Nanomedicines for Brain Drug Delivery [1st ed.] 9781071608371, 9781071608388

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Neuromethods 157

Javier O. Morales Pieter J. Gaillard Editor

Nanomedicines for Brain Drug Delivery

NEUROMETHODS

Series Editor Wolfgang Walz University of Saskatchewan Saskatoon, SK, Canada

For further volumes: http://www.springer.com/series/7657

Neuromethods publishes cutting-edge methods and protocols in all areas of neuroscience as well as translational neurological and mental research. Each volume in the series offers tested laboratory protocols, step-by-step methods for reproducible lab experiments and addresses methodological controversies and pitfalls in order to aid neuroscientists in experimentation. Neuromethods focuses on traditional and emerging topics with wide-ranging implications to brain function, such as electrophysiology, neuroimaging, behavioral analysis, genomics, neurodegeneration, translational research and clinical trials. Neuromethods provides investigators and trainees with highly useful compendiums of key strategies and approaches for successful research in animal and human brain function including translational “bench to bedside” approaches to mental and neurological diseases.

Nanomedicines for Brain Drug Delivery Edited by

Javier O. Morales Department of Pharmaceutical Science and Technology, University of Chile, Santiago, Chile

Pieter J. Gaillard 2-BBB Medicines BV, Leiden, The Netherlands

Editors Javier O. Morales Department of Pharmaceutical Science and Technology University of Chile Santiago, Chile

Pieter J. Gaillard 2-BBB Medicines BV Leiden, The Netherlands

ISSN 0893-2336 ISSN 1940-6045 (electronic) Neuromethods ISBN 978-1-0716-0837-1 ISBN 978-1-0716-0838-8 (eBook) https://doi.org/10.1007/978-1-0716-0838-8 © Springer Science+Business Media, LLC, part of Springer Nature 2021 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. Cover illustration: Cover image by Ignacio Morales Soto. This Humana imprint is published by the registered company Springer Science+Business Media, LLC, part of Springer Nature. The registered company address is: 1 New York Plaza, New York, NY 10004, U.S.A.

Preface to the Series Experimental life sciences have two basic foundations: concepts and tools. The Neuromethods series focuses on the tools and techniques unique to the investigation of the nervous system and excitable cells. It will not, however, shortchange the concept side of things as care has been taken to integrate these tools within the context of the concepts and questions under investigation. In this way, the series is unique in that it not only collects protocols but also includes theoretical background information and critiques which led to the methods and their development. Thus it gives the reader a better understanding of the origin of the techniques and their potential future development. The Neuromethods publishing program strikes a balance between recent and exciting developments like those concerning new animal models of disease, imaging, in vivo methods, and more established techniques, including, for example, immunocytochemistry and electrophysiological technologies. New trainees in neurosciences still need a sound footing in these older methods in order to apply a critical approach to their results. Under the guidance of its founders, Alan Boulton and Glen Baker, the Neuromethods series has been a success since its first volume published through Humana Press in 1985. The series continues to flourish through many changes over the years. It is now published under the umbrella of Springer Protocols. While methods involving brain research have changed a lot since the series started, the publishing environment and technology have changed even more radically. Neuromethods has the distinct layout and style of the Springer Protocols program, designed specifically for readability and ease of reference in a laboratory setting. The careful application of methods is potentially the most important step in the process of scientific inquiry. In the past, new methodologies led the way in developing new disciplines in the biological and medical sciences. For example, Physiology emerged out of Anatomy in the nineteenth century by harnessing new methods based on the newly discovered phenomenon of electricity. Nowadays, the relationships between disciplines and methods are more complex. Methods are now widely shared between disciplines and research areas. New developments in electronic publishing make it possible for scientists that encounter new methods to quickly find sources of information electronically. The design of individual volumes and chapters in this series takes this new access technology into account. Springer Protocols makes it possible to download single protocols separately. In addition, Springer makes its print-on-demand technology available globally. A print copy can therefore be acquired quickly and for a competitive price anywhere in the world. Saskatoon, SK, Canada

