with silica shell (a) or with copolymers (b). The silica layer binds to the QD surface through an anchoring group (A) and possesses functional groups (F) at the periphery. The copolymers most frequently used for encapsulation are polymaleic anhydride (PMA)- or poly(acrylic acid) (PAA)-based copolymers, but end-functionalized polyethylene glycol (F-PEG) phospholipids are also used

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derivatives that make the biotinylation of QDs and BMs a rather straightforward process [56, 62]. QDs and BMs may be also functionalized with avidin, although it should be noted that the attachment of avidin to the QD during initial modification will probably obscure one or more available biotin binding sites [56]; at a later moment, however, avidin-functionalized QDs could be attached to biotinylated BMs. Conversely, biotin-functionalized QDs can be used to join avidin-functionalized BMs. Even biotin-labeled QDs can be coupled to biotin-labeled BMs through an intermediary avidin linker [56, 61] although unexpected results may be obtained since the avidin can bind up to four biotin moieties [56, 61]. There are many more types of specific non-covalent affinity between pairs of molecules other than avidin/biotin interactions that are useful in bioconjugation; these include histidine–nickel nitrilotriacetic acid interaction, barnase–barstar interaction and antibody–ligand interaction [62]. 4.5 Covalent Coupling Strategies

O O

P

O

O

O C

1

8

H 7

CO OH

The focus in this section is on covalent bonding between ligands anchored onto the QD surface (directly or attached to an encapsulating shell) and the incoming BMs. In this regard, we consider biotin and avidin (or straptividin or neutravidin) to be BMs. The number of functional groups useful for bioconjugation reactions is rather limited in natural BMs [56] (see Fig. 8). Carboxylic and amino groups are present in peptides and proteins not only as terminal groups but also as side groups in peptides such as aspartic or glutamic acids or lysine, respectively. Less common in peptides and proteins are the thiol, phenol and imidazole groups that can be found in the amino acids cysteine, tyrosine and histidine, respectively. Other functional groups

Naturally ocurring biomolecules

6 HO

5

NH

2

3

SH

CARBOHYDRATES 6.- Alcohol 7.- Aldehyde

4

N

OH

N H

2

AMINOACIDS 1.- Carboxylic (Glutamic, Aspartic) 2.- Amino (Lysine) 3.- Thiol (Cysteine) 4.- Phenol (Tyrosine) 5.- Imidazole (Hystidine)

NUCLEOTIDES 8.- Phosphate

Fig. 8  The most important functional groups found in naturally occurring BMs. 1–5 Functional groups present in amino acids: carboxylic, amino, thiol, phenol, imidazole. 6, 7 Functional groups from carbohydrates and derivatives: alcohol and aldehyde. 8 Functional group derived from nucleotides: phosphate Reprinted from the journal

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that are available in even less common amino acids, such as tryptophan, will not be considered in this review. Carbohydrates and their derivatives provide alcohol and aldehyde as reactive groups, the latter are obtained by oxidation of the former. Nucleic acids possess sugars, phosphates and some bases (the bases are not included in Fig. 8 because they are not usually modified). Although the number of available functional groups in BMs for bioconjugation reactions would appear to be low, the number of possible reactions by which BMs can be joined covalently to the ligands attached to the QDs described in the literature and used in the commercial sources is rather numerous [56, 62, 63, 71, 76, 79–81]. However, only a small portion of these seem to have been actually used when QDs were involved [62, 63, 82]. One of the most well-studied and easy-to-perform bioconjugation reactions is between a terminal carboxylic acid and a peripheral amine group, conducted under mild conditions, to yield an amide group, with the help of EDC (1-ethyl-3-(3dimethylaminopropyl) carbodiimide hydrochloride) and sulfo-NHS (N-Hydroxysulfosuccinimide sodium salt). Despite all the disadvantages that this method presents, it is still widely used [62, 63, 82]. An alternative is to use carbonyldiimidazol (CDI) instead of the EDC/sulfo-NHS pair [63, 83]. Other common routes are the reaction of amines with carbonyl groups to yield imine groups, which are usually subsequently reduced with sodium cyanoborohydride [62, 63], and the Michael addition of a terminal thiol to a maleimido group [63, 80]. Another popular coupling method is the utilization of heterobifunctional molecules, such as sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo–SMCC). The NHS ester end of sulfo-SMCC can react with primary amine groups, and the other terminal maleimido function can add a thiol [62, 63]. Similar crosslinker molecules are described in the literature [56, 62, 80]. 4.6 Bioorhogonality The traditional coupling methods described in this review thus far have a number of limitations, among which the most important is undesirable side reactions [56]. The solution to this and other problems is bioorthogonal chemistry. Bioorthogonal chemical reactions involve only the target functions (in QDs and BMs) and do not affect the other functional groups present in either the affected QD and BM or in the biological environment [84, 85]. Although numerous biorthogonal chemical reactions are described in the literature [84–86], only some of these seem to have been carried out when QDs are involved (see those described in Fig.  9). The latter include the copper-catalyzed alkyne-azide cycloaddition (click chemistry); the cycloaddition between tetrazine and strained double bonds (tetrazine ligation); and hydrazone formation by reacting hydrazine and carbonyl groups (hydrazine ligation). It should be noted that not one of the functional groups shown in Fig.  8, i.e those present in “natural” BMs, is involved in these bioorthogonal reactions. This is, of course, the most important advantage of bioorthogonal chemical reactions: the reactions, as described in Fig. 9, do not affect normal molecules present in the biological milieu. Some effort would

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Topics in Current Chemistry (2020) 378:35 "CLICK" CHEMISTRY Cu+

N

N3

N N

Alkyne + Azide (Cu+)

TETRAZINE LIGATION N N N N Norbornene

+

Tetrazine

HYDRAZONE LIGATION O

O

N

N H

O

NH2

Hydrazine

N +

N H

N

Carbonyl

Fig. 9  The main bio-orthogonal reactions carried out utilizing QDs. Top: copper-catalyzed alkyne-azide cycloaddition. Middle: cycloaddition between tetrazine and strained double bonds. Bottom: hydrazone formation by reacting hydrazine and carbonyl groups

need to be made to design procedures for attaching these “new” functional groups to the natural BMs, however no difficulties are foreseeable to bind these to the QDs. In this regard, it has been determined that virtually any functional group can be sitespecifically introduced into peptides and nucleotides as needed during the initial synthesis or through subsequent modification [56].

5 QD Biosensing Applications: Point‑of‑Care Diagnostics Quantum dot–BM hybrids (i.e. those bound to antibodies, DNA, aptamers, etc.) have been used as sensing probes in a wide variety of in vitro bioassays and biosensors for the detection of different clinical relevant BMs. QDs can be used as labels in a wide spectrum of detection methods (Fig. 10). Most of the reported QD-based bioassays and biosensors have been developed by using QDs as fluorescence labels (Fig.  10a) in fluorescence quenching-based (turn-off), fluorescence enhancementbased (turn-on) and—especially—FRET assays [87–92]. FRET is a very sensitive technology for studying BM interactions that involves the transfer of energy from Reprinted from the journal

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Fig. 10  Detection methods for QD-based biosensing. a Fluorescence. Jablonski diagram explaining the effect of fluorescence (left), and a photograph and emission spectra illustrating size-controlled fluorescence of QDs. Adapted from Wen et  al. [87], with permission. b Förster resonance energy transfer (FRET): Jablonski diagram explaining the effect of FRET (left) and schematic illustration of a FRETbased sandwich bioassay (right). c Electrochemiluminescence (ECL): schematic illustration explaining anodic ECL. A hole is created by the electrode in the valence band of QDs with the concomitant injection of an electron from a previously oxidized coreactant (C). The recombination of electron and hole lead to an anodic ECL emission. d Photoelectrochemical (PEC) reaction: schematic illustration explaining anodic PEC reaction. An electron–hole pair is created on QDs after their photoexcitation. The electron transferred from the valence band to the conduction band of the photoexcited QDs is then ejected to the electrode with the concomitant transfer of electrons from an electron donor (C), generating an anodic photocurrent. e Electrochemical (EC) reaction: schematic illustration explaining the electrochemical detection of QDs by anodic stripping voltammetry. After the dissolution of QDs, metallic species are deposited (reduced) on the electrode and re-oxidized again to be detected Adapted from from Wen et al. [87], copyright 2017, with permission

an excited state donor (usually a fluorophore) to a proximal ( 100-fold when NIR QDs emitting at 1320  nm (NIR-II region) were employed as contrast agents rather than QDs emitting at 850 nm (NIR-I region), with reduced autofluorescence and a superior tissue penetration observed at the longer wavelengths. Thus, more recently there have been some efforts to try to develop QDs that emit in the NIR-II window, based on NP cores of different metallic elements, such as PbSe, PbS or hybrid CdHgTe. More recently, NIR-II QDs have also been synthesized that avoid the use of toxic elements: a mirage of reports propose ­Ag2S QDs as NIR-II emitting agents [154].

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To date, there have been only a few reports on successful specific targeting employing ­Ag2S QDs [23]. In all such reportes, ­Ag2S NPs were surface functionalized with appropriate recognition elements for in vivo imaging following different bioconjugation approaches. In a very recent study, A ­ g2S NPs were surface functionalized with plerixafor, a small molecule drug used for the inhibition of CXC chemokine receptor 4 (CXCR4). The bioconjugate was used for in  vivo imaging of metastatic breast cancer cells based on the selective linkage of the functionalized ­Ag2S NPs to highly metastatic breast cancer cells (4T1 tumor model) via their CXCR4 receptor [155]. Moreover, the use of the surface-decorated ­Ag2S NPs together with their photothermal properties resulted in a unique and tumor-specific theranostic element. 6.3 Multimodal Imaging There is currently an increasing interest among researchers on the development of new nanomaterials for multimodal imaging applications in biology and medicine. In this context, multimodal fluorescent-magnetic based nanomaterials deserve particular attention as they can be used both as diagnostic and drug delivery tools, which could facilitate the diagnosis and treatment of many diseases. The frequently investigated QD-based hybrid-NPs with multiple capabilities are probably the magnetic-QDs. As an example, differently sized infrared-emitting QDs have been incorporated, together with variable amounts of Fe-based magnetic NPs, into poly(styrene/acrylamide) copolymer nanospheres for the preparation of fluorescent-magnetic nanocomposites [156]. The dual-encoded nanobioprobes developed as such exhibited different luminescent behavior (due to the different sizes of the NPs) and magnetic susceptibility. They were proven to be capable of simultaneously recognizing and separating multiple biocomponents from complex samples when three kinds of lectins were used as the targets. Multimodal imaging can integrate structural/functional information from several imaging modalities, thus promising more accurate diagnosis than any single imaging modality. One important advantageous feature of liposome encapsulation is the possibility to co-immobilize several NPs exhibiting different properties to develop multimodal imaging platforms. In a very recent article, Xu et al. reported the integration of a theranostic liposome (QSC-Lip) with superparamagnetic iron oxide NPs (SPIONs) and QDs and cilengitide (CGT) into one platform, with the aim to target glioma in magnetic targeting (MT) for guiding the surgical resection of glioma [157]. In vivo dual-imaging studies show that QSC-Lip not only produces an obvious negative-contrast enhancement effect on glioma by MRI but also makes tumor emitting fluorescence under MT. Among the different techniques widely used for molecular imaging, MRI is currently one of the main in  vivo imaging techniques used routinely in diagnosis, while fluorescence imaging is nowadays most widely used for in vitro studies; thus these two imaging techniques are complementary. Clearly, there is much research interest directed towards preparing fluorescent imaging/MRI imaging dual‐modality nanoprobes to be used in many diagnostic and biomedical applications, such Reprinted from the journal

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as cell labeling, enzyme activity measurements, tumor diagnosis and therapy and anatomical localization and real‐time assessment during surgery [158]. Nanostructures based on fluorescent QDs can be synthesized to provide magnetic properties to the nanomaterial, thereby creating opportunities for multi-modality biomedical imaging. Fluorescent QDs exhibiting magnetic susceptibility can be synthesized following four different methodologies: metal doping, covalent conjugation, isocrystal growth and co-encapsulation or electrostatic assembly. In particular, a large number of fluorescent imaging/MRI dual-modality imaging nanoprobes combine G ­ d3+ or 2+ ­Mn ions with QDs. As an example, a dual contrast nanoreagent was developed by doping Gd ions into ­CuInS2/ZnS QDs (Fig. 18) [159]. The resulting NPs exhibited NIR fluorescence emission and MRI contrast capabilities with a high longitudinal relaxivity (r1), which was 2.5-fold higher than that of clinically approved Gd agents. In addition, the in vivo imaging experiments showed that the Gd-doped NPs could enhance both NIR fluorescence and T1-weighted MRI of tumor tissue through passive targeting accumulation.

7 Conclusions and Perspectives In general, photoluminescent QD probes are widespread and used in countless biomedical applications. For biosensing, a great potential of QD-conjugates also lies in multiplexing as well as in vitro and in vivo fluorescent imaging. There has been major progress in the development of in  vivo drug delivery systems, and interest remains high in this area. It is important to note that all of these applications are possible because of the advances in QD stabilization in biological media by appropriate surface functionalization and their bioconjugation to suitable BMs.

Fig. 18  Fabrication procedure and functional description of the Gd-doped QDs with dual-mode imaging capabilities. Reprinted from Yang et al. [159], copyright 2017, with permission from the American Chemical Society

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All of the recent advances in bioconjugation chemistry has made it possible to attach almost any BM of interest to the surface of a QD. However, work is till needed to further enhance the development and applications of QD bioconjugates. In this context, we have identified the following issues. The orientation of the BMs is a key issue that still needs to be addressed. Many often random orientations are sufficient when the QDs are used in conventional hybridization applications. However, controlled orientations may be needed for the assembly of functionalized 3D structures. The functionalization of QDs with different BMs (e.g. antibodies, peptides, nucleic acids or aptamers) offer a wide range of opportunities for applying the nanoassemblies in clinical diagnosis, including ultrasensitive detection of disease biomarkers, in  vivo targeted imaging or drug delivery applications. The multiplexing capabilities of these QDs open new avenues for the use of differently sized QDs for the simultaneous detection of multiple biomarkers (a key aspect in efficient clinical diagnosis). Moreover, encapsulation of multiple QDs in highvolume nanocarriers (e.g. nanosomes or PLGA NPs) may enable the construction of a panel of multifunctional systems for targeted drug delivery and molecular imaging. The development of new multimodal imaging nanoprobes is a focus of many researchers. The use of NPs as imaging probes offers several advantages over conventional molecular-scale contrast agents; these include high loading capacity, where the concentration of the imaging agents can be controlled within each NP during the synthesis process; tunable surface that can potentially extend the circulation time of the contrast agents in the blood or target them to specific locations in the body; or provision of multimodal imaging capacities because NPs can combine two or more contrast properties, which can be used in multiple imaging techniques simultaneously [160]. Recent advances in nanotechnology has enabled the development of multifunctional QDs by doping the nanocrystals with appropriate metals, thus integrating two or more imaging contrast agents and thereby enabling their detection by different imaging techniques [42]. One of the major challenges when developing novel bioassay methods for clinical applications is the requirement for high sensitivity in the detection because of the ultralow concentrations of the biomarkers to be detected. Here, the use of QDs as tags in immunoassays could be a powerful approach to achieve the desired ultrasensitivity. As an example, ultrahigh sensitivity for BMs could be easily achieved through metal deposition on the surface of the NP tags acting as catalytic seeds, thus effectively amplifying the size of the metallic NPs after the immunoassay [161]. Obviously, QDs cannot be safely used as tags for in  vivo applications until the problem of their toxicity is solved. Despite very extensive studies of toxicity of QDs in different cellular and animal models, the in vivo toxicological effect of QDs remains controversial [37]. The possible release of toxic heavy metals from the core of the QDs as a result of intensive UV illumination has to be taken into account [44]. The preparation of heavy metal-free QDs is being addressed as a promising avenue to overcome such toxicity problems. Additionally, it must be considered that an ideal solubilization strategy should reduce QD toxicity and undesirable nonspecific QD uptake by living tissues, thus reducing cytotoxic effects. Reprinted from the journal

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Paper-based microfluidic systems have been revealed as the most suitable platform for POC analysis, with the use of QDs as labels becoming increasingly popular in the development of this type of systems. Although fluorescence QD-based POC systems using hand-held readers or even smartphone-based detectors have been successfully reported, they suffer from an important limitation related to the need for bulky and complex detectors for quantification. However, it is expected that the use of alternative detection methods (e.g. electrochemical) and the rapid development of portable devices and mobile phone technology will allow the miniaturization of the detection systems for POC devices in the near future. Miniaturized signal-recording devices also require a merging of QD barcode technology and POC testing. In the sensing field, there is also a great expectation for recently developed GQDs and CQDs. To summarize, even though there is still a long road to go before bioconjugated QDs are considered to be routine in in vitro and especially in vivo diagnosis, overall we firmly believe that the rapid development of new bioconjugated nanomaterials will move bioconjugated QDs forward to real-life diagnostic applications in modern biology and medicine. Acknowledgements Financial support from the FC-GRUPIN-ID/2018/000166 project (Asturias Regional Government, Spain) and the CTQ2017–86994-R and CTQ2016–79412-P projects (MINECO, Spain) is gratefully acknowledged. A. de la Escosura-Muñiz acknowledges the MICINN (Spain) for the “Ramón y Cajal” Research Fellow (RyC-2016-20299).

