Exploring Drug Delivery to the Peritoneum 3031316932, 9783031316937

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Ranjita Shegokar  Editor

Exploring Drug Delivery to the Peritoneum

Exploring Drug Delivery to the Peritoneum

Ranjita Shegokar Editor

Exploring Drug Delivery to the Peritoneum

Editor Ranjita Shegokar Freie Universität Berlin Berlin, Germany

ISBN 978-3-031-31693-7    ISBN 978-3-031-31694-4 (eBook) https://doi.org/10.1007/978-3-031-31694-4 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed 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. Editorial Contact: Charlotte Nunes This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

The peritoneal cavity (PC) is the key metastatic site for intra-abdominal malignancies (e.g., GI tract and rectal cancer). PC sites can be used to target several other diseases where lymphatic drug delivery is desired without dumping large amounts of drugs. Till recently, it was thought that treatment with curative intent was impossible, but that was challenged by the introduction of cytoreductive surgery (CRS), heated intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). Recently, a growing number of preclinical and clinical studies advocate intraperitoneal (IP) chemotherapy as an alternative post-­operative therapy for cancer. Although their effectiveness has been proven both experimentally and clinically, there is still little understanding of the role of drug delivery systems (DDS) in targeting drugs in the IP cavity. There are two main Challenges: one posed by IP cavity where the residence time of a small molecular weight drug ( >

43.9% (35.7 to 51.2) 33.0% (15.7 to 55.7) 221.2% (165.6 to 273.4) 45.6% (37.5 to 53.9) 178.6% (135.5 to 198.6) 138.7% (66.0 to 175.1)

18 16

> >

165.5% (146.8 to 197.4) 138.5% (112.0 to 154.9)

11


> > < >


175.9% (124.2 to 313.6)

26 27

<
2), advanced peripheral component interconnect (PCI), and/or unresectable peritoneal involvement. All patients underwent 3 cycles of PIPAC. It was seen that the response is more pronounced after the second PIPAC. Out of 21 successful PIPAC procedures performed, a patient of mesothelioma underwent complete histological remission; three patients had partial response, one had stable disease, and one patient had no response with clinical progression. They concluded that PIPAC is a safe and feasible procedure in patients with non-resectable peritoneal carcinomatoses [21].

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V. S. Gaikwad and V. Vishwani (Late 1990s) CRS and HIPEC initiated

(2000-2010) PSO not well established with only a couple of centres performing standardised intraperitoneal chemotherapy including HIPEC

(2010-2015) PSO recognised as an entity with widespread adaptation of CRS and HIPEC. Surgical oncology training centres incorporated CRS and HIPEC

( May 2017) First PIPAC performed in India by Katdare et al in Mumbai, Maharashtra (2017) Indian Society of Peritoneal Surface Malignancies established

(2018) Society of Peritoneal Surface Oncology established

(2019) First studies of PIPAC are published by Katdare et el and Somashekhar et al

(2019-2021) Various studies established safety and efficacy in the Indian subset of patients Segregation of results based on disease pathologies such as pseudomyxomas, ovarian cancer, etc.

(2021) First certification program conducted in the country by Dr. Somashekhar in Bengaluru, Karnataka

(2022) International multicentric collaborative studies reported Drug regimen results reported (taxane based)

(2023) More than 25 certified surgeons and centres performing PIPAC with ongoing studies being conducted

Fig. 2  Important milestones regarding PIPAC in India

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Fig. 3  Centers currently performing PIPAC in India

Katdare et  al. presented an initial experience from three Indian centres. They evaluated the safety and feasibility of the procedure in the first few Indian patients with PM from various primary sites treated with PIPAC using standard drug regimens. The median hospital stay for the patients was 1 day, with only two patients experiencing major complications and a single post-operative death. Disease progression was seen in two patients, among patients who completed 6 weeks of follow-­up [17]. Another randomized controlled study from India is currently evaluating the quality of life (QoL) of patients with end-stage peritoneal metastasis treated with PIPAC in comparison to intravenous chemotherapy using European organization for

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research and treatment of cancer (EORTC) QLQ-C30 (Version 3.0) questionnaire. The primary objective of this study is to evaluate the QoL after three cycles of PIPAC therapy in comparison with six cycles of iv chemotherapy [22]. The expected sample size for this study is 120 patients and the imminent results are eagerly awaited. Table 2 outlines the various drug regimens explored for usage in PIPAC [1]. Figure 4 shows the intraoperative and histological images before and after PIPAC. Table 2  Drug regimens used for PIPAC Drug Oxaliplatin Doxorubicin Cisplatin Mitomycin C Irinotecan Paclitaxcel Nab-­ Paclitaxcel