Wolfgang Walz

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Preface Nanomedicines have revolutionized research on drug delivery in multiple diseases, and leading strategies have achieved clinical success. Moreover, a significant number of clinical trials are conducted to continue expanding the reach of nanomedicines to new, more effective and with less side effects therapies. The central nervous system (CNS) has similarly been the focus of extended research in the design and evaluation of novel nanocarriers for brain drug delivery. As a target site, the CNS represents a unique challenge given its anatomy and physiology. The blood brain barrier (BBB) is not only a restrictive limitation for systemically administered drugs but also continues to be a largely restrictive barrier to achieve significant CNS nanocarrier bioavailability. While the BBB represents one of the main limitations for significant CNS biodistribution, overcoming it is not the sole reason for limited bioavailability and targeting effects. Successfully targeting the brain microvasculature, distribution through the CNS (after passage through the BBB), and internalization in target brain cells become important challenges once there is a BBB penetration strategy in place. As such, this book will be a source for finding the latest research in CNS-targeted nanocarriers, methods for their synthesis and thorough characterization. Moreover, a chapter addressing toxicity aspects to be considered in the design and use of brain-targeted nanocarriers will be of interest to the reader. The first two chapters of the book delve into the most widely investigated nanocarriers as brain-targeted delivery systems, i.e., polymeric nanoparticles and liposomes. With a thorough description of the state of the art as well as key aspects of their characterization, the first two chapters also highlight physiological properties relevant to particle design. Chapter 4 depicts the use of self-assembled peptidebased scaffolds for lesions of the nervous system, while Chapter 5 describes not only the use of peptides as CNS drugs but also as potential carriers to optimize brain-targeted delivery. Chapters 6 and 7 describe inorganic and magnetic nanoparticles used for targeting drugs to the CNS as well as their potential in the design of triggerable and aimed systems. Chapter 8 inspects the long-researched nose-to-brain delivery route, highlighting its potential and how the limitations this route presents could be addressed to harness its clinical potential. Chapter 9 is an excellent compilation of characterization methods to model and assess BBB absorption of drugs and drug delivery systems, and as such, this chapter will be of great use to scientists designing brain-targeted delivery systems to predict brain distribution. Finally, Chapter 10 presents the concerns that the use of nanomaterials raises in the context of braintargeted systems. As such, the last chapter will be a good source to understand the potential neurotoxic effects and the potential role of nanomaterials in neurodegeneration progress. The editors are immensely grateful to all the individual contributions and authors for sharing their time, effort, and knowledge to create this book. Their outstanding work in the fields covered in this book we hope will be of great interest to the reader and will help guide and move forward the field of nanomedicines to target the brain and the nervous system. Santiago, Chile Leiden, The Netherlands

Javier O. Morales Pieter J. Gaillard

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Contents Preface to the Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 Biodegradable Polymeric Nanoparticles for Brain-Targeted Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kristian Kempe and Joseph A. Nicolazzo 2 Liposomes as Brain Targeted Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Francesco Lai, Michele Schlich, Chiara Sinico, and Anna Maria Fadda 3 Nanofibers and Nanostructured Scaffolds for Nervous System Lesions . . . . . . . . Jose L. Gerardo Nava, Jonas C. Rose, Haktan Altinova, Paul D. Dalton, Laura De Laporte, and Gary A. Brook 4 Self-Assembling Peptide Nanofibrous Scaffolds in Central Nervous System Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Na Zhang, Liumin He, and Wutian Wu 5 The Use of Peptide and Protein Vectors to Cross the Blood-Brain Barrier for the Delivery of Therapeutic Concentration of Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mei Mei Tian and Reinhard Gabathuler 6 Inorganic Nanoparticles and Their Strategies to Enhance Brain Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eduardo Gallardo-Toledo, Carolina Velasco-Aguirre, and Marcelo Javier Kogan 7 Magnetic Nanoparticles as Delivery Systems to Penetrate the Blood-Brain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joan Estelrich and Maria Anto`nia Busquets 8 Nose-to-Brain Drug Delivery Enabled by Nanocarriers . . . . . . . . . . . . . . . . . . . . . . Zachary Warnken, Yang Lu, Hugh D. C. Smyth, and Robert O. Williams III 9 In Vitro Models of Central Nervous System Barriers for Blood-Brain Barrier Permeation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sounak Bagchi, Behnaz Lahooti, Tanya Chhibber, Sree-pooja Varahachalam, Rahul Mittal, Abhijeet Joshi, and Rahul Dev Jayant 10 Safety and Nanotoxicity Aspects of Nanomedicines for Brain-Targeted Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Johanna Catalan-Figueroa and Javier O. Morales Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contributors HAKTAN ALTINOVA • Department of Neurosurgery, University Hospital RWTH Aachen, Aachen, Germany SOUNAK BAGCHI • Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA GARY A. BROOK • Institute of Neuropathology, University Hospital RWTH Aachen, Aachen, Germany MARIA ANTO`NIA BUSQUETS • Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Catalonia, Spain; Institute of Nanoscience and Nanotechnology, IN2UB, Barcelona, Catalonia, Spain JOHANNA CATALAN-FIGUEROA • Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile; Department of Biochemistry, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile; Experimental Pharmacology Institute, CONICET, National University of Cordoba, Cordoba, Argentina; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile TANYA CHHIBBER • Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA PAUL D. DALTON • Department for Functional Materials in Medicine and Dentistry and Bavarian Polymer Institute, University of Wu¨rzburg, Wu¨rzburg, Germany LAURA DE LAPORTE • DWI—Leibniz-Institute for Interactive Materials, Aachen, Germany; Insitute of Applied Medical Engineering, RWTH Aachen University, Aachen, Germany; Insitute of Technical and Macromolecular Chemistry RWTH Aachen University, Aachen, Germany JOAN ESTELRICH • Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Catalonia, Spain; Institute of Nanoscience and Nanotechnology, IN2UB, Barcelona, Catalonia, Spain ANNA MARIA FADDA • Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy REINHARD GABATHULER • Faculty of Life Sciences and Medicine, Blood-Brain Barrier Group, Kings College London, London, UK EDUARDO GALLARDO-TOLEDO • Departamento de Quı´mica Farmacologica y Toxicologica, Facultad de Ciencias Quı´micas y Farmace´uticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile JOSE L. GERARDO NAVA • Institute of Neuropathology, University Hospital RWTH Aachen, Aachen, Germany; DWI—Leibniz-Institute for Interactive Materials, Aachen, Germany LIUMIN HE • Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, People’s Republic of China RAHUL DEV JAYANT • Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA ABHIJEET JOSHI • Centre for Biosciences and Bio-medical Engineering, Indian Institute of Technology Indore (IIT-I), Indore, Madhya Pradesh, India