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Affiliations María Díaz‑González1 · Alfredo de la Escosura‑Muñiz1 · Maria Teresa Fernandez‑Argüelles2 · Francisco Javier García Alonso3 · Jose Manuel Costa‑Fernandez2  1

NanoBioAnalysis Group, Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, 33006 Oviedo, Spain

2

GEAB Research Group, Department of Physical and Analytical Chemistry, University of Oviedo, Avda. Julián Clavería 8, 33006 Oviedo, Spain

3

NanoBioAnalysis Group, Department of Organic and Inorganic Chemistry, University of Oviedo, Avda. Julián Clavería, 8, 33006 Oviedo, Spain



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Topics in Current Chemistry (2020) 378:15 https://doi.org/10.1007/s41061-019-0278-8 REVIEW

Carbon Nanotubes in Biomedicine Viviana Negri1   · Jesús Pacheco‑Torres2   · Daniel Calle3   · Pilar López‑Larrubia4  Received: 18 October 2019 / Accepted: 31 December 2019 / Published online: 14 January 2020 © Springer Nature Switzerland AG 2020

Abstract Nowadays, biomaterials have become a crucial element in numerous biomedical, preclinical, and clinical applications. The use of nanoparticles entails a great potential in these fields mainly because of the high ratio of surface atoms that modify the physicochemical properties and increases the chemical reactivity. Among them, carbon nanotubes (CNTs) have emerged as a powerful tool to improve biomedical approaches in the management of numerous diseases. CNTs have an excellent ability to penetrate cell membranes, and the sp2 hybridization of all carbons enables their functionalization with almost every biomolecule or compound, allowing them to target cells and deliver drugs under the appropriate environmental stimuli. Besides, in the new promising field of artificial biomaterial generation, nanotubes are studied as the load in nanocomposite materials, improving their mechanical and electrical properties, or even for direct use as scaffolds in body tissue manufacturing. Nevertheless, despite their beneficial contributions, some major concerns need to be solved to boost the clinical development of CNTs, including poor solubility in water, low biodegradability and dispersivity, and toxicity problems associated with CNTs’ interaction with biomolecules in tissues and organs, including the possible effects in the proteome and genome. This review performs a wide literature analysis to present the main and latest advances in the optimal design and characterization of carbon nanotubes with biomedical applications, and their capacities in different areas of preclinical research. Keywords  Carbon nanotubes · Biomedical research · Preclinical applications · Cancer · Neurodegeneration · Imaging · Theranostic compounds · Tissue engineering

Chapter 6 was originally published as Negri, V., Pacheco‑Torres, J., Calle, D. & López‑Larrubia, P. Topics in Current Chemistry (2020) 378: 15. https://doi.org/10.1007/s41061-019-0278-8. * Pilar López‑Larrubia [email protected] Extended author information available on the last page of the article Reprinted from the journal

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Abbreviations AFM Atomic force microscopy AGP Angiopep-2 BBB Blood–brain barrier BLI Bioluminescence imaging BRB Berberine CA(s) Contrast agent(s) CNT(s) Carbon nanotube(s) DMF Dimethylformamide DNA Deoxyribonucleic acid DOX Doxorubicin EM Electron microscopy FTIR Fourier-transformed infrared spectroscopy Gd Gadolinium GNTs Gado-nanotubes HA Hyaluronic acid MRI Magnetic resonance imaging MWCNT(s) Multi-walled carbon nanotube(s) NGF Nerve growth factor NIR Near-infrared radiation NP(s) Nanoparticle(s) PEG Polyethylene glycol PET Positron emission tomography PLK1 Polo-like kinase 1 PTT Photothermal therapy RNA Ribonucleic acid SC Stem cells SDBS Sodium dodecyl benzene sulfonate SEM Scanning electron microscopy siRNA Small interfering ribonucleic acid SPECT Single-photon emission computed tomography STM Scanning tunneling microscopy SWCNT(s) Single-walled carbon nanotube(s) TEM Transmission electron microscopy XPS X-ray photoelectron spectroscopy

1 Introduction Nanotechnology is the understanding, design, and development of new materials with interesting characteristics at the nanometric scale where the effects of quantum mechanics are noticeable. These nanomaterials have at least one dimension between 1 and 100  nm, and adapt the shape of nanoparticles, nanotubes, or nanosurfaces. On the other side, nanobiotechnology refers to the intersection of nanotechnology and biology, combining the efficacy of biological materials and the rules and tools of basic sciences like physics and chemistry. It is also defined as the science that

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investigates, beyond the molecular level, the design and development of highly ordered structured materials that offer specific responses when exposed to stimuli. The development of these nanomaterials has reached a wide use in numerous scientific and technical fields, including water treatment [1, 2], electrocatalysis [3, 4], catalysis [5–9], materials [10], and biomedical applications from cancer treatment to regenerative medicine [11–13]. In fact, these structures have become increasingly useful in two main areas of biomedicine: (1) nanomedicine, with noteworthy applications in imaging, biosensors, drug delivery systems, and photo thermal therapy; and (2) tissue and implants engineering either as scaffold-based nanomaterials or as components of biomedical devices. These nanocompounds can be subcategorized into four wide groups depending on their composition: carbon-based, inorganic-based, organic-based, and composite-based. Among the carbon-based materials, carbon nanotubes (CNTs)—found by Ijima in 1991—constitute a new allotrope of carbon [14] (Fig. 1) that deserves special interest due to their inherent features (surface, shape, and physical properties) that make them especially suitable for preclinical applications [15]. CNTs are tubular structures made of a layer of graphene rolled up into a cylinder [16]. These NPs are classified according to the number of wall sheets in their structure as single-walled carbon nanotubes (SWCNTs), consisting of a single graphene sheet with diameter that typically varies in the range of 0.4–40 nm, and multi-walled carbon nanotubes (MWCNTs), consisting of multiple sheets forming concentric cylinders with an interlayer distance of 0.35 nm, similar to the basal plane separation in graphite, with diameters from 2 to 100 nm (Fig. 2a). The nanotubes are usually closed at the ends with half-fullerene molecules shape, with pentagonal defects that form the tips. CNTs can be also be categorized into three types, depending on the rolling up of the sheets (Fig. 2b) as armchair, zig-zag, or chiral nanotubes (Fig. 2b) [17].

Fig. 1  Carbon allotropes: diamond, graphite, lonsdaleite, C60-fullerene, graphene, amorphous carbon, C540-fullerite, and single-walled carbon nanotube Reprinted from the journal

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Fig. 2  Carbon nanotube classifications. a According to the number of sheets, there are single- (SWCNTs) and multi-wall carbon nanotubes (MWCNTs); b depending on the rolling up of the sheets, they can be armchair, zig-zag, or chiral

In CNTs, each carbon atom is bonded with sp2 hybridization, stronger than the sp3 bonds in diamond, which provide these compounds with exceptional mechanical [18–20], electrical [21–24], optical [25], and thermal properties [26]. Other unique features owing to their large surface, needle shape, and residual metal impurities content placed them among the most promising nanomaterials for potential applications that range from nanomedicine to nanoelectronics, including the production of quantum dots by introducing fullerenes [27] and nanowires by filling CNT with pure elements for molecular electronics [28]. Regarding the use of carbon nanotubes in biomedicine and preclinical research, and due to their ability to cross the cell membrane, these materials has been tested as transporters for different drugs [29], biomolecules as enzymes, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) [30], as well as to form ion transport channels [31]. CNTs have also been used as nanoreactors, taking advantage of their reduced inner size and the special electronic characteristics due to the CNT wall curvature [32]. Nevertheless, despite their wide range of biomedical applications, carbon nanotubes have two deficiencies to solve: their inherent toxicity, due to the metal catalyst residue remaining from the synthesis process, and their low solubility in water. On these grounds, we have focused this review on the presentation of the main functionalization processes, characterization methodologies, and biomedical applications of CNTs, identifying also the most relevant strategies to overcome the inherent problems that currently hinder their preclinical use.

2 Functionalization of Carbon Nanotubes Carbon nanotubes are produced using several synthetic methods [33], but most of them left metallic impurities in the sample and render a mixture of CNTs with different diameters, lengths, and chirality properties. Additional problems are the

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tendency of nanotubes to agglomerate uncontrollably due to the high surface energy, and the stabilization of the bundles by van der Waals forces and π–π electron interactions among them. This phenomenon entails weak dispersibility and makes CNTs insoluble in most biocompatible solvents, highly limiting their biomedical applications. Functionalization solves many of these problems by modifying the CNT surface properties. Through functionalization, CNTs can be purified achieving high homogeneity, decreased toxicity, increased dispersibility, and solubility [34]. It also allows specific CNT decoration for different purposes and applications. This review presents the main functionalization pathways, with specific examples based on preparing nanotubes for preclinical research. There are multiple strategies for functionalization of CNTs with applications in biomedicine [35]. Traditionally, they have been categorized according to the functionalization approaches into covalent and non-covalent, but a higher hierarchy factor can be introduced: the location of the functionalization. Endohedral functionalization accounts for changes in the inner face of the CNTs, whereas exohedral functionalization aims to add new functionalities in the outer face. Endohedral functionalization does not involve the formation of bonds between CNT and functional groups, but filling the inner part of the CNT with host material [36]. The first described endohedral functionalization was the filling with water through capillarity [37], but soon other solvents followed [38]. Hydrophobic molecules can also be successfully entrapped in the inner space of CNTs by simple incubation [39, 40]. Some other examples of endohedral functionalization by fullerene encapsulation were reported by Karousis et al. [41]. Nevertheless, this synthetic approach is limited due to the small diameter of the inner cavity of the CNTs, greatly restricting the size of the encapsulated elements. Exohedral functionalization, on the other hand, aims to decorate the CNTs in their outer face. In principle, it has no size limitations and can potentially attach almost any type of functional group. The covalent strategies imply the formation of new chemical bonds altering the original CNT structure, and the non-covalent ones are based on the interaction through π–π stacking forces and/or van der Waals preserving the CNT skeleton intact. We present here the different types of functionalization categorized for clarity purposes, but it is important to notice that most of the synthetic procedures employed nowadays use a combination of several of the methodologies described here. 2.1 Covalent Functionalization Covalent functionalization implies the formation of new chemical bonds, altering the original CNT structure. This reaction will change the carbon hybridization from sp2 to sp3, causing the loss of the π-conjugation system of the graphene layer [42] responsible for most of the optical, electrical, and thermal properties of CNTs [43]. Despite this drawback, covalent functionalization presents many characteristics that make this approach highly attractive: it provides strong and very stable attachment of functional groups, entails higher selectivity, is more robust and better controlled

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than non-covalent functionalization, can be done in organic solvent or even without solvent, and offers a huge plethora of functional groups that can be used [44]. All these benefits highly assist the potential use of carbon nanotubes in biomedicine. Briefly, covalent functionalization can be classified depending on whether the modifications are performed at the sidewalls or in defect sites. 2.1.1 Side Wall Functionalization The sidewalls of carbon nanotubes are considered to be very inert, so their direct functionalization will only occur if a highly reactive agent is used [45]. Singh et al. [46] widely describe the main side-wall derivatization strategies in SWCNTs, including halogenation, arylation, nucleophilic addition, radical addition, cycloadditions, and carboxyl chemistry reactions. Here we present the most commonly used strategies in preparing CNTs in order to increase their solubility and dispersivity [34], decrease the inherent toxicity [47], and improve their biocompatibility with biomedical purposes. 2.1.1.1  Halogenation  Fluorination was first used to overcome the lack of CNT reactivity using elemental fluorine at temperatures between 25 and 600 °C [48, 49]. These new C-F bonds are weaker than those in alkyl fluorides [50] and can be employed for further functionalization [51], replacing fluorine with amines [52], alcohols [53], or alkyl groups using Grignard [54] or organolytic reagents [55] (Scheme 1). Besides fluorination, chlorination and bromination of CNTs can also be achieved using electrolysis [56]. 2.1.1.2  Electrophilic and Nucleophilic Additions  Electrophilic addition of alkyl halides results in the formation of alkyl and hydroxyl groups, whereas nucleophilic addition of amine-based nucleophiles leads to amino-functionalized CNTs (Scheme 2). As an example of electrophilic reaction, Friedel–Crafts acylation between MWCNT

Scheme 1  Fluorination and further functionalization of carbon nanotubes

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and p-aminobenzoic acid in the presence of polyphosphoric acid renders MWCNTNH2 (Scheme 2a), which can be used for further functionalization with poly(l-lactide) polymer [57] or with collagen using glutamic acid as a crosslinker [58]. As an example of nucleophilic addition, SWCNT can be alkylated by the treatment with t-butyllithium and subsequent reoxidation of the intermediates to obtain neutral CNTs decorated with tert-butyl moieties [59]. 2.1.1.3  Radical Additions  Originally, this approach was developed using substituted aryl diazonium salts electrochemically reduced in organic media (Scheme 2c) [60, 61]. The electron transfer between the CNT and the aryl diazonium salt triggered the formation of the aryl radicals. Posterior developments allowed performing this reaction in water [62] and to generate highly functionalized carbon nanotubes using micelle-coated CNTs [63, 64]. In situ generation of the diazonium salt provided functionalized well-dispersed nanotubes in organic solvents [65, 66], in aqueous solutions [67] and in solvent-free conditions [68]. Finally, electrochemistry allows both the reductive and the oxidative attachment of substituted phenyl groups [69, 70].

Scheme 2  Surface derivatization of CNT: a Friedel–Crafts acylation; b electrophilic aromatic addition; c radical additions using diazonium salts reaction; d ozonolysis Reprinted from the journal

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2.1.1.4  Cycloaddition  Cycloadditions are another important way of functionalizing the walls of nanotubes to tune their biocompatibility and biodegradability, both crucial characteristics to perform in vivo studies. Delgado and colleagues [71] described for the first time the [4 + 2] Diels–Alder reaction of o-quinodimethane assisted by microwaves on SWCNT surface (Scheme  3). More recently, anhydride-functionalized CNTs were produced using a cascade of Diels–Alder cycloaddition reactions employing 1,3-butadiene generated from 3-sulfolene in the presence of atmospheric oxygen [72]. A very versatile methodology uses 1,3-dipolar cycloadditions between the nanotube and azomethine ylides generated in situ by condensation of α-amino acids and aldehydes [73, 74]. This approach yields bi-substituted pyrrolidines and highly functionalized CNTs (Scheme 4) [75, 76]. Using this strategy, Calcio Guadino et al. [77] obtained multi-decorated SWCNTs in a single step. Single microwave-assisted grafting reaction labels nanotubes’ surface with amino acidic β-cyclodextrin derivative and the (1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid monoamide) moiety with a 1:1 ratio. 2.1.2 Defect Functionalization Defect functionalization makes use of the structural weaknesses of CNTs to create new bonds. Although nanotubes are highly unreactive, all the preparation methods to obtain them leave some defects in their structure, both in the lateral walls and in the tips. Among the lateral walls, these defects include dipoles of heptagon–pentagon pairs in the hexagonal network called Stone–Wales defects, sp3-hybridized defects, and vacancies in the sp2 network [45]. The nanotube’s ends are usually closed with fullerene, presenting mixed pentagonal–hexagonal structures more reactive than the pristine lateral walls [45]. Defect functionalization employs these intrinsic defects or generates new ones on the nanotube structure, normally by aggressive oxidative processes either in liquid or gas phase, or by electrochemical oxidation [78]. This approach has the advantage of generating more functional groups, but also implies higher structural damage. Using less aggressive oxidative approaches, the structural damage is minimized preserving CNT’s properties [79]. Defect functionalization can be classified according to the nature of the chemical transformation occurring at the defect sites, like oxidation, amidation, thiolation, etc. These attached functional groups are normally used as the starting point for further derivatization [80]. Oxidation and carboxyl-based coupling constitutes one of the most relevant strategies for CNTs functionalization, including the formation of esters [81, 82], amides [83], and ammonium carboxylate salts [84]. This modification is achieved in a twostep process. The first one often involves the treatment of commercially available carbon nanotubes with a mineral acid [85] such as nitric acid [86] or a sulfonitric mixture [87]. This step shortens CNTs, narrowing length distribution [88], and reduces the metal concentration left from their synthesis, decreasing toxicity and improving the preclinical possibilities. Nanotube defects will suffer the effects of the oxidant creating carboxylic and other oxygen-bearing groups [85]. The second step occurs via carboxylic acid formation, and can be carried out using two methodologies: (1) employing in situ acid chloride formation with thionyl chloride and

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Scheme 3  [4 + 2] Diels–Alder reaction of o-quinodimethane assisted by microwaves on SWCNT surface

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Scheme 4  1,3-Dipolar cycloaddition reaction between carbon nanotubes’ surface and azomethine ylide generated in situ

subsequent reaction with a primary amine or alcohol (Scheme  5a) [87]; (2) using activating agents, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysulfosuccinimide sodium salt (NHS), and subsequent reaction with a primary amine (Scheme 5b) [89]. 2.2 Non‑covalent Functionalization Non-covalent functionalization does not imply the formation of new chemical bonds. The linkage with the nanotube is achieved through van der Waals forces, π–π interactions, hydrogen bonds, and/or electrostatic interactions, preserving the CNT’s structure intact. As a result, non-covalent functionalization ensures the sp2-hybridized six-membered ring network and the extended π-conjugation, maintaining the physical, electric, thermal, and optical properties of CNTs. However, this comes at the cost of a weaker anchoring of the functional groups that can be detached by changes in environmental conditions, as modifications in pH, temperature, or solvent. This weaker bonding could be transformed into an advantage, making this functionalization reversible, something especially useful for therapeutic and