PIPAC dose, mg/ m2 46–135 1.5–2.1 7.5–10.5 1.5 (14 mg total dose) 20 30 112,5

PIPAC/IV % 50–160 10–13 10–13 43–75

Whether drug regimen explored in the Indian setting Yes Yes Yes Yes

11–16 17–22 90

No Yes Yes

Fig. 4  Intraoperative and histological images before and after PIPAC

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4.2 Drug Safety and Efficacy Studies Two empirical regimens have been recommended for PIPAC, a single-agent oxaliplatin for PM of colorectal and appendicular origin and a combination of cisplatin and doxorubicin for the rest of the malignancies. The drug doses that are used have been set arbitrarily. One-tenth of the dose used for performing HIPEC has been widely adopted by centres worldwide. There are no drug-to-drug comparison studies till date. Other drugs (Nab-paclitaxel, mitomycin, irinotecan) and drug combinations (Nab-paclitaxel + cisplatin) are under evaluation. A phase I dose-finding study (Singapore study) was performed in Asian patients for single-agent oxaliplatin-based PIPAC. The recommended phase II dose was observed to be 120  mg/m2 and the procedure was well tolerated by most of the patients at this dose [23]. Mehta et al. evaluated the feasibility and safety of Taxane-PIPAC in patients with peritoneal malignancies in a retrospective study from two Indian centres. To date, there is no published literature on the use of Taxane-PIPAC.  The primary sites included in the study were ovarian cancer, gastric cancer, and colorectal cancer. PIPAC with docetaxel in combination with adriamycin and cisplatin was seen to be feasible and safe with grade 3–4 toxicity of 8.5%. Reduction in ascites was observed in 35.4% of patients presenting with ascites. About 19.1% of patients had conversion to operability leading to a subsequent CRS ± HIPEC. Therefore, this study has given light to the concept of PIPAC as a neoadjuvant treatment modality [24]. Recently, a consensus statement has been published regarding the treatment protocols for PIPAC and describes the drug regimens commonly used [1].

4.3 PIPAC for Ovarian Origin PM Somsahekhar et al. presented the first Indian study on PIPAC for advanced peritoneal carcinomatosis secondary to epithelial ovarian cancer and its impact on quality of life. Fifteen patients were evaluated who had ECOG ≥ 2 and who could not tolerate HIPEC. Out of 15 patients, ten patients could complete all three cycles. The Median PCI of the patients was 19.2 with a median performance score of ECOG 2. All patients had previously received systemic chemotherapy. Cisplatin and doxorubicin-­based chemotherapy was used. The median hospital stay was 1.5 days. One patient had bowel perforation; one had major bleeding during the procedure. Nine patients had a partial response and 2 had a complete response. They suggested that the procedure has low morbidity with no mortality, has short learning curve, and was well tolerated by Indian patients. There was no therapy-related deterioration of quality of life after PIPAC [25]. Another Indian study evaluated the activity of PIPAC in unresectable platinum-­ resistant ovarian cancers. The standard treatment for these patients is systemic chemotherapy which is associated with significant side effects and poor overall response. This RCT assessed the objective tumour response of PIPAC in comparison to systemic intravenous chemotherapy for women with platinum-resistant ovarian cancer

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with an ECOG performance status of 0–2 and those who had no indication for CRS and HIPEC. They recently published the interim results of the study and found that the mean PCI of the evaluated patients was 24.45  ±  6.39, with nearly 45.5% of patients having previous surgery and 72.5% of patients having received at least 2 lines of prior chemotherapy. The objective response rates were 66.6% in the PIPAC arm versus 22.5% in the systemic chemotherapy arm. They also found significantly higher grade 3–4 events among patients receiving systemic chemotherapy. Global health score at day 120 was superior in the patients undergoing PIPAC [22].

4.4 PIPAC for Appendicular Origin PM Peritoneal metastases (PM) from appendiceal tumours are a distinct entity of peritoneal disease when compared to colorectal tumours. They behave differently when it comes to disease behaviours, progression and response to treatment [26]. In a multicentre study by Somashekhar et al., survival and treatment response after PIPAC for peritoneal metastases of appendiceal origin was evaluated. In this study, the majority of the patients received oxaliplatin-based chemotherapy as their first line of treatment and irinotecan-based chemotherapy as the second line. The median OS in this study was 20.9 months from the time of diagnosis and 9.9 months from the time of the first PIPAC. This was at par with the results by Shapiro et al. which showed that systemic chemotherapy prolonged OS up to 20.4  months in patients who are deemed suboptimal candidates for CRS +/− HIPEC. Complete tumour response after the third PIPAC was observed in 11.4% of patients [27].