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KRISTIAN KEMPE • ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, and Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia MARCELO JAVIER KOGAN • Departamento de Quı´mica Farmacologica y Toxicologica, Facultad de Ciencias Quı´micas y Farmace´uticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile BEHNAZ LAHOOTI • Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA FRANCESCO LAI • Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy YANG LU • Department of TCM Pharmaceutical, School of Chinese Material Mecica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China RAHUL MITTAL • Laboratory of Human Molecular Genetics, Department of Otolaryngology, Miller School of Medicine, University of Miami (UM), Miami, FL, USA JAVIER O. MORALES • Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile; Center of New Drugs for Hypertension (CENDHY), Santiago, Chile; Pharmaceutical and Biomaterial Research Group, Department of Health Sciences, Lulea˚ University of Technology, Lulea˚, Sweden JOSEPH A. NICOLAZZO • Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia JONAS C. ROSE • DWI—Leibniz-Institute for Interactive Materials, Aachen, Germany MICHELE SCHLICH • Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy CHIARA SINICO • Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy HUGH D. C. SMYTH • Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA MEI MEI TIAN • Bioasis Technologies Inc., Guilford, CT, USA SREE-POOJA VARAHACHALAM • Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA CAROLINA VELASCO-AGUIRRE • Departamento de Quı´mica Farmacologica y Toxicologica, Facultad de Ciencias Quı´micas y Farmace´uticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile ZACHARY WARNKEN • Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA ROBERT O. WILLIAMS III • Molecular Pharmaceutics and Drug Delivery Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA WUTIAN WU • Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, People’s Republic of China; Re-Stem Biotech, Suzhou, People’s Republic of China NA ZHANG • Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, People’s Republic of China

Chapter 1 Biodegradable Polymeric Nanoparticles for Brain-Targeted Drug Delivery Kristian Kempe and Joseph A. Nicolazzo Abstract The blood-brain barrier (BBB), formed by endothelial cells lining the cerebral microvessels, remains a formidable challenge for the delivery of many therapeutics into the central nervous system (CNS). In an attempt to enhance the CNS disposition of therapeutics, which either have poor inherent permeability across the BBB or whose brain uptake is limited by the function of efflux transporters, a multitude of polymeric nanocarriers have been exploited. Common natural and synthetic polymers used for the development of these nanocarriers include polysaccharides, poly(alkylcyanoacrylate)s, and polyesters such as poly (lactic-co-glycolic acid). To avoid recognition by circulating macrophages and, therefore, minimize their systemic clearance, these polymeric nanocarriers are often coated with polyethylene glycol or emulsifiers such as polysorbate 80, and to enhance their targeting to the BBB, addition of various targeting entities such as antibodies to brain microvascular receptor-mediated transporters is common. Unlike liposomes however, polymeric nanoparticles are more stable, allow for a detailed control of the carrier properties (e.g., size, shape, charge, surface morphology and chemistry), facilitate the delivery of a range of different cargoes with high capacities, and can be engineered with different drug release mechanisms and modified with various targeting ligands. This chapter will provide an up-to-date account on the various polymeric nanoparticle approaches which have been exploited to target therapeutics to the CNS, with particular focus on biodegradable polymers and practical techniques that can be employed for the preparation of these polymeric nanoparticles. Key words Polymer, PLGA, Nanoparticle, Blood-brain barrier, Targeting, Surface coating