Scheme 5  Functionalization of carbon nanotubes through carboxylate via acid chloride (a) and EDCNHS (b)

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theranostic purposes in preclinical research. Non-covalent functionalization can be categorized according to the derivatization process like: small molecule adsorption or π–π stacking attachments, use of surfactants, and interaction with biomolecules. 2.2.1 Small Molecule Adsorption or π–π Stacking Aromatic derivatives, such as pyrene, porphyrins, and aromatic macrocycles, can functionalize the sidewalls of CNT through π–π stacking interactions [88] or donor–acceptor systems [90]. 2.2.1.1  Pyrene Derivatives  Pyrene is the smallest peri-fused planar hydrocarbon. It is highly symmetrical, having 16π electron and aromatic character despite not following Hückel’s 4n + 2 rule [91]. Pyrene-containing molecules have been extensively used as bridges to functionalize nanotubes’ surface with different biomolecules, polymers, dendrimers, and DNA derivatives, among others [92]. Zhu and coworkers anchored CNTs onto oxide surfaces using bifunctional molecules, with succinimidyl ester and pyrene groups as a bridge [93]. Chen et  al. employed 1-pyrenebutanoic acid, succinimidyl ester to functionalize carbon nanotubes with proteins [90]. Calle et al. used 1-amine pyrene to obtain homogenous π–π stacking adducts with MWCNT [88]. Once the pyrenyl group is anchored to CNTs, they can be further decorated with ester groups that are highly reactive to primary and secondary amines ubiquitous on the surface of proteins. 2.2.1.2  Porphyrin Derivatives Porphyrin is a π-conjugated system in a planar arrangement with a total of 18 π electrons and aromatic character. Using this structure, Zhang and coworkers [94] prepared polymeric porphyrin-functionalized CNTs by the condensation of terephthaldehyde and pyrrole in the presence of carbon nanotubes. Subsequent metalation with ­Ru3(CO)12 incorporated ruthenium to the composite, which showed excellent catalytic performance toward hydrogenation of biomassrelated compounds. Derivatized porphyrins can also be employed [95]. 2.2.2 Surfactants Amphiphilic molecules interact with carbon nanotubes in aqueous media through their hydrophobic parts while their hydrophilic ends face outwards [96]. Surfactants have been widely used to suspend CNTs in aqueous solutions, increasing their dispersibility [97] and reducing their cytotoxicity [98]. Examples of this type of molecule include deoxycholic acid, sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, and sodium dodecyl sulfate, among others [96, 99, 100]. This procedure is very effective in dispersing carbon nanotubes, allowing studying CNTs individual properties, and can be used as the starting point for further functionalization. Furthermore, if the hydrophobic tails of the surfactant present aromatic moieties, particularly strong π–π stacking interaction will be established with the CNT, as with sodium dodecyl benzene sulfonate (SDBS) [101].

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Some examples of this approach include the work of Niezabitowska et al. [102] that employed sodium dodecyl sulfate as anionic surfactant to disperse carbon nanotubes and polycaprolactone. Negri et  al. [103] used SWCNT oxidized with 2% SDBS suspensions to generate nanotubular paramagnetic probes, with potential utility as contrast agents (CAs) in magnetic resonance imaging (MRI). Cerpa et al. [104] used a SDBS solution to disperse single-walled carbon nanotubes to obtain anisotropic relaxation probes for diffusion MRI studies. Bharti et al. [105] compared the role of a cationic an anionic surfactants in the synthesis and resulting properties of MWCNTs decorated with bi-metallic Pt–Pd nanoparticles. Yasujima [106] used Triton X-100® to disperse CNTs in a bioanode preparation process in a multienzyme immobilized carbon-felt electrode. Martinez-Paz et  al. [107] employed 0.015% Pluronic F68 culture medium solution to obtain a homogenous suspension of oxidized MWCNTs in order to determine the possible toxic effects in invertebrate Chironomus riparius caused by CNTs environmental dispersion. 2.2.3 Biomolecules The non-covalent functionalization by attaching biomolecules to the CNTs surfaces is attracting great attention in biomedical research because of their promising preclinical possibilities. With this aim, different biological molecules and macromolecules can be bound to the nanotubes, like polypeptides, DNA bases, DNA oligonucleotides, amino acids, phospholipids, etc. 2.2.3.1  Proteins  Carbon nanotubes can interact directly with proteins through π–π stacking of their aromatic residues (Trp, Phe, and Tyr) enhancing their absorptivity and biocompatibility [108, 109] and so increasing the possibilities of being used in preclinical evaluations. A different approach uses a bridge to anchor proteins to CNTs, either through covalent modifications of nanotubes [110], or by a non-covalent method employing pyrene derivatives [90]. 2.2.3.2  DNA Derivatives  DNA can bind to carbon nanotubes, forming helices around them [111] or can form non-covalent conjugates through the π–π staking with the aromatic bases [30]. DNA-functionalized CNTs can be used as biological transporters and also as biosensors [111, 112]. 2.2.3.3  Phospholipids  Due to their amphiphilic nature, phospholipids can be used as surfactants to solubilize CNTs. Lysophospholipids, or single-chained phospholipids, are very efficient in this task [113]. In this case, the lipid part wraps the nanotubes as striations, whereas the hydrophilic part provides CNT solubility and biocompatibility. Using this approach, phospholipid-polyethylene glycol (PEG) is employed to functionalize SWCNT for a range of different biomedical applications [114] (Fig. 3). In a different approach, lipid bilayers can encapsulate CNTs, creating a model to study different biological process occurring at the cell membranes [115].

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Fig. 3  Functionalization protocol of SWCNT with PEG (steps 1–5), and further conjugation of targeting ligands to SWNTs (A and B), radiolabeling of SWNT (C), siRNA conjugation (D), and doxorubicin loading onto functionalized SWNTs (E) (with permission from [114])

3 Characterization of Carbon Nanotubes As stated before, all the production methods for carbon nanotubes generate nonhomogeneous material, varying in diameter, length, chirality, purity, etc. Thus, adequate CNTs characterization is a fundamental step previous to the use of these NPs in biomedicine. Parameters to be studied include thermal stability, homogeneity, conductivity, optical properties, and identification of the functional groups in case of covalent modifications. Characterization is also key in determining the metal traces from the synthesis, estimating carbonaceous impurities and studying structural defects in the sidewalls and tips. The main techniques for CNT characterization include photoluminescence spectroscopy, X-ray photoelectron spectroscopy, electron microscopy, scanning tunneling microscopy, X-ray diffraction, neutron diffraction, Raman spectroscopy, thermal analysis, absorption spectroscopy, and infrared spectroscopy, among others [116]. It is important to bear in mind that despite the wide range of techniques available, multiple characterization techniques must be used to obtain a complete description of a carbon

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nanotube sample. Also, measurements are highly dependent on sample preparation and specific protocol details, and most of the times a reference is needed [117]. As stated previously, this article does not pretend to be an extensive review on the characterization techniques used to study nanotubes, but we just would like to give a brief overview of the main techniques used for characterization of CNTs with biomedical applications. For a more detailed review, interested readers could go to Refs. [117–119]. 3.1 Raman Spectroscopy Raman spectroscopy is one of the most powerful and used techniques for carbon nanotube characterization [120]. It is fast, does not need sample preparation, and is non-destructive. For SWCNTs, Raman spectroscopy provides qualitative and quantitative information about diameter, purity, crystallinity, and electronic structure, allowing to distinguish between metallic and semiconducting CNTs [121]. Furthermore, it supports studying and bundle CNTs [122, 123]. The most characteristic bands of nanotubes in Raman spectra are: (1) A ­ 1g or “breathing mode”, related to the diameter of the tube, (2) D-line, assigned to residual ill-organized graphite, and (3) G-band, related to highly ordered CNT sidewalls. The ratio between D- and G-bands can provide quantitative information about sidewall damage and changes produced by functionalization [124]. 3.2 Electron Microscopy (EM) EM includes transmission electron microscopy (TEM) and scanning electron microscopy (SEM). These are essential tools for studying directly the local structure of CNT at the nanometer level. TEM allows determining lengths and outer and inner diameters (Fig.  4) [88]. It also gives a qualitative estimation of the metallic and carbonaceous impurities, which appear as dark dots in the images [104]. The main disadvantages of EM techniques include possible damage to the sample due to the high energy of the electronic beam, and the large impact of sample preparation and drying in the results. 3.3 Scanning Probe Microscopy Among the different techniques encompassed within the scanning techniques, the two most commonly used to characterize functionalized CNT are atomic force microscopy (AFM) and scanning tunneling microscopy (STM) [46, 125]. AFM can be used to evaluate the stiffness and strength of individual MWCNT as well to measure their size distribution [126]. STM can reveal the atomic structure and the electronic properties of individual SWCNT [127], and is also able to image functional groups attached to the nanotube [125].

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Fig. 4  TEM images of oxidized MWCNTs at 200  kV (left), and aminopyrene–MWCNT π–π stacking adducts showing open ends and aminopyrene adsorption (right). The image on the right was acquired with a GRANDARM300cFEG microscope with corrective aberration in the objective lens

3.4 Fourier‑Transformed Infrared Spectroscopy (FTIR) FTIR provides information about the impurities remaining from the nanotube synthesis, the catalytic activity of CNTs [128], and the functional organic groups attached during functionalization [124]. As an example, Fig.  5 presents two

Fig. 5  FTIR spectra of pristine MWCNT (black), oxidized MWCNT (blue). Note peak at 1691 cm−1 due to C=O stretching and broad band at 3300 cm−1 O–H Reprinted from the journal

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spectra of pristine and oxidized CNTs, where the band due to carbonyl stretching of carboxylic group is clearly visible at 1691  cm−1. The main disadvantages of this technique include their qualitative nature and that some modifications cannot be observed due to the weak infrared-associated signals. 3.5 X‑Ray Photoelectron Spectroscopy (XPS) XPS provides information about the chemical structure of CNT (except for hydrogen) and, most importantly, the structural modifications due to chemical functionalization [129]. This technique irradiates CNTs with X-rays and determines the binding energy of the ejected photoelectrons. As an example, Fig.  6 shows the spectra of different CNTs, where the relative increase in O1s’ peak confirms the presence of carboxylic groups on oxidized nanotubes. Some inconveniences of this methodology are the requirement of relatively large amounts of sample and that peak fitting can be ambiguous. 3.6 Thermogravimetric Analysis Thermogravimetric analysis measures changes in the mass of the CNTs over time as the temperature varies under a control atmosphere. This technique is used to assess the purity of the sample and the concentration of organic molecules attached to the nanotubes. Thermogravimetric analysis is based on the lower decomposition temperatures of the adsorbed molecules and amorphous carbon compared to pristine CNTs. When the assay is carried out under air, the sample is completely oxidized and the remaining constitute the metallic impurities [116]. The main disadvantages include the destruction of the sample, requirement of large amounts of sample, and that data interpretation is often subjective.

Fig. 6  XPS of MWCNT (black), oxidized MWCNT (blue) and US shortened MWCNT (green) (with permission from Calle et al. [88])

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4 Biomedical Applications of Carbon Nanotubes As we anticipated in the previous sections, CNTs present some physical features very interesting for biomedical applications, including a large surface area [130], electrical [23] and thermal conductivity [131], and optimal mechanical properties [132]. Some of these applications are achievable through the CNT’s conjugation with different biomolecules or compounds like polymers, proteins, DNA and RNA, among others, as above described (Fig. 7). Besides, their needle shape permits them to cross biological membranes and access cells and tissues in a non-affordable way for most of the common drugs and compounds. Nevertheless, some challenges need to be overtaken to boost their potential in biomedicine. These include low biocompatibility [133], mainly due to poor water solubility, low dispersivity, and high toxicity [47]. Even so, numerous groups have reported different and very interesting applications for CNTs also in the preclinical and in the clinical settings. 4.1 Diagnostic applications Early diagnosis and proper monitoring of disease is vital for efficient treatment of illnesses. This encourages the development of improved methodologies that solve some of the inconveniences and handicaps of the current methods, including sensitivity and selectivity, spatial and temporal resolution, cost, etc. The use of nanoparticles in general, and carbon nanotubes in particular, offers a wide range of possibilities that could be key in achieving these improvements. 4.1.1 Biosensors Biosensors are devices incorporating biological elements with unique binding specificities towards target analytes. In this field, CNT’s characteristics make them very interesting to investigate as relevant constituents of electrochemical biosensors [135]. Nanotubes are well suited for transduction of electric signals generated

Fig. 7  Schematic representation of surface functionalization and loading of carbon nanotubes for biomedical applications (with permission from Fernandes et al. [134]) Reprinted from the journal

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upon recognition of a target, so, numerous applications are reporting the design of nanotube-based biosensors to detect and monitor different pathologies [136, 137]. Recently, a three-dimensional network of carbon nanotubes on Si pillar substrate has been developed for the accurate detection of oral squamous cell carcinoma in clinical saliva samples [138]. In this work, Song and colleagues described the preparation of the sensor, the in  vitro characterization, and the clinical applicability. The results obtained with this new CNT network showed a good correlation with data obtained using the commercially available electrochemiluminescence detection system employed in the hospital. Also, a novel CNT-based biosensor has been used for ultrasensitive detection of hydrogen peroxide and glucose in human serum, with a great interest for basic research and disease diagnosis [139]. In this study, the authors constructed a ratiometric fluorescent nanosensor based on the peroxidaselike properties of a hierarchical cobalt/carbon nanotube hybrid nanocomplex. This system assay developed reaches a detection limit of H ­ 2O2 of 100 nM and a selective and sensitive detection of glucose as low as 150  nM. In a different approach, multivalent electrodes for glucose biosensing were constructed through multiple functionalization of CNTs [140]. Three different pyrene derivatives were simultaneously immobilized on the nanotube surface by π–π-stacking: adamantane-pyrene, biotinpyrene, and nitrilotriacetic. They were adsorbed on the nanotube sidewalls to allow the step-by-step immobilization, via supramolecular host–guest interactions, of β-cyclodextrin modified glucose oxidase, biotinylated glucose oxidase, and histidine modified glucose (Fig.  8). The calibration curves for the glucose responses were performed by amperometry and using glucose oxidase as an enzyme model for all immobilization steps. DNA detection is a very active research area holding great promise in the early detection of many diseases and pathological processes, and CNTs offer strong opportunities to achieve that [141]. An interesting study reported the synthesis of a multi-functional gold/iron-oxide nanoparticle-CNT as a virus DNA-sensing platform [142]. The authors prepared the sensor through a simple two-step method obtaining the hybrid nanostructure that exhibited excellent detection potential and DNA sensing performance for different diseases. Chen and collogues also reported the fabrication of a DNA nano-biosensor system containing carbon nanotubes to detect the presence of Mycobacterium tuberculosis rapidly and with a great sensitivity [143]. CNTs have also been experimentally and theoretically investigated as conducting channels in a chemiresistor for the electrochemical detection of doublestranded DNA [144]. More recently, the development of a CNT-based field-effect transistor for DNA hybridization detection was reported [145]. In this sensor, DNA can bind well to a suspended CNT, avoiding the adverse effects of a substrate on a sensing material, and reaching a detection limit up to 10 aM. 4.1.2 Imaging Carbon nanotubes can be powerful tools with diagnosis purposes not only as biosensors but also to be used in imaging technologies. Due to their excellent intrinsic properties, CNTs have been employed as CAs in photoimaging techniques and are good platforms to carry molecules that make them detectable with different imaging

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Fig. 8  SWCNT multivalent glucose biosensor by a coating process with adamantane-pyrene, biotin-pyrene and nitrilotriacetic acid-pyrene, and further host–guest interaction with avidin and β-cyclodextrin

modalities, as positron emission tomography (PET) or magnetic resonance imaging, among others [146]. MRI is probably the most powerful and versatile of all imaging techniques used in the clinical routine, biomedical research, and preclinical studies. Among its advantages, MRI presents wide implementation, high cost efficiency, non-invasiveness, and it does not use ionizing radiation. Although this imaging technique offers a great contrast between pathological and healthy tissues, the use of contrast agents is often required. CNTs are highly explored as CA candidates, with great sensitivity and specificity, low dose and reduced side effects, with numerous in  vitro and in vivo studies reported in the literature [147]. The most direct approach is to use them as negative T2 CAs making use of the remaining metal catalyst employed in the synthesis of CNTs [148], but these structures can be also prepared as positive T1 contrast media either by addition or trapping of gadolinium (Gd) complex [149, 150]. In both situations, some issues have to be solved to boost their widespread use, like toxicity and dispersion capacity [34]. Despite this, CNT-based CA are promising for cell labeling and MRI tracking, being of great interest on stem cell-based therapies that have emerged as a promising approach for the treatment of different diseases. With this aim, Moghaddam et al. developed a method to coat the surface of gado-nanotubes (GNTs) with Gd and polyacrylic acid polymer generating a powerful MRI T1 contrast agent, with an extremely short T1 relaxation and an improved dispersibility in water without the need of surfactants [151]. The authors used these Reprinted from the journal

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GNTs to safely label porcine bone marrow-derived mesenchymal stem cells that displayed excellent image contrast in phantom MRI. Our group reported an interesting and original application of SWCNTs to induce anisotropy in the diffusion of water molecules in a phantom [103]. This work offers new perspectives for contrast generation in diffusion tensor magnetic resonance imaging, a powerful MRI technique to explore the microstructure of healthy and pathological brain. The near-infrared radiation (NIR) absorption property of CNTs [152] can also be used to image their biodistribution in vivo. Yudasaka et al. [153] covered SWCNTs with a biocompatible polymer, which accumulated in brown fat, providing an imaging tool to visualize the distribution of this tissue in a preclinical model. Kim et al. [154] developed SWCNTs coated with gold and conjugated with antibody specific to the lymphatic vessel endothelial hyaluronan receptor to image the lymphatic vessels in mice. They induced a temperature increase of CNTs by NIR absorption using a laser beam and detected the nanotubes in the lymphatic vessels using photoacoustic and photothermal imaging. The NIR imaging techniques can also be combined with NIR guide photothermal therapy [155]. In this work, Liang et al. functionalized SWCNTs with polyethylene glycol to administrate them in BALB/c mice carrying 4T1 murine breast tumors in the inner knee. CNTs were directly injected on the primary tumor and visualized using photothermal imaging and MRI, not only in the tumor but also in the nearest metastatic lymph. CNTs can be functionalized with different radioisotopes like Y-86 [156], C-14 [157], I-125 [158], Tc-99 m [159] or Cu-64 [160], making them promising CAs for nuclear medicine approaches. Al-Jamal and coworkers [161] used single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging to study in vivo the internalization of three different MWCNTs radiolabeled with 111In (Fig. 9). Furthermore, the particular features of carbon nanotubes make them good candidates to act as multimodal contrast agents with different imaging techniques. 4.2 Therapeutic Applications Nanoparticles have revolutionized the field of drug delivery in the last two decades. Currently used therapeutic drugs suffer from low selectivity and low half-life, making necessary it to give high doses to achieve the expected response, and thus increasing undesirable side-effects. A proper and selective drug delivery system would overcome most of these issues, and carbon nanotubes have been widely studied for this end [15]. As previously indicated, the nature of nanotubes permits a versatile chemistry allowing the attachment of drugs in a covalent or non-covalent manner with an efficient drug-loading capacity. Besides, these nanostructures can be appropriately functionalized with different hydrophilic molecules to specifically recognize the receptors overexpressed in the target cells, according to the alterations related to the specific pathology to be treated [162]. So, the optimal functionalization of CNTs make them promising drug-delivery systems in numerous therapies owing to their achieved biocompatibility, suitable size, ability to penetrate the cells, and

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Fig. 9  Nano-SPECT/CT fused images of the whole body of a mouse. Images were recorded at 0.5, 3.5, and 24 h after injection of the 111In-DTPA-MWCNTs structures shown on the left side (with permission from Al-Jamal et al. [161])

their exceptional cell transfection capabilities [163, 164]. Hopeful studies have been reported to treat some of the most devastating pathologies nowadays, like cancer and neurodegenerative diseases, with CNT-based therapies using them either as drug carrier and delivery systems or taking advantage of nanotube physicochemical properties. 4.2.1 Cancer Treatment Nowadays, the main challenge of cancer therapies relies on the preparation of smart carriers able to accurately target the tumoral cells and to perform a controlled release of the therapeutic drug in response to the tumor microenvironment properties. The classic approach of nanotubes for cancer treatment is based on the transport and delivery of chemotherapeutic drugs that suffers from systemic toxicity, narrow therapeutic window, drug resistance, and low cellular penetration. CNTs provide a unique opportunity to improve the drug delivery to the tumor, enhancing Reprinted from the journal

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local accumulation in the desired site and reducing the toxic effect of chemotherapy [165]. Relevant achievements in the field of nanotechnology to improve cancer treatment include carbon nanotubes loaded with classical therapeutic drugs and other anticancer agents like siRNA, chemosensitizers, radiosensitizers, and antiangiogenic compounds [166]. Liu et  al. [167] developed hyaluronic acid (HA)-modified amino SWVCNTs to target breast cancer cells overexpressing CD44, improving doxorubicin (DOX) deliver. In  vitro studies in MDA-MB-231 breast cancer cells showed an increased intracellular DOX delivery, higher inhibition of proliferation and induction of apoptosis, and decreased cell migration. The tubular structure of nanotubes is also optimal to attach DNA or RNA molecules to modulate the expression of specific genes [168]. In this sense, Taghavi et  al. [169] functionalized SWCNTs with AS1411 aptamer as ligand to target tumor cells and with DOX and small interfering RNA (siRNA) molecules to perform chemotherapy and gene therapy, respectively. This nanoplatform increased cell death in a model of human gastric cancer measured in vitro when compared to the individual CNT-based treatments or with free DOX. Chang Guo et al. [170] prepared cationic MWCNT-NH3+ to deliver siRNA against polo-like kinase 1 (PLK1) in a lung carcinoma model in  vivo. CNTs were injected directly in the tumoral mass, finding higher efficiency of PLK1 silencing compared to liposomes due to a higher CNT cell penetration. The possibilities that carbon nanotubes offers as drug carriers in the treatment of malignant tumors is very large [171–173], but they afford other potential approaches in cancer treatment, like photothermal therapy (PTT) [174]. CNTs can be used as external agents in PTT because they absorb NIR radiation and efficiently convert it into heat energy, allowing the ablation of the cells in the CNT surroundings. Virani et  al. used this phenomenon to target bladder cancer cells [175]. They conjugated SWCNTs with annexin V, which specifically binds to bladder cancer cells and tested the method in vivo. Once the CNTs reached the cancer, the tumor was heated using NIR light, inducing cell death and preserving the healthy bladder wall. They founded no damage on the bladder 24 h after treatment and no tumors were visible. To date, the main approach for PTT with CNTs has been based on the irradiation by laser or infrared light, limiting the application to superficial tissues due to low penetration capacity, but CNTs can also be exposed to external electromagnetic fields in a non-contact manner, achieving higher penetration while obtaining the desired thermal effects [176]. Nowadays, chemoresistant tumors with a high tumor load and in advanced stages require the combination of different therapies for effective treatment. CNTs are well suited for this, with carbon-based nanoparticles being used for combining thermal therapy with other therapeutic approaches based on drug delivery [177]. Wang et  al. reported the use of NIR photothermal therapy and RNAi to enhanced tumor cells death in a prostate cancer model [178]. They synthesized SWCNTs functionalized with polyethylenimine to allow siRNA complexation, and decorated the CNT with a peptide motif that specifically binds to tumor cells. The cancer therapy effect of these CNTs was tested in  vitro and in  vivo using PC-3 tumor cells. The CNTs silenced the target gen, causing significant inhibition

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of the tumor growth, and, when combined with photothermal therapy, the results showed a more effective treatment. 4.2.2 Neurodegeneration Treatment One of the big problems in the treatment of neurodegenerative diseases like Parkinson, dementia, or Alzheimer’s, is the presence of the blood–brain barrier (BBB). The BBB restricts the passage of bacteria and toxic molecules to avoid brain damage but also prevents the brain uptake of most pharmaceuticals, precluding the pass of drugs from blood circulation to brain tissue. In fact, neurological disorders belong to the group of pathologies with the greatest need of new technologies to improve diagnosis and provide an adequate therapy, and nanobiotechnology can help in both. Al-Jamal’s laboratory proved [179–181] that CNTs are able to cross the blood–brain barrier without damaging it. They used in  vitro cultures of primary porcine brain endothelial cells, which simulate the BBB, showing that MWCNTs functionalized with N ­ H3 crossed 13% of the layer in 72 h. They also demonstrated in vivo that 5 min after intravenous injection of MWCNTs-NH3 in mice, 1% of the injected dose crossed the BBB. In further experiments, they studied the impact of the diameter of the nanotube and the functionalization with angiopep-2 (AGP), a ligand for the low-density lipoprotein receptor related protein-1, in the extent of passing the BBB. They found that wider nanotubes linked with AGP showed a higher effect on crossing the BBB than those not functionalized. Thinner CNTs did not depict any improvement in the brain uptake between functionalized and unfunctionalized MWCNTs, although they exhibited more uptake than the wider ones. Finally, they tested them in vivo using a GL261 glioma model, showing higher uptake for CNT functionalized with AGP. Costa et al. [182] took advantage of this property to develop an Alzheimer’s biomarker based on gadolinium. MWCNTs were functionalized with the Pittsburgh Compound B, a molecule that binds to the amyloid beta plaques present in Alzheimer’s disease and is currently used for imaging Alzheimer’s with PET. The group studied the in vivo distribution of the nanotubes, finding that they were able to cross the BBB, making them a good contrast agent to detect the presence of the plaques with MRI. Lohan et al. [183] reported the development of MWCNTs functionalized with berberine (BRB), an isoquinoline alkaloid used in dementia and other mental disorders, to evaluate the anti-Alzheimer’s potential of the drug. The authors injected the nanotubes in healthy male Wistar rats after intracerebroventricular administration of amyloid beta peptide. They proved that BRBMWCNTS crossed the BBB, reaching the plaques, and found a decrease of malondialdehyde and reduced glutathione, two of Alzheimer’s biomarkers. The structural damage occurring in some neuro-diseases can also be minimized with carbon nanotubes. Hassanzadeh et  al. [184] prepared MWCNTs-NGF complexed with nerve growth factor (NGF), a protein related to the survival and maintenance of neurons population, and investigated its effect in an in  vitro model of ischemia. The results were compared with those obtained with free NGF, finding higher protection for the new CNT-NGF complex. As in cancer, CNTs found further applications in neurodegenerative diseases beyond drug delivery. CNTs can be used to activate brain cells due to their electrical Reprinted from the journal

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properties and tubular shape. Silviana Fiorito et al. [185] reported the activation of microglia using MWCNTs with highly electro-conductive properties, polarizing the microglia cells into M1 state (pro-inflammatory) after 24 h of cell exposure and M2 state (anti-inflammatory) after 48 h of exposition. They detected this phenomenon in vitro using primary rat microglial cells, suggesting that the electro-stimulation of these CNTs could modulate microglial responses. The use of carbon nanotubes as scaffolds for neurons has also been well studied, as they are good platforms for protecting neuron damage in ischemia [186]. Jung Lee et al. pretreated rats with amine-modified SWCNTs before an ischemic surgery, finding less tissue damage and better motor function in the treated animals after the insult. More recently, CNTs were reported as good scaffolds for different types of neurons, like retinal neurons or sciatic nerve [187]. In this work, the authors studied retinal cell growth in  vitro using MWCNTs as frame to these cells. They followed the procedure with rat and human retinal cells, finding an efficient growth for both of them. Salehi et al. [188] developed a conduit produced from polylactic acid, MWCNTs, and gelatin nanofibrils coated with the recombinant human erythropoietin-loaded chitosan nanoparticles. They loaded this conduit with Schwann cells and implanted it in rats with sciatic nerve defect, finding improved recovery rate. Finally, carbon nanotubes have also shown some neuroprotector properties. Xue et al. [189] reported that C57BL/6J mice pretreated with aggregated SWCNTs significantly inhibited self-administration of methamphetamine. The electrochemical assays indicated that nanotubes made the oxidation of extracellular dopamine in the striatum easier, suggesting the potential use of aggregated SWCNTs for the treatment of methamphetamine addiction. 4.3 Theranostic Applications Theranostic compounds are nanoparticles integrating both diagnostic and therapeutic capabilities into a platform. CNTs have been intensively studied for theranostic applications [163], as they can be easily coupled with different molecules/structures achieving synergetic analytic and curative effects [190]. Basically, this approach relies on the CNT functionalization with structures carrying abilities for detecting and treating the disease, achieving at the same time cell targeting and delivering of the drug under microenvironmental stimuli. Some examples have already been presented in earlier. Mashal et al. [191] constructed tissue-mimicking materials and found that SWCNTs could enhance dielectric contrast between tumoral and healthy tissue for microwave detection and hyperthermia treatment in breast cancer. More recently, Al Faraj et al. [192] described the preparation and the in vitro and in vivo characterization of drug-conjugated SWCNTs as nanocarriers for breast cancer therapy. The authors aimed to target a stem cell subpopulation with a combination of therapeutic drugs (paclitaxel and salinomycin) selectively delivered via biocompatible CD44 antibody-conjugated SWCNTs with a pH-responsive release. The therapy was non-invasively monitored in tumor-bearing mice with MRI and bioluminescence imaging (BLI), and the results clearly showed enhanced therapeutic effect of

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Fig. 10  In vivo drug-conjugated SWCNT therapeutic efficacy assessed using BLI and MRI: a schematic diagram illustrating the functionalized SWCNTs as theranostic carriers, b representative bioluminescence images, c representative axial MR images, and d quantitative measurements of tumor volume in MDA-MB-231 tumor-bearing mice. Imaging protocols were performed pre- (t = 0) and up to 35 days post-treatment (modified with permission from Al Faraj et al. [192])

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the combined therapy compared to treatment with individual drug-conjugated nanocarriers or free drug suspensions (Fig. 10). CNTs can also be coupled to other nanosystems with this purpose, such as magnetic particles, quantum dots, nanocomposites, etc. Zhang et al. [193] functionalized magnetofluorescent MWCNTs for MRI/fluorescence imaging by adding a Gd complex doped with quantum dots. They also combined the nanotubes with doxorubicin to be used as a chemotherapeutic agent. The nanotubes were intratumorally injected in a preclinical model of adenocarcinoma, and visualized with photoacoustic imaging and magnetic resonance T1-weighted images. Using NIR absorption properties, the authors carried out photothermal therapy in combination with selective release of DOX in the tumor. In a similar way, Hou et  al. [194] functionalized SWCNTs with HA, DOX, and gadolinium to visualize with MRI the biodistribution of the nanotubes and their antitumor effect in a preclinical model of breast cancer. CNTs can also be used as theranostic dual contrast agents for fluorescence/MRI and photothermal therapy, all in a system [195]. The authors So, Zhang, and colleagues reported the preparation of and in  vitro and in  vivo characterization of MWCNT-magnetofluorescent carbon quantum dots/DOX nanocomposites. They validated the diagnostic and therapeutic capacities of the compounds with MRI and fluorescent methodologies in adenocarcinoma cells and a pulmonary cancer mouse model. The study confirmed that the platform is able to target cancer cells and deliver drugs intracellularly upon NIR irradiation, achieving the effective elimination of the tumors through chemo/photothermal synergistic therapeutic effect. In a similar way, Xiaojing Wang et al. [196] described the synthesis of modified DNASWCNTs with gold-decorated nanoparticles and a surface modification with PEG, which achieve the selective photothermal ablation of cancer cells. These SWNT-AuPEG nanocomposites are optical theranostic probes for cancer treatment by PPT and detectable by Raman spectroscopic imaging. Another study, carried out by Zhao and coworkers [197], reports the coating of CNTs with polydopamine and further modification by PEG to chelate manganese, achieving contrast in MRI, and to label 131I enabling nuclear imaging and radioisotope cancer therapy. The system was tested in  vitro and in a mouse model of breast cancer, assessing radioisotope therapy in combination with NIR-triggered photothermal treatment. Results revealed efficient tumor accumulation of the nanotubes and confirmed a remarkable synergistic antitumor therapeutic effect. 4.4 Tissue Engineering Applications The main clue in regeneration and construction of tissues is the development of a suitable biological scaffold. In this context, owing to their unique characteristics and properties, carbon nanotubes are emerging as smart nanomaterials for tissue engineering purposes. They are valued as ideal structures that can support and boost the growth and proliferation of many different tissues [15].

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4.4.1 CNTs and Cell Growing Nanobiotechnology can have a great impact in the management of nervous system pathologies by developing optimal structures for neural prosthetic applications. The design of biocompatible implants for neuron repair/regeneration ideally requires high cell adhesion as well as good electrical conductivity. Carbon nanotubes entail all of these requirements, including high binding affinity and excellent electrical conductivity, making them ideal materials for neuro-implant development aimed to grow neurons and repair neuronal damage. Some examples have already presented in earlier. Lovan et al. [198] showed that carbon nanotubes possess a good surface for supporting dendrite elongation and cell adhesion. Experiments were carried out on neonatal hippocampal neuron networks cultured on dispersed MWCNTs. Results suggested that the growth of neuronal circuits on a nanotube grid is accompanied by a significant increase in network activity, probably due to the high electrical conductivity of these nanomaterials. In the same line, Mazzatenta et al. [199] described the preparation of an integrated SWCNT–neuron system by growing hippocampal cells on the CNTs. Theoretical and experimental results indicated that SWCNTs can stimulate the activity of the brain circuits. However, CNT applications in tissue regeneration or engineering expand far beyond nervous tissue. Ren et al. [200] used CNTs to develop artificial myocardial tissue where cell growth was aided by the conductivity of oriented CNTs. Special nanotube geometry also beneficiated artificial bone generation, making CNTs a very suitable bone scaffold both in vitro and in vivo [201, 202]. Finally, CNTs make an important contribution in the generation of synthetic fiber muscle [203, 204]. 4.4.2 CNT‑Based Hydrogels Although conventional hydrogels are biocompatible and suitable for culturing or fabricating different cell types and tissues, their low mechanical strength and lack of electrical conductivity have limited their biomedical applications for skeletal muscles, cardiac and neural cells. Nevertheless, the development of hybrid nanocomposite systems can overcome these limitations enabling the preparation of bioscaffolds with tunable electrical and mechanical features. In fact, in the last few years, CNTbased hybrid hydrogels are emerging as innovative candidates with applications in regenerative medicine and tissue engineering [205]. Shin et al. [206] prepared different nanotube–hydrogel hybrid systems that showed significantly improved electrophysiological and mechanical properties. The authors seeded neonatal rat cardiomyocytes onto these hybrid MWCNTs hydrogels, obtaining functional cardiac patches that showed excellent mechanical integrity and advanced electrophysiological functions. Another study reports the addition of functionalized MWCNTs to alginate to generate composite hydrogels improving the mechanical, physical, and biological features compared with the starting materials [207]. The obtained hybrid MWCNT–alginate gels were porous, showed less degradation, enhanced HeLa cells adhesion and had greater cell proliferation, proving the potential utility of these structures as novel substrates for tissue preparation. Sun et  al. [208] incorporated SWCNTs into collagen hydrogels, which improved cell alignment and assembly, Reprinted from the journal

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leading to the formation of engineered cardiac tissues with stronger contraction capacity. The in vitro studies suggested that hybrid SWCNT/collagen hydrogels can be promising tissue scaffolds for cardiac regeneration after myocardial arrest. In a similar line, a recent study described a biohybrid hydrogel prepared from hydrazidefunctionalized CNTs and solubilized pericardial matrix. This hydrogel is a suitable environment for maturation of human-induced pluripotent stem cell-derived cardiomyocytes, constituting a promising material for stem cell-based cardiac tissue engineering [209]. 4.4.3 CNTs and Stem Cells Stem cells (SC) have attracted the attention of researchers around the world during the last decade due to their ability to self-renew and differentiate, depicting multiple potential applications for tissue engineering and regenerative medicine. CNTs presented excellent properties as culture substrate [210], having the ability to dynamically direct the SC lineage, modulating proliferation and differentiation of various types of SC. Different studies have reported the improvements achieved by growing SC in CNT-based nanocomposites. These materials were able to promote differentiation of mouse neural SC to neurons and oligodendrocytes [211], neural differentiation of human embryonic stem cells [212], and differentiation of human mesenchymal stem cells [213], among others. 4.5 Other Applications The versatility of carbon nanotubes in biomedicine and preclinical setup is very large, with many studies reporting the use of CNTs to solve the problem under investigation. Carbon nanotubes are being used, for example, to construct brain electrodes [214], or as biosensors for bone cells [215] or the influenza virus [112]. By linking CNTs to antigenic peptides, they could improve the major hurdles associated with vaccine delivery [216]. In fact, they can act as excellent vaccine carrier systems having a great potential to stimulate the innate immune response. Also, the combination of CNTs with antibiotics could help to overcome the growing problem of antibiotics resistance [190]. When properly functionalized, CNTs can also be used in antiviral drug delivery [217].