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Introduction Nanotechnology innovations have paved the way to novel therapeutic and diagnostic agents/carriers and tools for pharmaceutical and biomedical research. However, drug delivery to the brain has remained one of the biggest challenges in biomedical research with numerous obstacles which have to be overcome. Drugs for treatment of brain-related diseases have to enter the brain in order to exhibit a therapeutic effect, which can be accomplished by invasive and noninvasive methods. In the latter and more clinically relevant case, the compound has to be able to cross the blood-brain barrier

Javier O. Morales and Pieter J. Gaillard (eds.), Nanomedicines for Brain Drug Delivery, Neuromethods, vol. 157, https://doi.org/10.1007/978-1-0716-0838-8_1, © Springer Science+Business Media, LLC, part of Springer Nature 2021

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(BBB), an obstacle which limits the ability of many therapeutics to gain access to their target within the central nervous system (CNS) [1, 2]. The BBB is a selective barrier which controls ionic and fluid movement from the systemic circulation to the neural tissue. It prevents harmful substances from entering the brain and at the same time supplies the brain with essential nutrients. Small gaseous and lipophilic molecules can diffuse through the lipid membrane of brain microvascular endothelial cells forming the BBB, whereas larger compounds such as peptides, macromolecules, and hydrophilic drugs exhibit poor transport across this membrane, unless through the assistance of a membrane transporter. Thus, the BBB represents an obstacle for both efficient therapy and diagnosis of brain-related diseases with most state-of-the-art drugs and diagnostic agents, respectively. Among others, polymeric nanomaterialmediated brain delivery has been proven to be a suitable strategy to overcome this issue. Colloids, in general, have been widely applied in the field of drug delivery [3, 4]. In recent years, polymeric nanoparticles (PNPs), which are in the size range of 10–300 nm, have emerged as ideal carrier systems as they allow for a high level of modularity and thus can be tailored for individual applications [5]. PNPs can be divided into two major groups, polymer nanocapsules and polymer nanospheres [6]. The latter are composed of a dense polymer matrix, whereas the former represent vesicular-type aggregates which consist of a liquid core surrounded by a polymer layer. PNPs are more stable than other delivery systems and are amenable to a detailed control of the carrier properties, including their size, shape, charge, surface morphology, and chemistry [5]. They facilitate the delivery of a range of different cargo with high capacities, which is advantageous compared to a single or prodrug approach. Nanospheres allow drugs to be uniformly dispersed in the polymer matrix mainly by physical interactions, and nanocapsules can encapsulate drugs in their liquid core. Besides the protection of the cargo from enzymatic or chemical degradation, PNPs also enable the triggered release of the cargo through specific engineering of drug release mechanisms into the carrier [7]. However, challenges associated with nanomedicines include their nonspecific interaction with the human body and their in vivo fate, specificity, and possible toxicity [8]. A range of polymer classes have been developed to overcome these limitations, including the use of coating with poly(ethylene glycol) (PEG) and its alternatives [9]. Carriers composed of, or modified with, these classes enable a prolonged blood circulation time and lower the overall toxicity of the PNPs. Moreover, targeted approaches have increased the therapeutic efficacy of encapsulated drugs through the accumulation of the carrier at the site of action [10]. Altogether, PNPs represent promising drug delivery systems.

Biodegradable Polymeric Nanoparticles for Brain-Targeted Drug Delivery

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This book chapter focuses on PNPs, specifically polymeric nanospheres and their application as brain delivery nanomedicines. It sets out design principles for PNPs, reviews commonly used biodegradable polymer classes, and provides background information on polymerization and formulation techniques employed for the fabrication of polymeric brain delivery vehicles. Moreover, strategies used to improve transport of PNPs across the BBB are highlighted using recent examples of PNPs based on polyesters, poly(alkyl cyanoacrylate)s, and polysaccharides.

2 Design Principles of Commonly Employed Polymeric Nanoparticles for Brain Delivery Noninvasive methods for crossing the BBB have received significant attention in recent years. However, for this purpose, drugs and carriers have to be designed carefully and need to meet certain criteria. To cross the BBB, the modification of existing drugs and their physicochemical properties and, in particular, the attachment of ligands onto molecules or colloids which target the BBB have proven promising, at least in rodent models. PNPs provide an ideal platform for the delivery of therapeutics to the brain because of their abovementioned characteristics. As highlighted in a recent review article by Saltzmann and coworkers, for drug delivery to the brain, PNPs should possess a number of specific properties; in particular, they should be biocompatible, biodegradable, nontoxic, and non-immunogenic, exhibit a size