5 Conclusions Bionanotechnology is a new promising tool for improving the management of numerous pathologies. A wide range of nanomaterials have been prepared, characterized, and evaluated for numerous biomedical applications to solve specific problems not achievable with classical approaches. Among them, carbon nanotubes present unique features and physical, chemical, and biological properties. These intrinsic attributes can be notably improved though coating, surface functionalization, and decoration with different molecules, ligands, or nanostructures. All of

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these turn CNTs into ideal platforms with diagnostic, therapeutic, and theranostic possibilities not accessible for other nanoparticles and with promising preclinical and clinical applications. In this review, the biomedical applications of CNTs have been addressed in different fields of drug and/or gene delivery, bioimaging, and tissue engineering. The special electronic and mechanical qualities of nanotubes make them suitable for theranostic applications as providing an exceptional platform for combining disease detection and treatment capacity at the same time. These structures can be used in diagnosis as efficient biosensors or contrast agent for non-invasive imaging, and at the same time, increase the lifetime of drugs in organism and facilitate their direct delivery within cells of a target-specific tissue. Also, nanotubes have reached a vital relevance in biotechnology, being an excellent scaffold on their own or taking the part of hybrid materials for regenerative medicine. They have proved to be useful in cell growth and proliferation, enabling the engineering of different tissues. The studies included in this review have highlighted the potential of CNTs and justified all the efforts in optimizing their use as an alternative therapy for complicated medical conditions with no current treatments. Nevertheless, despite the numerous and intensive studies, some important inconveniences, which preclude potential clinical applications, need to be overcome, with toxicity probably being the most important handicap. The triad of CNTs functionalization, type, size, and purity have been identified as leading causes determining the utility of nanotube-based complex in vivo. Collating reliable cellular and animal data with respect to molecularly well-defined architectures provides a basis for further breakthroughs on the horizon. Acknowledgements  This study was funded by grants from the Ministry of Economy, Industry and Competitivity (SAF2017-83043-R), and by the Program MULTITARGET&VIEW-CM from Community of Madrid, Spain (S2017/BMD-3688), involving contributions from FEDER and FSE funds. Authors Contributions  Pilar López-Larrubia had the idea for the article. Viviana Negri, Jesús PachecoTorres, Daniel Calle, and Pilar Lopez-Larrubia performed the literature search and data analysis, drafted and critically revised the work.

Compliance with Ethical Standards  Conflict of interest  The authors declare that they have no conflicts of interest.

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Affiliations Viviana Negri1   · Jesús Pacheco‑Torres2   · Daniel Calle3   · Pilar López‑Larrubia4  1

Departamento de Biotecnología y Farmacia, Facultad de Ciencias Biomédicas, Universidad Europea de Madrid, Villaviciosa de Odón, Spain

2

Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

3

Laboratorio de Imagen Médica, Hospital Universitario Gregorio Marañón, c/Dr. Esquerdo 56, 28007 Madrid, Spain

4

Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, c/Arturo Duperier 4, 28029 Madrid, Spain





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Topics in Current Chemistry (2020) 378:8 https://doi.org/10.1007/s41061-019-0273-0 REVIEW

Bioconjugated Plasmonic Nanoparticles for Enhanced Skin Penetration David Alba‑Molina1 · Juan J. Giner‑Casares1 · Manuel Cano1  Received: 7 November 2019 / Accepted: 3 December 2019 / Published online: 16 December 2019 © Springer Nature Switzerland AG 2019

Abstract Plasmonic nanoparticles (NPs) are one of the most promising and studied inorganic nanomaterials for different biomedical applications. Plasmonic NPs have excellent biocompatibility, long-term stability against physical and chemical degradation, relevant optical properties, well-known synthesis methods and tuneable surface functionalities. Herein, we review recently reported bioconjugated plasmonic NPs using different chemical approaches and loading cargoes (such as drugs, genes, and proteins) for enhancement of transdermal delivery across biological tissues. The main aim is to understand the interaction of the complex skin structure with biomimetic plasmonic NPs. This knowledge is not only important in enhancing transdermal delivery of pharmaceutical formulations but also for controlling undesired skin penetration of industrial products, such as cosmetics, sunscreen formulations and any other mass-usage consumable that contains plasmonic NPs. Keywords  Plasmonic nanoparticles · Transdermal drug delivery · Bioconjugated nanomaterials · Skin penetration · Gold and silver nanoparticles

Chapter 7 was originally published as Alba‑Molina, D., Giner‑Casares, J. J. & Cano, M. Topics in Current Chemistry (2020) 378: 8. https://doi.org/10.1007/s41061-019-0273-0. * Juan J. Giner‑Casares [email protected] * Manuel Cano [email protected] 1



Department of Physical Chemistry and Applied Thermodynamics, Institute of Nanochemistry (IUNAN), University of Córdoba, Campus Universitario de Rabanales, Ed. Marie Curie, 14014 Córdoba, Spain

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1 Introduction This review is focused on plasmonic nanoparticles (NPs) from among the whole range of inorganic NPs. Plasmonic NPs are composed of colloidal particles of noble metals that present a characteristic surface plasmon resonance (SPR) band. The SPR band is attributed to the electric field of incident light, which induces coherent oscillation of conduction band electrons of the positively charged metallic core (Fig. 1). The optical and electronic properties of plasmonic NPs can be tuned easily by changing their size, shape, and surface chemistry [1–3]. Among the different plasmonic NPs, this work is focused mainly on Au and Ag-based NPs, which are considered as non-allergenic compounds that should not induce cytotoxicity, and are therefore highly attractive for biomedical applications [4, 5]. In addition to the inherent characteristic properties of nanometric materials, such as small size and high surface-area-to-volume ratio, the surface chemistry of AuNPs can be modified easily through covalent Au–S bonds [6, 7]. These features have made AuNPs one of the most widely used nanomaterials in both technological and biomedical applications, such as electronics [8, 9], catalysis [10, 11], sensory probes [12, 13], plasmonic photothermal therapy [14, 15], targeted drug delivery

Fig. 1  Schematic representation of surface plasmon resonance (SPR) band in A spherical and B rodshaped plasmonic nanoparticles (NPs)

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carrier [16, 17], contrast agents in X-ray imaging and computed tomography for cancer diagnosis [18, 19], to name only a few. AgNPs display an inherent antimicrobial capacity against bacteria, viruses, and other eukaryotic microorganisms [20, 21]. Indeed, silver compounds have been used historically to prevent microbial growth in many fields, such as in wound care and in products such as odor-reducing clothing, acne creams, and face masks [22, 23]. Topical administration of compounds presents several advantages compared with other routes such as oral, nasal, and intravenous administration. Transdermal delivery overcomes first-pass hepatic metabolism and can reduce harmful side-effects [24–26]. However, skin is a complex multilayer structure (composed mainly of epidermis, dermis, and hypodermis) and is a highly impermeable barrier to most molecules on the basis of particle size, water-solubility and surface charge [24]. In addition, hair follicles have also been explored as a more permeable transport channel for transdermal drug delivery [27–29]. An excellent review of the influence of size on the penetration of both metal and non-metal NPs through skin was published by Larese Filon et al. [30]. Naked NPs do not overcome skin barriers efficiently, as reported by NúñezLozano et  al. [31] In other words, non-functionalized NPs constitute poor transdermal drug delivery systems [32, 33]. Therefore, many efforts have been made to enhance the skin penetration of NPs through purposely designed chemical functionalization with biomolecules and bioinspired polymers to form biomimetic NPs providing additional abilities in skin penetration. Herein, the latest advances in the development of different approaches to fabricate bioconjugated plasmonic NPs for enhanced skin penetration are presented. This review is organized as follows: first, the influence on the skin penetration of key parameters of non-bioconjugated plasmonic NPs is discussed, and, second, some of the more recently reported bioconjugated plasmonic NPs for enhanced skin penetration are presented.

2 Influence of Key‑Parameters on the Skin Penetration of Non‑bioconjugated Plasmonic NPs The ability of plasmonic NPs to penetrate skin can be tuned by controlling their core-composition, particle-size and -shape, surface charge, water solubility and functionalization strategy, including both capping-ligands and delivered cargoes, i.e., drugs, genes, and proteins. Relevant examples of the most prominent studies in each of these parameters are mentioned below. 2.1 Core Composition (Noble Metal Type) The literature indicates a significant difference in terms of skin penetration behavior between organic and inorganics NPs. There are also significant differences in skin internalization depending on the chemical composition (i.e. T ­ iO2, ­SiO2, ZnO, FeO, CdSe, Pd, etc.) within the latter group, as previously reported by Larese Filon et  al. [30]. In the case of plasmonic NPs, in  vitro penetration of AgNPs through

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intact human skin samples has been reported for several authors (with particle size in a narrow range between 19 and 25 nm), suggesting that ion release is the most feasible penetration mechanism [34, 35]. Whilst, for AuNPs, penetration through intact human skin samples (size ~ 12 nm) has been demonstrated by several authors, although the penetration process is unclear, although the ions release mechanism could be discounted. The absence of Au ions in physiological solutions of AuNPs has been reported, indicating higher long-term colloidal stability than AgNPs [30, 36]. This high stability could explain the absence or low cytotoxicity of this type of plasmonic NPs. 2.2 Particle Size Effects Although the literature reports contradictory results on this issue, skin penetration of NPs is considered a size-dependent process [30]. Note that the stability of the NP coating should be taken into account because it plays a key role in the interactions between skin and both NP core (see section on  Influence of the Capping-Ligand, Including Surface-Chemistry and -Charge), and the NPs (i.e., steric stabilization) by avoiding particle aggregation when they come into contact with the stratum corneum and constituent cells of the skin, mainly keratinocytes. A representative study showing that AuNPs penetrate through intact skin samples in a size-dependent manner was reported by Sonavane et al. [37], who analyzed the penetration of 15, 102 and 198 nm citrate-capped AuNPs, with spherical shapes and surface negative charge, through rat-skin and rat-intestine using Franz diffusion cells. The smallest AuNPs showed higher permeation than the larger particles. In a similar study with rats, Raju and co-workers reported that 22  nm citrate-capped AuNPs showed higher penetration than 105 and 186  nm particles across the thick stratum corneum of the plantar rat skin [38]. A key aspect of the experimental design for assessing the skin penetration of plasmonic NPs is the in vitro or in vivo model used to perform the analysis. Indeed, the choice of a biologically relevant and realistic model for studying the biological effect of NPs is a comparatively unexplored field [39]. Although rat, mouse and rabbits have been used extensively for these penetration studies, pig skin is probably the most similar animal model to the human skin [40]. Pig and human skin are structurally very similar in thickness and dermal-epidermal thickness ratio. Hair follicles and blood vessel patterns in the skin are also similar. In addition, the thickness of the human skin varies considerably as a function of the body region, gender and age, among other factors. For this reason, the results obtained are quite different depending on the in vivo model used, and even depending on the part of the human body used. An interesting study on porcine skin using AgNPs was reported by Samberg and co-workers [22], who evaluated the in  vitro and in  vivo toxicity of eight different commercial AgNPs supplied by nanoComposix (San Diego, CA), such as unwashed/uncoated (diameter of 20, 50, and 80 nm), washed/uncoated (20, 50, and 80  nm), and carbon-coated AgNPs (25 and 35  nm). They observed that the toxicity of AgNPs in human embryonic kidney (HEKs) was influenced significantly by residual contaminants in their supernatant, and that AgNPs themselves may not be

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responsible for the observed increase in cell mortality. The degradation of AgNPs within the cell was also considered as a source of reactive oxygen species that would be damaging to the cell machinery and DNA [41]. Obviously, human skin would be ideal to perform in vitro skin penetration analysis. In 2012, Liu et co-workers [42] investigated the in vitro penetration and metabolic effects of 10, 30 and 60 nm citrate-capped AuNPs within viable excised human abdominal skin after 24-h exposure. Using multiphoton tomograph-fluorescence lifetime imaging microscopy, these authors observed penetration only into the stratum corneum, without significant penetration into the lower layers. They demonstrated that viable human skin resists permeation of small NPs, which had been previously reported to penetrate deeply in other animal skin models. Note that a remarkable attempt to categorize the size range with its skin penetration ability was carried out by Larese Filon et al. [30] They suggested that: (1) NPs smaller than 4 nm can both penetrate and permeate intact skin, (2) NPs in the size range between 4 and 20  nm can permeate both intact and damaged skin, (3) NPs with diameter between 21 and 45 nm can penetrate and permeate damaged skin, and (4) NPs higher than 45 nm can neither penetrate nor permeate the skin. They also considered the hydrodynamic diameter of the NPs, which is an important parameter of the colloidal particles that can be affected greatly both in terms of ligand-coating and the electrolyte composition of the colloidal solution [43]. 2.3 Shape‑Effect Despite the enormous literature reporting protocols for the synthesis of plasmonic NPs with different morphologies, such as rod, triangle, bipyramid, star, cube and others, [44–46], as well as the important effects on the resulting NP flow characteristics, with altered cell membrane interactions, macrophage uptake and circulating lifetimes [47–49], research papers investigating the influence of the NPs shape on skin penetration are rare (Fig.  2). This fact can be attributed mainly to the resulting higher size (e.g. > 45  nm) and to the lower resulting long-term stability of the anisotropic NPs (i.e. non-spherical geometries). Only comparative studies between spherical and rod-shape AuNPs can be found in the literature. A relevant study was reported by Fernandes et al. [50], with their culture experiments in mouse and human skin samples showing that the percentage of PEG-capped Au-nanorods (with an aspect ratio 2.8 ± 0.5) found in all samples was higher than that obtained in similar PEG-capped spherical 15 ± 1 nm AuNPs. These results were obtained for both positively and negatively surface charged NPs, suggesting the great influence of NPshape on penetration capacity. In the case of AgNPs, Tak and co-workers reported a skin penetration study of differently shaped NPs using both in  vitro and in  vivo models [51]. They used spherical, rod-shape and triangular AgNPs with similar hydrodynamic diameter (~ 50 nm) and zeta-potential (+ 30 mV) to perform in vitro analysis on ultra-thin mouse skin section by the Franz cell system, and in vivo analysis on hairless mice. In agreement with previous results for AuNPs, they showed that rod-shaped AgNPs presented a higher permeability index than spherical and triangular AgNPs. They concluded that different shapes of AgNPs may exhibit diverse Reprinted from the journal

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Fig. 2  Schematic representation of A plasmonic NPs with different geometries and B human skin layers

antimicrobial activities and skin penetration capabilities depending upon their active metallic facets. 2.4 Influence of the Capping‑Ligand, Including Surface‑Chemistry and ‑Charge Other important parameters that greatly affects the skin penetration rate of NPs are the surface charge and chemistry, which are associated directly with the stabilizing ligand composition and the type of metal–ligand bonding interaction. Figure 3 summarizes the most frequently found capping ligands, including the type of interaction with the metallic core. Citrate is the main ligand for the synthesis of plasmonic NPs [52, 53], and is the most widely reported. Although the resulting water-soluble NPs present good long-term stability, with a negatively charged surface due to their carboxylate groups, the NPs tended to aggregate easily in contact with the skin (especially for the smallest sizes) due to their relatively weak metal–ligand interactions [7]. Labouta and co-workers [54] showed that water-soluble spherical-shape 15 nm citrate-capped AuNPs tended to aggregate on the superficial stratum corneum. In this study, the penetration rate of hydrophilic 15  nm citrate-capped AuNPs versus hydrophobic 6  nm dodecanethiol-capped AuNPs was also compared, showing that non-water-soluble particles penetrated through the stratum corneum and into viable epidermal layers of human skin. This enhanced skin penetration using dodecanethiol as capping ligand could be attributed to: (1) stronger Au–S binding interaction, which avoided aggregation of NPs in contact with the stratum corneum; and (2) the solubility in organic solvent (i.e., toluene), which could facilitate interaction with cell membranes. A related study from the same research group compared the different penetration rates through human skin of two water-soluble AuNPs (15 nm citrate- and 6 nm lecithin-capped) against two toluene-solved AuNPs (6 nm dodecanethiol- and cetrimide-capped) [55]. They concluded that the vehicle (toluene-versus-water) had a minimal effect on skin penetration of AuNPs.

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Fig. 3  Representative stabilizing ligand for plasmonic NPs

Not only should the bond strength of the metal–ligand interaction be considered but also the coating thickness and the degree of surface coverage. Previous studies have demonstrated that polymeric capping ligands, such as poly(N-vinyl-2-pyrrolidone) (PVP), are well suited to stabilizing the surface of AuNPs for skin penetration, despite the weak metal–ligand interactions via pyrrolidone groups [56]. Huang and co-workers [56] showed that water-soluble 5  nm PVP-capped AuNPs with a spherical shape were mice skin permeable. They attributed this effect to the nanobio interaction with skin lipids, and the consequent induction of transient and reversible openings on the stratum corneum. In addition, they highlighted that co-administration of these PVP-capped AuNPs with protein drugs could enhance transdermal drug delivery. Reprinted from the journal

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Additionally, the capping ligand confers a given surface charge on NPs, which greatly affects the resulting skin penetration rate. For instance, positively charged drug carriers, such as dendrimers and liposomes, are well-known to induce greater drug delivery in the skin [57, 58]. In this context, Fernandes et al. [50] showed that positive charged PEG-capped AuNPs were found in the skin at levels from  2- to 6-fold higher than in their negative counterparts. These results were obtained both for spherical- and for rod-shaped NPs, and were in agreement with the enhanced skin permeation of cationic liposomes, which was attributed to the “Donnan exclusion effect” and to the better interaction of cationic particles with negatively charged skin cells [59]. Furthermore, in this study, they also showed that AuNPs functionalized with cell penetrating peptides (CPPs) TAT and R7 were found in the skin in larger quantities than PEGylated AuNPs, demonstrating that bioconjugation greatly enhances skin penetration rate [50]. In an alternative strategy, Lee and co-workers investigated the influence of the surface charge of Au-nanorods on skin penetration using a layer‐by‐layer (LbL) polyelectrolyte coating technique [60]. They observed that negative charged CTAB/ PSS-capped Au-nanorods penetrated more rapidly through the skin than the positive ones (CTAB- and CTAB/PSS/PDADMAC-capped). For this, three different multi-layer coated Au-nanorods with a particle size of 18 × 40  nm were used: two positively charged, CTAB- and CTAB/PSS/PDADMAC-capped, and one negatively charged, CTAB/PSS-capped. These surprising results were attributed to both aggregation of the positively charged Au-nanorods on the stratum corneum and the adsorption of proteins released from the dermis layer to the surface of Au-nanorods. In line with these results, Mahmoud et al. [61] observed that positively charged Aunanorods aggregated extensively upon exposure to human skin compared to their negatively and neutrally charged counterparts. They attributed these findings to the adsorption of proteins released from the dermis layer to the surface of Au-nanorods. In this latter study, they prepared 49.5 × 12.0 nm Au-nanorods capped with four different surface ligands: cetyltrimethylammonium (CTAB), polyacrylic acid (PAA), poly(allylamine hydrochloride) (PAH), and methoxy-polyethylene glycol-thiol (m-PEG-SH). Conversely, Hao et al. [62] also investigated the influence of the surface charge on the skin penetration of spherical AuNPs using human reconstructed 3D Episkin model. In this study, three different surfaces charged 5  nm-AuNPs capped with citrate (negative), PVP (neutral), and CTAB (positive) were tested. They observed that, although all AuNPs induced the phase change of lipid lamella and passed through the epidermis, positively charged AuNPs exhibited the most efficient skin penetration through both the paracellular routes and the transcellular pathway when compared to neutrally or negatively charged NPs. An interesting alternative for stabilizing NP surfaces is PEGylation, which is an approach commonly used for improving the drug and gene delivery efficiency of NP-based systems to target cells and tissues [63]. Hsiao and co-workers [64] employed this approach to investigate the positive effects of polyethylene glycol (HS-PEG-COOH) and HS-PEG-oleylamine (OAm) functionalization on the skin permeation of spherical 10 nm AuNPs. Using an in vivo rat model, they showed that PEG- and PEG-OAm-functionalized AuNPs were able to overcome the skin barrier and deposit in the deeper subcutaneous adipose tissue. Moreover, the follicular

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deposition of AuNPs increased 2-fold after PEG-OAm functionalization, demonstrating a preferential accumulation mediated by the stabilizing ligand. Mahmoud et  al. [65] evaluated the preferential accumulation of Au-nanorods into abdominal human skin hair follicles. To this end, they prepared 11.4 × 46.6  nm Au-nanorods with five different surface chemistries (i.e., neutral, anionic, cationic, and hydrophobic), such as CTAB, PAA, methoxy-polyethylene glycol-thiol (m-PEG-SH), PEG-Cystamine, and polystyrene (PS). They observed that the lipophilic properties of sebum-rich hair follicles enhanced the accumulation of hydrophobic PS-Aunanorods into hair follicles, while neutral m-PEG-S-Au-nanorods were distributed into all skin compartments, especially the dermis, which exhibits hydrophilic characteristics. In addition, both charged Au-nanorods showed a negligible percentage of penetration into any of the skin compartments.

3 Bioconjugated Plasmonic NPs for Transdermal Delivery of Different Cargoes A seminal study on the development of bioconjugated plasmonic NPs for enhancing the skin penetration of different cargoes was reported in 2010 by Huang et al. [56]. They demonstrated significant enhancement of the transdermal delivery of protein-drugs by co-administration with 5  nm PVP-capped AuNPs. This fact was attributed to the nano-bio interaction with skin lipids, which allowed a reversible openings of the stratum corneum. Thus, this work provided a simple and efficient NP-mediated method for overcoming the skin barrier for percutaneous protein drug delivery. Labala et al. [66] reported the first bioconjugated plasmonic NPs for iontophoretic transdermal delivery of imatinib mesylate to treat melanoma, using an LbL assembly approach. This LbL polymer capped AuNP contained PVP and polyethylene imine (PEI), was subsequentially coated with anionic poly(styrenesulfonate) (PSS) and cationic PEI for drug loading. The resulting bioconjugated nanosystem showed an average particle size and a zeta-potential of 98 ± 4 nm and + 32 ± 1 mV, respectively, and a shift in the SPR wavelength from 518 to 530  nm. The in  vitro skin penetration studies were performed on excised porcine ear, and demonstrated that iontophoresis application enhanced the skin penetration of imatinib mesylate loaded AuNP by 6.2-fold compared with passive application. Bessar et  al. [67] prepared water-soluble sodium 3-mercapto1-propansulfonate(3MPS)-capped AuNPs, which were loaded with methotrexate (MTX) via electrostatic adsorption. The resulting Au-3MPS@MTX conjugate showed an average size and a zeta-potential of ~5 nm and −32 ± 1 mV, respectively. It was then administrated topically on C57BL/6 mouse normal skin in order to assess its absorption behaviour. In vitro and in vivo studies showed that MTX-conjugated AuNPs were much more efficient than MTX alone, suggesting this nanosystem as a potential candidate for topical treatment of psoriasis (see Fig. 4A). An interesting application of bioconjugated plasmonic NPs for enhanced transdermal gene delivery was the reported by Niu and co-workers [69]. In order to facilitate the skin penetration of plasmid DNA (i.e., pDNA encoding miRNA-221 inhibitor -Mi221-) deep into melanoma tissues, these authors synthesized 20–25 nm Reprinted from the journal

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Fig. 4  A Electron microscopy images of normal human keratinocytes. a Control, b cells treated with bioconjugated plasmonic NPs [67]. Copyright Elsevier, 2016. B Wounds treated with non-coated and bioconjugated plasmonic NPs, showing the absence of granulation tissue [68]. Copyright Elsevier, 2018

conjugated AuNPs containing a cell-penetrating TAT peptide and the cationic PEI that could compact the pDNAs into cationic nanocomplexes (i.e., zeta-potential ~ +35  mV). They demonstrated that the resulting plasmonic bioconjugates can penetrate through the intact stratum corneum without any additional physical enhancement method. This study proposed a novel topical gene therapy strategy for skin cancer with great priority to reverse both the progression and metastasis of advanced melanoma. Chen et  al. [70] fabricated a biocongugate plasmonic NP for the transdermal delivery of vascular endothelial growth factor (VEGF) in wound repair. To that end, they performed the bioconjugation of AuNP-PEG-COOH with VEGF through carbodiimide bonds, obtaining a negative surface charged nanosystem, whose absorption capability was evaluated by a mouse skin model. After treatment, they observed not only the presence of VEGF in the dermis but also its effect for promoting angiogenesis, demonstrating that, in this case, the binding of protein biological factors to AuNPs could preserve the activity of the protein. Another study was reported by Safwat et  al., who fabricated AuNPs capped with benzalkonium chloride and with PEI for enhanced loading and skin permeability of 5-fluorouracil (i.e., 5-FU/BC-AuNPs and 5-FU/PEI-AuNPs, respectively) [71]. They performed ex  vivo permeability studies of different 5-FU preparations using mice skin, demonstrating that the permeability of 5-FU was significantly higher for drug-loaded AuNPs compared with the other tested 5-FU samples. This same research group also

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prepared 5-FU loaded through ionic interactions onto CTAB capped AuNPs, and the resulting nanocomposite was incorporated into gel and cream bases to evaluate its permeability both ex vivo in mice dorsal skin and in vivo in A431 tumor-bearing mice [72]. They observed that the nano-formulation provided around 2-fold higher permeability through mice skin compared with free 5-FU gel and cream formulations, and achieved 6.8- and 18.4-fold lower tumour volume than the untreated control with the gel- and the cream-based nano-formulation, respectively. On the other hand, Boca et  al. [73] performed the first preliminar study to evaluate the potential use under dermatological conditions of Ruxolitinib-conjugated 15  nm AuNPs as alternative for treating alopecia. Using in  vitro preclinical setting, they showed that AuNPs@TWEEN-20@Ruxolitinib inhibited the proliferation of fibroblasts by inhibiting JAK2 protein, suggesting it as a potential strategy to treat alopecia. Another novel and alternative administration strategy of bioconjugated plasmonic NPs was proposed by Anirudhan et al. [74], who fabricated a nanocomposite film containing methacrylate-stitched β-cyclodextrin embedded with AuNPs and hydrophobic titanium nanotube (TNT) and tested the transdermal delivery of ibuprofen through in vitro rat skin. They showed that the resulting film exhibited an improved drug-delivery performance, which was attributed to synergistic action of AuNP and hydrophobic TNT. They proposed this nanocomposite film as an alternative skin permeation strategy for transdermal drug delivery. Similarly, this same research group proposed a polyelectrolyte membrane fabricated with guar gum, poly(vinyl alcohol) and a nanogold-nanocellulose composite for the topical administration of diltiazem hydrochloride. In vivo use of this film on human skin was analyzed, suggesting its potential use for transdermal drug delivery [75]. Pan et al. [68] explored the effects on wound healing of keratinocyte growth factor (KGF) cross-linked to AuNPs. Using an animal full-thickness wound model, they showed that KGF-AuNPs were more favorable to wound healing than bare AuNPs or KGF, thus proposing KGF-AuNPs as a promising wound healing drug for clinical application, see Fig. 4B. Crisan et al. [76] evaluated the impact on psoriatic inflammation of AgNPs and AuNPs complexed with Cornus mas (i.e., polyphenols-rich extracts) by using an in vitro model based on pro-inflammatory macrophages. The results obtained from all the performed in  vitro analysis suggested that these bioconjugated plasmonic NPs provide an efficient tool for modern psoriasis therapy, circumventing immunosuppression-related side effects of biologicals. In another study, Wang et al. [77] fabricated an antimicrobial peptide (LL37) grafted ultra-small AuNPs (AuNPs@LL37, ~7 nm), which was combined with proangiogenic (VEGF) plasmids to analyze its potential use for the topical treatment of diabetic wounds with or without bacterial infection. The resulting bioconjugate (AuNPs@LL37/pDNAs) combined the advantages of cationic surface charged NPs that condense DNA with those of antibacterial peptides and enhance the cellular and nucleus entry to achieve high gene delivery efficiency. AuNPs@LL37/pDNAs were shown to greatly improve the gene transfection efficiency in keratinocytes compared with pristine AuNPs/pDNAs, exhibiting a similar expression to Lipo2000/pDNAs (a well-known highly efficient gene transfection agent), whilst displaying higher antibacterial ability. Thus, this bioconjugated plasmonic NPs were suggested as a suitable strategy for treating chronic diabetic wounds. Reprinted from the journal

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More recently, Fratoddi et al. [78] analyzed the effects of AuNPs functionalized with 3-mercapto-1-propansulfonate (AuNPs-3MPS) and loading MTX topically administered in vitro on a skin model and in vivo on an imiquimod-induced psoriasis-like mice model. The showed that treatment with this system was able to induce a reduction in keratinocyte hyperproliferation, epidermal thickness and also the volume of inflammatory infiltrate in the in vivo model used. Hernández-Martínez et al. [79] synthetized and evaluated a nanocomposite of AuNPs functionalized with calreticulin. Using in  vitro and in  vivo wound healing mice models of diabetes, they assessed the ability of the nanocomposite to promote proliferation and migration. Their results confirmed the utility of this bioconjugated plasmonic NPs (AuNPscalreticulin) as potential treatment for wound healing of diabetic ulcers. In the case of AgNPs-based bioconjugates, Mandal and co-workers [80] fabricated a nanocomposite hydrogel comprised of in  situ formed Ag nanowires (AgNWs) deposited with chemically cross-linked carboxymethyl cellulose (CMC), which demonstrated superior efficacy as a transdermal anticancer drug-curcumin carrier. This plasmonic bioconjugate had the capacity to encapsulate both hydrophobic/hydrophilic transdermal drugs. In vitro experiments suggested that the presence of AgNWs on cross-linked CMC enhanced both the penetration power of nanocomposite hydrogel and drug release in a sustained manner. Whilst ex vivo rat skin permeation analysis confirmed that drug delivery through the nanocomposite hydrogel was permeable through the rat skin in controlled fashion, efficiently killing the MG 63 cancer cells. Table 1 summarizes the bioconjugated plasmonic NPs cited in this review, indicating both the loaded active molecule and the potential application.

4 Conclusions Bioconjugated plasmonic NPs are a promising approach for topical administration of different cargos for several diseases. The excellent biocompatibility and readily adjustable physical and chemical features of plasmonic NPs are highly attractive options for purposefully designed nanomaterials aimed at biomedical applications. Several examples have been presented herein, illustrating the wide range of cargoes and functionalization strategies that might be included when designing a bioconjugated plasmonic NPs. Different physical and chemical parameters should be taken into account when analyzing the effect of plasmonic NPs on human skin. While chemical routes for obtaining on-demand plasmonic NPs are relatively wellestablished, and a large number of simple and reproducible experimental protocols are available, the main frontier for mass usage is still a correct assessment of the toxicity of the NPs. Providing a relevant model for human skin, the experimental conditions for studying location and local concentration of plasmonic NPs differ greatly from those found in synthesis laboratories. Therefore, this fruitful field of research requires more efforts to fully understand the penetration mechanisms of these bioconjugated plasmonic NPs, enabling a decrease in associated toxicity and potential long-term environmental impacts. In view of the latest contribution to the field, we speculate that a reliable framework will be available in the short term, enabling a

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Topics in Current Chemistry (2020) 378:8 Table 1  Representative cargoes in through bioconjugated plasmonic nanoparticles (NPs) for skin disease treatments Active molecule

Cargo type

Activity/application

NP Au

References

Imatinib mesylate

Drug

Anticancer

Methotrexate (MTX)

Drug

Anti-inflammatory (psoriasis) Au

[67, 78]

[66]

microRNA mir-221

Gene

Tumour suppressor (melanoma)

Au

[69]

Vascular endothelial growth factor (VEGF)

Protein

Wound repair

Au

[70]

Ibuprofen

Drug

Anti-inflammatory

Au

[74]

Diltiazem hydrochloride

Drug

Vasodilator

Au

[75]

5-fluorouracil (5-FU)

Drug

Anticancer

Au

[71, 72]

Ruxolitinib

Drug

Anti-alopecia

Au

[73]

Keratinocyte growth factor (KGF)

Protein

Wound repair

Au

[68]

Polyphenols-rich extracts (Cornus mas)

Natural extract

Anti-inflammatory (psoriasis) Au & Ag [76]

Antimicrobial peptide LL-37 and pDNA: Pro-angiogenic (VEGF) plasmids

Protein and gene Diabetic wound healing

Au

[77]

Calreticulin

Protein

Diabetic wound healing

Au

[79]

Curcumin

Natural extract

Anticancer

Ag

[80]

second wave of research of directed synthesis and application of plasmonic NPs under in vivo conditions. Acknowledgements  We apologize to authors whose work could not be included in this review due to space restrictions. Support from the Ministry of Science, Innovation and Universities of Spain is acknowledged through the MANA project CTQ2017-83961-R  and JEANS project  CTQ2017-92264-EXP. J. J. G.-C. acknowledges the Ministry of Science, Innovation and Universities of Spain for a “Ramon y Cajal” contract (#RyC-2014-14956). M. C. thanks the “Plan Propio de Investigación” from the Universidad de Córdoba (UCO) and the “Programa Operativo de fondos FEDER Andalucía” for its financial support through both postdoctoral contracts (Modality 5.2.A).

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Topics in Current Chemistry (2020) 378:43 https://doi.org/10.1007/s41061-020-00306-6 REVIEW

Proteins‑Based Nanocatalysts for Energy Conversion Reactions Daily Rodriguez‑Padron1 · Md Ariful Ahsan2,3 · Mohamed Fathi Sanad2 · Rafael Luque1,4 · Alain R. Puente Santiago2  Received: 2 January 2020 / Accepted: 10 June 2020 © Springer Nature Switzerland AG 2020

Abstract In recent years, the incorporation of molecular enzymes into nanostructured frameworks to create efficient energy conversion biomaterials has gained increasing interest as a promising strategy owing to both the dynamic behavior of proteins for their electrocatalytic function and the unique properties of the synergistic interactions between proteins and nanosized materials. Herein, we review the impact of proteins on energy conversion fields and the contribution of proteins to the improved activity of the resulting nanocomposites. We address different strategies to fabricate proteinbased nanocatalysts as well as current knowledge on the structure–function relationships of enzymes during the catalytic processes. Additionally, a comprehensive review of state-of-the-art bioelectrocatalytic materials for water-splitting reactions such as hydrogen evolution reaction (HER) and oxygen evolution reactions (OER) is afforded. Finally, we briefly envision opportunities to develop a new generation of electrocatalysts towards the electrochemical reduction of ­N2 to ­NH3 using theoretical tools to built nature-inspired nitrogen reduction reaction catalysts. Keywords  Proteins · Nanomaterials · Energy conversion Daily Rodriguez-Padron and Md Ariful Ahsan contributed equally to this work.

Chapter 8 was originally published as Rodriguez‑Padron, D., Ahsan, M. A., Sanad, M. F., Luque, R. & Santiago, A. R. P. Topics in Current Chemistry (2020) 378: 43. https://doi.org/10.1007/s41061-02000306-6. * Alain R. Puente Santiago [email protected] 1

Departamento de Química Orgánica, Universidad de Córdoba, Campus de Rabanales, Edificio Marie Curie (C‑3), Ctra Nnal IV‑A, Km 396, 14014 Córdoba, Spain

2

Department of Chemistry, University of Texas at El Paso, 500 W. University Avenue, El Paso, TX 79968, USA

3

Nanosystems Engineering Research Center for Nanotechnology-Enabled Water Treatment, Houston 77005, USA

4

Peoples Friendship University of Russia, (RUDN University), 6 Miklukho‑Maklaya Str., 117198 Moscow, Russia



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1 Introduction Proteins are well-designed nanosized machines that can dynamically catalyze myriad catalytic reactions with molecular-level accuracy [1–4]. As an example of heterogeneous catalysis, electrocatalysis, which explores the relationship between the physicochemical properties of electrode materials and both their underlying mechanism and rate of the electrode reactions, have been widely investigated. Particularly, the development of bio-based advanced energy conversion nanosystems has recently emerged as an important and attractive topic. Water-splitting reactions represent a promising and sustainable way to obtain hydrogen and oxygen through the development of renewable energy fuel devices, which fulfill a crucial role in solving the global energy crisis. The mechanistic principles that proteins use to acts as efficient catalysts towards the generation of fuels have been intensively investigated [5]. As a result, bio-inspired synthetic catalysts have been generated to deeply study the biological activity of different kinds of enzymes for the production of added-value chemical compounds. Additional efforts have been performed to unravel the connection between the structure and the catalytic performances of active enzymes for water-splitting reactions [6–9]. It has been established that there is a good relationship between the structural or conformational changes of enzymes and their catalytic activity on the ms–μs timescale. [10–15] In this sense, small conformational variations or motions of just a few residues in the three-dimensional (3D) protein frameworks can also improve the efficiency of the electrochemical reaction that occurs at the electrode–electrolyte interface and, in turn, the overall electrocatalytic process. The impressive abilities of proteins to adopt catalytically competent configurations via efficient conformational changes on specific domains of their tertiary structures towards environmental changes such as pH, temperature or even ionic strength then become promising candidates for the development of high-performance electrocatalysts. Although several enzymes exhibit high catalytic performances, electronic conductivity through the amino acids of the tertiary structure is still being low, which represents a drawback to obtaining effective electrocatalytic nanosystems [16–19]. To address this limitation, several strategies have been attempted in the past years. Among them, the engineering of nanobiointerfaces at the molecular level using different immobilization approaches to optimize the efficiency of electrocatalytic reactions has become one of the most effective strategies [20]. To develop the latter strategy, a couple of key factors have been fairly well determined. Firstly, the enzyme immobilization process should be optimized to reach a high coverage of active molecules on the electrode surface. Secondly, the electronic wiring between the active sites of the immobilized enzyme molecules and the electrodes plays a crucial role in generating advanced electrocatalysts. Consequently, they have been integrated via covalent or non-covalent functionalization to a large number of conductive nanomaterials (i.e., gold nanoparticles, graphene sheets, and nanotubes) to generate the most electroactive orientations of active centers assuring faster electron transfer (ET) processes and enhancing the conductive wiring and, in turn, the catalytic efficiency of the resulting biomaterials [21–26].

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N-doped carbon nanostructures have been widely employed as high-performance electrocatalysts for water-splitting reactions. Particularly, the development of N‐doped graphene and N‐doped carbon nanotubes has sparked a lot of interest in recent years in the material science community. In this direction, Junji Nakamura and coworkers, through a seminal work, have elucidated, after a long period of controversy, the mechanism of the oxygen reduction reaction (ORR) in N-doped carbon materials. They discovered that pyridinic N can generate carbon atoms with Lewis basicity, which leads to the adsorption of ­O2 molecules onto them at the first step of oxygen electroreduction [27, 28]. Finding new avenues to synthesize metal-free electrocatalysts, proteins have been used as a N-source to create very promising N-doped carbon nanocatalysts due to the significant contents of pyrrolic N, pyridinic N and amine groups in their molecular architectures. Among the most significant contributions found is the covalent attachment of hemoglobin to fructose-functionalized graphene oxide nanostructures to built high-performance ORR electrocatalysts [6]. Through an elegant and pioneering work, Santiago and coworkers have developed a methodology to multiply the electrocatalytic activity of graphene-oxide nanoplatforms through the unfolding of adsorbed hemoglobin molecules using fructose linkers as denaturing agents. During the denaturalization process, the proteins adopt a fibrin-like structure, releasing almost all their redox-active centers and exposing their pyridine groups to electrochemical interfaces. The fixed hemoglobins significantly boosted the ORR properties of the graphene oxide nanoplatforms in terms of onset potential and current density. This work paved the way towards the development of metalfree nanobioelectrocatalysts. Inspired by nature, Compton and coworkers developed a revolutionary methodology to amplify the ORR bioelectrocatalytic signal of redox proteins using layered structured films composed of conductive polymers and hemoglobin molecules in a sandwich-like configuration [29]. The synergistic interactions between Nafion and hemoglobin gave rise to the full conversion of oxygen to water by a four-electron pathway of the water-splitting process, which, in turn, boosted electrocatalytic activity. Redox enzymes possess myriad different types of redox sites, including hemes, chlorins, quinones, favins, Fe–S clusters, tyrosine and tryptophan residues, copper, molybdenum, and manganese ions, which can catalyze a large portfolio of redox reactions based on their electron-transporting properties and structural affinity for the reactant molecules [30–34]. Remarkably, they could be easily integrated into different types of nanoplatforms to significantly boost their electrocatalytic performances. In this review, we provide a timely summary of recent methodologies developed to fabricated high-performance protein-based nanoelectrocatalysts for water-splitting reactions. We describe the relationship between the structural properties of the nanobiomaterials and their electrocatalytic performances based on an understanding of the reaction mechanisms and the role of the biomolecule structure. Additionally, we envision the development of molecular biocatalytic nitrogen reduction reaction (NRR) nanomaterials for the efficient electrochemical production under mild conditions of ammonia, which is used as a refrigerant gas, for purification of water Reprinted from the journal

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supplies, and in the manufacture of plastics, explosives, textiles, pesticides, dyes, and other chemicals.

2 Proteins as Efficient Building Blocks to Construct Advanced Electrocatalytic Materials Currently, many researchers, motivated by the high efficiency observed in nature, have directed their studies towards the design of bioinspired materials. In this sense, enzymes are highly efficient and selective biological catalysts. The presence of redox groups in this type of biomolecule has led to different electrochemical applications. Enzymes can catalyze a series of redox reactions with great technological importance, which generally require high overpotentials [35]. It is worth highlighting that the use of enzymes provides many advantages, such as high electrocatalytic currents and the possibility of carrying out electrocatalytic processes in a reversible way. For instance, hydrogenases are metalloenzymes, which catalyze the reversible conversion of hydrogen [36]. Depending on the metal content in the active sites of the protein, three main classes of hydrogenases can be highlighted: [FeFe], which contains two iron atoms and is a faster biological catalyst for hydrogen oxidation/ reduction reactions; [NiFe], which possesses an active heterobimetallic site; and [Fe], which contains only one iron atom in its structure. Due to their ability to efficiently electrocatalyze hydrogen production, a series of hydrogen fuel cells has been designed using these enzymes, representing a valuable alternative in the design of biodegradable energy devices [37–39]. Hemoglobin, in particular, is a protein that contains iron atoms in its structure, and that has been widely characterized due to its importance for living beings [40]. Hemoglobin comprises a redox, globular, and tetrameric structure. Each subunit is formed by polypeptide chains, mostly in alpha-helix conformation, that encompass in their structure a heme group containing an atom of Fe. This ­Fe2+ ion is in the center of an organic heterocycle called porphyrin, which is responsible for reacting with oxygen and carrying out blood oxygen transport. These characteristics allow these types of proteins to act as smart catalytic platforms in the oxygen evolution reaction, as well as in other types of oxidation reactions. Moreover, peroxidases are another class of enzymes that have been used as sustainable electrocatalysts. These ­ 2O2, thanks to the presproteins catalyze the oxidation of organic molecules using H ence of the Fe-porphyrin group [41]. In particular, enzymes known as multicopper oxidases (MCOs) show excellent properties towards electroreduction of O ­ 2 at high potentials [42]. MCOs are a family of metalloenzymes that possess three different copper sites: Cu types 1, 2 and 3. In this case, oxidation of the reducing substrate occurs at the Cu type 1 site (T1), while the reduction of ­O2 occurs in the trinuclear group T2/T3 [43]. A wide range of strategies has been used to immobilize these enzymes, from covalent bonding to carbon nanotubes and graphene conductive nanomaterials to encapsulation in silica structures [44, 45]. Furthermore, it is known that specific enzymes exhibit excellent ability to reduce ­CO2–CO and formic acid, behaving as reversible electrocatalysts. For example, the

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carbon monoxide dehydrogenase enzymes present in anaerobic organisms contain a group (NiFe-4 S) that catalyzes the interconversion of C ­ O2 and CO [41]. The enzyme formate dehydrogenase, with active sites of pyranopterin molybdenum/ tungsten, can catalyze the interconversion of C ­ O2 and formate [45]. In particular, formate has attracted much interest as an energy source, since it is easier to store and transport than hydrogen. Using a bio-synthetic approach, many scientists have developed models to mimic metalloenzymes such as hydrogenases and nitric oxide reductase, among others [46–48]. Although the catalytic efficiencies obtained for these artificial systems are still low in comparison with natural systems, such strategies are very promising and have great potential for the future.

3 Influence of Protein Conformational Variations on the Electrocatalytic Activity The structure–function relationship of protein-based nanocatalysts has been investigated thoroughly in order to gain insights into the rules that govern the bioelectrocatalytic process at the molecular scale. The understanding of bioelectrocatalytic mechanisms at a structural level constitutes vital knowledge towards the design of enzyme-based nanomaterials as potential electrocatalysts for bioenergy applications. Nevertheless, although the catalytic activity of various redox proteins has been studied widely and linked with their structural properties, the influence of structural modifications to the protein architecture on the bioelectrocatalytic properties of protein-based nanosystems have been scarcely reported. In this direction, Alina Sekretaryova and colleagues have studied the oxygen electroreduction behavior of single redox enzymes when they impact with ultramicroelectrode surfaces (Fig.  1) [49]. Interestingly, they found that the electrochemical signals followed spike-shaped patterns instead of steady-current steps, which could most likely be associated with the partial denaturation or structural changes of single laccase molecules during the adsorption process. In this regard, the conformational Fig. 1  Scheme showing the principle of detection of the catalytic current from a single enzyme molecule

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or structural variations of the proteins might be promoting direct electron transfer (DET) between the electrode and the T1 redox centers of the enzymes, and, therefore, the electroreduction of molecular oxygen to water. Despite the aforementioned breakthrough, there is a lack of knowledge of the structural and conformational properties of enzymes at each catalytic step. Therefore, the chemical and structural factors that enable electrochemical activity, as well as a deep understanding of the electron transfer processes associated with the catalytic reaction, has yet to be completely unraveled experimentally. In this direction, amplifying the low electrocatalytic signal of enzyme-electrode signals using lowdimensional materials to improve the electronic communication of proteins with the surface electrodes and, in turn, facilitate the electrochemical investigation of the catalytic role of enzymes, represents a suitable alternative. Also, a large number of advanced electrochemical techniques, quartz-crystal microbalance measurements, and spectroscopic techniques such as resonance Raman and infrared spectroscopy should be coupled in situ to the resulting nanocomposites to gain insightful advances in the mechanistic understanding of enzyme-based electrocatalysts [2]. As a first approach, Rafael Luque and coworkers have reported that the partially unfolded states of laccase molecules mechanochemically immobilized on magnetic nanoparticles give rise to very low onset potential and outstanding currents towards the direct bioelectrocatalytic reduction of molecular oxygen [50]. The low content of α-helix, together with the increase in the number of low-frequency β-sheets, was associated directly with improved electrocatalytic activity (Fig.  2). This pioneering work sheds light on the nature of the nanometric interaction between proteins and low-dimensional materials and the impact on their bioelectrocatalytic function. However, the detailed mechanism of how conformational variations of proteins can lead to improvements in electrocatalytic activity is still unclear. Therefore, investigation of the underlying chemistry of protein-based nanocatalysts in the electrocatalytic process is still in its infancy. A lot of research should be carried out to disentangle the structural variations that proteins attached to lowdimensional materials undergo under electrocatalytic conditions. Molecular dynamics studies of the movement of these proteins during bioelectrocatalysis can be applied successfully to unravel their dynamic catalytic performances at the molecular scale. Additionally, control of the structure–function properties of nanobiocatalyts using molecular biology approaches such as the replacement of specific amino acids to greatly improve their electrocatalytic yields constitutes a promising strategy. Briefly, we envision that this knowledge will open the door towards the development of a new generation of biomaterials with unbeatable electrocatalytic properties.

4 Protein Based‑Materials as High‑performance Water‑Splitting Electrocatalysts Proteins have ultimately inspired the design of powerful nanomaterials towards the electrochemical reduction of ­O2. Two approaches have delivered impressive outcomes: (1) N-based nanocomposites fabricated using N-containing proteins and (2) the incorporation of redox-active sites into the nanohybrid structures.

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Fig. 2  Fourier-transform infrared (FT-IR) spectroscopy of a laccase functionalized waste-derived iron oxide nanoparticles (LAC-DA-Fe2O3) and b deconvoluted FT-IR spectrum of LAC-DA-Fe2O3 nanobioconjugates (reprinted from ref. [50])

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4.1 N‑Containing Proteins ORR-based electrocatalysts are considered as essential components of metal–air batteries and fuel cells [51, 52]. The most common ORR electrocatalysts are mainly platinum and its alloys due to their higher current density and relatively lower overpotential. But the higher cost, availability, anode crossover and severe intermediate tolerance, etc. of platinum impose restrictions on the advancement of fuel cell technologies. Therefore, the development of low-cost, as well as high-performance ORR catalysts, has being investigated in recent times [53]. In this regard, low-cost and metal-free carbon-based electrocatalysts have drawn immense attention owing to their superior durability and excellent electrocatalytic activity. There are different types of carbon materials, including porous carbon, graphene, activated carbon and carbon nanotubes, which have been used to improve the catalytic activity and durability of electrocatalysts by maximizing their electroactive surface area. Recently, it was found that the electrocatalytic performance of the ORRs can be enhanced by nitrogen doping of carbon materials [28]. The presence of abundant and free-flowing sp2 hybridized pi electrons are mainly responsible for this significant enhancement in performance. Lone pair electrons of nitrogen atoms also help to connect the delocalized conjugated systems, thereby resulting in additional improvement in electrocatalytic activity. Nitrogen doping of carbon nanostructures can be accomplished by two conventional procedures such as ‘in situ doping,’ which is done during the synthesis of carbon materials, and ‘post doping,’ which is achieved through the post-treatment of carbon nanostructures. But these methods usually require expensive hardware, multi-step processes and high energy consumption, which eventually restricts their practical applicability. To overcome these problems, exploitation of N-containing proteins can be beneficial because of their easy availability as well as the simplicity of preparing N-doped carbonaceous materials. Blood proteins (BPs) from animals, which can be sourced from the meat industry, contain various amino acids such as proline, glutamic acid and tyrosine, and an abundance of hemoprotein. These substances can successfully produce active electrocatalysts for ORR in both acidic and alkaline environments. Therefore, BP could be used as a potential precursor material for making highly active electrocatalysts. Guo et  al. [54] reported a novel approach for designing nitrogen-enriched carbonbased electrocatalysts for ORR through the co-pyrolysis of a carbon black support and BP. At first, the BP was decomposed at 350 °C for 5 h under a constant flow of nitrogen. The pyropolymer obtained was then mixed with the carbon black support by ball milling. The sample yielded was again treated at 1000 °C for 2 h in a nitrogen atmosphere (BP350C1000) and then used as an electrocatalyst for ORR. As a control, the BP was also carbonized for 2  h at 1000  °C and the sample was denoted as BP1000. Furthermore, BP3501000 was prepared by the continuous heat treatment of BP for 5  h at 350  °C and 2  h at 1000  °C without adding the carbon black into it. The results demonstrated that the nitrogen present in the as-synthesized electrocatalyst from BP is mainly in the form of pyrrolic- and pyridinic-type nitrogen species. The electrocatalyst comprising higher amounts of pyrrolic-type nitrogen species exhibited better electrocatalytic performance towards the ORR in terms of limited current density, half-wave potential, and onset potential. In this

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study, the best electrocatalyst (BP350C1000) exhibited an onset potential of 0.90 V and a half-wave potential of 0.78 V, which are close to the Pt/C, and catalyzes the electrochemical reduction of ­O2 through a four-electron pathway (Fig. 3a–d). It was also found that the carbon black support plays a vital role in the pyrolysis process, resulting in improved catalytic activity. The difference between BP350C1000 and BP3501000 in the electrocatalytic activity of the ORR can be ascribed to three features: (1) introducing carbon support yields more exposed electrocatalytic active sites and delivers a greater space for more catalytically active sites by preventing aggregation during the pyrolysis process; (2) addition of carbon black support helps to create new catalytic active sites on modified carbon materials with other formed N-containing groups from the further decomposition of BP350 precursors during the high-temperature carbonization process, and (3) a larger amount of pyrrolic-N configuration is formed in BP350C1000 than in BP3501000. These results indicated that the utilization of carbon black as a conductive material and inserting a matrix to create catalytic active sites in the pyrolysis process can significantly enhance its ORR electrocatalytic activity in alkaline media. Collagen—the most abundant extracellular protein—is usually found in mammalian connective tissues. Animal skin wastes are used as a potential precursor to extract collagen easily, and the collagen obtained can also be used as an efficient precursor for the preparation of carbon nanostructures. Ajayan et al. [55] reported a

Fig. 3  a Oxygen reduction reaction (ORR) polarization curves for blood proteins (BP) BP1000, BP3501000, and BP350C1000 before and after accelerated aging tests (AAT) at a rotation rate of 1600  rpm. b Tafel plots for BP1000, BP3501000, and BP350C1000. c ORR polarization curves for BP350C1000 at different rotation rates. d Koutecky-Levich curves (reprinted from Ref. [54]) Reprinted from the journal

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facile method to prepare nitrogen-rich carbon nano-onions from collagen to use as an ORR electrocatalyst. They used goat skin wastes as a source of collagen. Electrochemical measurements demonstrated that the electrocatalytic activity of the prepared carbon samples is significantly comparable to that of commercially available 20% Pt/C electrocatalyst. The best electrocatalytic performance was observed for the carbon sample synthesized at 750 °C for 8 h with an onset potential of  −50 mV vs. Ag/AgCl while comparing to 81 mV for 20% Pt/C. The electrocatalyst with higher pyridinic nitrogen content exhibited an effective four-electron transfer ORR mechanism with a current density that is almost comparable to commercial Pt/C. The main driving force enhancing ORR performance is the existence of the pyridinic nitrogen atoms, which act as active sites as well as delivering net positive charge on the adjacent carbon atoms to facilitate oxygen adsorption along with the attraction of electrons from the anode. Furthermore, the nitrogen-rich carbon nano-onion-based electrocatalysts displayed outstanding durability performance in the alkaline medium as well as superior methanol tolerance as compared with the 20% Pt/C. Laccases are known as MCOs that are usually found in bacteria, fungi, and plants. They can couple the one-electron oxidation of four substrate equals with four-electron reduction of an oxygen molecule to water. The electroreduction mechanism happens by following a ping-pong mechanism. Oxidation of the substrates takes place near the solvent-accessible T1 site. The electrons are then transferred through the protein by following the Cys–His pathway over a distance of ∼12 Å to the trinuclear copper center where the ORR takes place. Luque et  al. [56] reported the synthesis of an unprecedented electrically active silica-encapsulated laccase material through a facile and eco-friendly one-pot biosilicification process and used for the ORR for the first time. The one-pot biosilicification preparation facilitated the lodging of the enzymes in the highly active alignments required for direct transfer of the electrons of T1 redox centers. As a result, the biosilicified laccase material that is deposited on the nickel electrodes displayed an effective bioelectrocatalytic reduction of oxygen, delivering an outstanding current density of up to 0.94 mA/cm2 and good long-term stability properties (Fig. 4). To design a metal-free ORR electrocatalyst, Chen et  al. [57] reported a novel strategy for preparing nitrogen-doped carbon nanomaterial-based electrocatalysts by utilizing pyrolysis of the protein-enriched enoki mushroom at 900  °C, along with carbon nanotubes as an inserting matrix and conductive agent. The mushrooms are an abundantly available, renewable biomass source and are amino acid-rich. They behave as a single precursor material for both carbon and heteroatoms, thus avoiding the utilization of complicated chemicals in the preparation method. It was found that numerous forms of nitrogen (graphitic, pyrrolic and nitrile) were inserted into the carbon molecular skeleton of the product, which displayed excellent ORR electrocatalytic performance as well as better durability behavior in alkaline medium compared with those in acidic medium. The onset potential of the electrocatalyst obtained in this study was about 0.94 V in the alkaline medium, which is comparable with state-of-the-art Pt/C electrocatalysts (0.98 V). Remarkably, the measured ORR half-wave potential of the prepared electrocatalyst was found to be 0.81 V in alkaline medium, which is slightly lower than that of the 20 wt% Pt/C electrocatalysts

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Fig. 4  Cyclic voltammograms of a free laccase and b biosilicified laccase under oxygen purging in 0.1 M phosphate-buffered saline (PBS) at pH 6. Scan rate: 0.01 V/s. b Chronoamperometric responses at Eapp = 0.2 V (reprinted from Ref. [56])

(0.86  V). Also, the reduction reaction followed the four-electron transfer ORR mechanism including the direct reduction pathway. The authors suggested that the graphitic-nitrogen species that are mostly responsible for the ORR performance can also function as an active center for the ORR reaction, whereas the pyrrolic-nitrogen species can behave as an active promoter for ORR only. Nature offers many biological materials such as proteins, enzymes, etc. that contain histidines, which could be utilized as a natural source of “pyridine-like” nitrogen species offering catalytically active sites for ORR. Among such proteins, hemoglobin (Hb) is a tetrameric redox protein comprised of four polypeptide chains wherein each polypeptide chain encircles at least one active iron redox center. Puente-Santiago et al. [6] reported an unprecedented bottom-up method to prepare a high-performance bioelectrocatalytic system for ORR from the covalent anchorage of Hb to fructose-modified graphene oxide nanoplatforms via the glycosylation reaction mechanism. The resulting nanobiomaterials were prepared at room temperature (GO-Fruc@Hb-RT) as well as at 80 °C (GO-Fruc@Hb-HT) to gain information on the structural characteristics of the redox enzymes in the prepared nanomaterials as well as their electrocatalytic activity toward ORR reactions. Electrocatalytic experiments revealed that the measured onset potentials for both three-component nanocomposites moved to more positive values than their individual parts, demonstrating their higher electrocatalytic activities. Furthermore, the limiting current density was also increased for both nanocomposites, with the best electrocatalytic activity for the nanocomposite being synthesized at a higher temperature because the number of pyridinic nitrogen species is increased at higher temperature due to the additional conformational changes. Additionally, a few examples in the literature have addressed the fabrication of protein-based nanosystems as high-performance HER catalysts. One outstanding strategy is the synthesis of engineered biocatalysts for ­H2 evolution. In this sense, Bren and coworkers [58] have elegantly synthesized a synthetic protein named cobalt mimochrome VI*, which is able to remarkably catalyze the hydrogen Reprinted from the journal

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evolution process, delivering an ultralow onset potential and a turnover number exceeding 230,000. Also, Santiago and coworkers have developed an innovative HER-based catalyst composed of graphitic carbon nitride nanostructures functionalized with different silver contents and α-rich proteins. The as-synthesized nanomaterials rendered an impressive overpotential of 79 mV at a current density of 10 mA/ cm2 towards molecular hydrogen production, which is comparable with the most efficient HER electrocatalysts reported in the literature [59]. 4.2 Redox Proteins Current energy requirements have demanded that we find new alternatives for the development of catalytic systems, which be able to carry out proton-coupled redox reactions. In particular, ORR has been a focus of attention of the scientific community in recent years, since it is the cathodic reaction of fuel cells [60, 61]. Indeed, ORR is crucial to the function of hydrogen fuel cells. Therefore, one of the biggest current challenges is the preparation of efficient catalysts for ORRs, particularly for regenerative or reversible fuel cells, which are fuel cells, and, in a reversible way, can produce ­H2 and ­O2, by water electrolysis [62]. Despite the enormous progress accomplished so far, the development of electrocatalysts with high activity and low costs is still a great challenge. The current bottleneck of fuel cells is ORR reactions, which are the limiting step for the generation of electricity. So far, the most used systems for ORR reactions are mainly platinumbased materials (or their alloys). However, due to the high cost of Pt, alternative catalysts based on other, less expensive, metals, such as transition metals, as well as other non-metal-containing materials are being actively sought [63]. The last few decades have shown considerable improvements in the design of efficient catalysts for ORR. An important factor that should be considered when choosing a good catalytic system is selectivity towards the 4­ H+/4e− reduction of O ­ 2 to ­H2O, as opposed to the ­2H+/2e− reduction of ­O2 to ­H2O2. Besides, the reduction of ­O2 by one electron, to yield ­O2−, is also undesired [64]. In this regard, in nature, biological systems possess specific proteins that favor the selective ­4H+/4e− reduction of O ­ 2. For instance, cytochrome c oxidase ©cO) catalyzes ­O2 reduction as part of the respiratory complex that drives adenosine triphosphate (ATP) biosynthesis. The active sites of CcO enzymes involve a Fe-containing heme (called heme α3), a distal Cu, and a post-translationally modified tyrosine amino acid (tyrosine 244) [65]. Another example of O ­ 2-reducing metalloproteins is the family of MCOs. In this case, the mechanism of the oxygen reduction reactions in MCOs favors the direct ­4e−/4H+ reduction process of ­O2 to ­H2O. It is worth mentioning that some MCOs mediate ORR close to the thermodynamic potential of the ­O2/H2O couple [66–69]. Several materials have been designed employing proteins that can act as active catalysts for ORR. For example, synthetic models of iron-porphyrins, incorporating a distal CuI center connected via a meso-position with a pendant ligand that resembles the active site coordination in CcO have been described. Such samples have been employed in ORR by immobilization on graphite disk electrodes. As well,

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mononuclear iron porphyrins adsorbed onto graphite surfaces have been employed successfully as catalysts for the mentioned reaction through a 4­ H+/4e− pathway. Immobilization of iron porphyrin catalysts onto edge plane graphite shifts the potential of FeIII/II redox couple to more positive values than those observed in homogeneous solutions, and, therefore, results in lower ORR overpotentials, in comparison to the homogeneous cases [70–73]. Furthermore, cobalt-porphyrin based catalysts have also been widely recognized as efficient electrocatalysts for oxygen electroreduction reactions. Nonetheless, such systems possess disadvantages related to the poor selectivity towards H ­ 2O, obtaining predominantly ­H2O2. In turn, Co-porphine immobilized onto edge plane graphite surface have shown ­4e− reduction of ­O2 under air-saturated 1  M ­HClO4 solution [74]. A recombinant enzyme, namely CotA laccase has been also employed successfully as a bioelectroctalytic system for ORR (Fig.  5). The metalloenzymes were immobilized onto citrate-coated gold nanoparticles (AuNPs) through attractive electrostatic interactions. Interestingly, electronic wiring of the enzymes via a T2/ T3 trinuclear with the T2/T3 redox groups facing the surfaces of the electrodes was observed. This work combined, for the first time, both advances in the synthesis of recombinant redox enzymes and the advantages of colloidal nanosystem synthesis to create electrostatically self-assembled nanomaterials with remarkable ORR properties [75].

5 Proteins‑Inspired Advanced NRR Electrocatalysts As is widely known, ammonia is very important to the global economy as a fertilizer feedstock and household chemical as well as a desirable refrigerant in industry; it is also a chemical precursor in addition to being considered a future fuel alternative [76]. Currently, the incumbent Haber–Bosch process (HBP) is the strategy most widely used to synthesize ammonia for industrial-scale production. Due to its large number of limitations, including high cost, energy consumption and process complexity, finding other alternatives is needed [77]; therefore, progress in the fields of biocatalysis and electrocatalysis to understand the electrochemical reduction of dinitrogen ­(N2) to ammonia (­ NH3) and enable a greener path to ammonia production

Fig. 5  Schematic diagrams of a spore coat protein A (CotA) laccase immobilized onto citrate-coated gold nanoparticles (AuNPs) and b ORR processes onto the nanobiomaterial surfaces (reprinted from Ref. [75]) Reprinted from the journal

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need to be developed. Electrochemical reduction of nitrogen to ammonia is thermodynamically predicted to be more efficient than the HBP by about 20%. Besides, an electrochemical process could provide the advantage of eliminating fossil fuels as the precursor of ­H2 and energy by the use of water molecules for hydrogen production [78]. In this manner, electrochemical systems offer additional benefits, including scalability and on-demand ammonia generation. The electrochemical catalysis community has progressed somewhat towards the fabrication of efficient electrochemical nitrogen reduction materials, but most efforts are plagued by low Faradaic efficiencies due to the competing hydrogen production reaction, which dominates all metal-based catalyst surfaces [19, 79–81]. Therefore, natural biocatalytic systems that are able to efficiently catalyze NRR reactions are highly desirable alternatives. Recently, several works on biological catalysts based on protein compounds have been published. These state that the conversion of ­N2 into ammonia occurs naturally in diazotrophic microorganisms through the enzyme nitrogenase, as shown in Fig. 6. [77] Also, they reported that nitrogenase operates at mild conditions of around 150 bar. The synthesis of N ­ H3 from dinitrogen by nitrogenase follows this reaction under optimal conditions.

N2 + 8H+ + 16MgATP + 8e− → 2NH3 + H2 + 16MgADP + 16Pi (where ATP is adenosine tri-phosphate, ADP is adenosine diphosphate and Pi is inorganic phosphate). The reaction includes the obligatory hydrolysis of ATP to release stored chemical energy and kinetic limitations of nitrogen reduction. According to the results of this work, for the molecule of nitrogen that is reduced, two molecules of ammonia are produced, and protons are also reduced to form one molecule of hydrogen. Following these ideas, theoretical scientists are starting to work on the design of nature-inspired NRR nanostructured materials. In this regard, a giant advance was recently achieved by He and coworkers in this innovative research line [82]. They reported the first theoretically designed asymmetrical dual-metal dimer catalytic centers embedded on N-doped carbon nanostructures toward the electrochemical reduction of ­N2–NH3 inspired by the function of FeMo cofactors in the nitrogenase molecules. The simulated Mo–Ru, Mo–Co, Mo–W, Mo–Fe and Fe–Ru dimers exhibited ultra-low onset potentials of only 0.17, 0.27, 0.28, 0.36 and 0.39 V vs reversible hydrogen electrode (RHE), opening the way for the development of promising nature-inspired NRR electrocatalysts (Fig. 7) [82].

6 Conclusions The development of protein-based nanomaterials for water-splitting reactions has becoming cutting-edge research in recent years. Their unique properties to competently catalyze several electrocatalytic reactions at the nanometric scale make them excellent candidates for the fabrication of promising enzymatic biofuel cells. Undoubtedly, the role of proteins as effective nanomachines in the overall catalytic process is crucial. In this direction, it is well-established that conformational and/or structural changes in protein structures significantly enhance their

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Fig. 6  Nitrogenase enzyme structure and functions. a Diagram of one half of the nitrogenase complex and electron transfer. b FeMo cofactor and its environment (reprinted from Ref. [77])

electrocatalytic yields. Despite these achievements, knowledge of the mechanisms that govern electrocatalytic reactions in nanobiosystems as well as the synergistic behavior between enzymes and nanosized materials are still in their infancy. Therefore, a lot of effort should be delivered to shed light on the underlying biochemistry of protein-based nanoelectrocatalysts. We envision that this upcoming Reprinted from the journal

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Fig. 7  The calculated Gibbs free energy changes for the first and last hydrogenation steps of nitrogen reduction reaction (NRR) on different MN4-NG and M1M2N6-NG catalysts (reprinted from Ref. [82])

knowledge will enable the design of biocatalytic nanohybrids with unprecedented electrocatalytic properties. Funding  This work was funded by the Prof. Rafael Luque Grant number CTQ2016-78289-P.

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