4.5 PIPAC for Colorectal Origin PM An international study, including 17 centres with one Indian centre, assessed the overall survival, radiological response, histological response, PCI change, and symptom response after PIPAC for colorectal PM.  A total of 256 patients were included of which 63% underwent PIPAC after 2 lines of systemic chemotherapy. The independent predictors of survival were radiological response and no symptoms. Objective treatment response and encouraging survival were recorded in this study, setting the stage for further trials [28].

4.6 PIPAC for Gastric Origin PM Presently, there are many studies working on the safety and the effectiveness of PIPAC procedure (using low-dose cisplatin and doxorubicin) in patients with unresectable PM from GC. However, there is a scarcity of Indian data working exclusively on GC with PM. A systematic review by Garg et al., an Indian author found

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a total of 10 studies with 129 patients with GC PM treated with PIPAC. Out of these two studies had an exclusive cohort of patients with GC and eight had a heterogeneous population having a small proportion of GC patients. This review concluded that PIPAC is a safe and effective procedure associated with low morbidity, thereby improving the quality of life of the patients with PM of GC origin [29]. Another review by Prabhu et al. identified five studies regarding PIPAC for gastric peritoneal metastasis. They concluded that PIPAC is safe and well tolerated with the potential to contain the spread of PM. The use of PIPAC in the neoadjuvant setting also sparked interest [30].

5 The Indian Healthcare Structure and Its Influence on PIPAC 5.1 Treatment Costs In India, almost 75% of patients bear healthcare expenditure out-of-pocket [31]. This includes cancer treatment, including PIPAC. Around 20% of people use private insurance, especially in first-tier cities [32]. Central and state government schemes contribute a small part, and may not currently include PIPAC as an approved procedure. It is estimated that the approximate cost of a sitting of PIPAC varies from 6000 to 8000 US Dollars (USD). This can be well beyond the reach of the common man. The primary consumable that contributes to the cost burden is the CapnoPen® which aersolizes the chemotherapy. Since it is not manufactured in the country, the cost is prohibitive [33]. Affordable alternatives are now available both locally and through import, which has made the use of PIPAC more widespread [34]. The CapnoPen® is also expected to release a more economical product to cater to this problem, particularly because it is disposable and a new pen needs to be used for every session. The short hospital stay, general anaesthesia, the standard laparoscopy equipment, pressure injector, and balloon trocars may not significantly impose on the financial burden.

5.2 Referral Patterns and Patient Attitudes There is no referral system for PSMs in the country. There is a substantial resistance among medical oncologists to refer patients for a PIPAC and thus the onus of exploring the option of PIPAC rests with the patient and his/her attendants. As the awareness about the availability, safety, and efficacy of the procedure is increasing, the patient volume continues to increase. There are many states in the country which still do not offer PIPAC and therefore the patient is required to travel fair distances to seek treatment [35].

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It is no surprise then that the level of education and awareness of the patient determines their accessibility to PIPAC as a treatment of option. The sad reality remains that most patients realize that their options are limited, especially for platinum-­resistant tumours. This motivates many of the more driven patients to seek out novel, pathbreaking treatments which eventually feature PIPAC as a promising palliative option. Due to the current lack of government support, it is usually up to the patients to fend for themselves with the support of the treating oncologist/surgeon [36]. However, the concept of life, death and longevity varies significantly within the population and more so varies when compared to individuals from more developed countries. It is therefore imperative that appropriate counselling and patient selection is always kept in mind.

6 Adaptation of PIPAC Among Clinicians The number of centres offering PIPAC is increasing directly proportional to the number of certified surgeons. It is mandatory that the performing surgeon has a certification from the International Society for the Study of Pleura and Peritoneum (ISSPP). Since most training programmes are out of the country, this is a limiting factor. The primary reason for compulsory certification is the biohazard to the healthcare personnel. In a survey conducted involving 147 clinicians actively involved in the treatment of PSMs, more than 75% stated that the reason for not performing PIPAC was the lack of training opportunities [36]. Perception regarding PIPAC for treating peritoneal surface malignancies is variable even among clinicians around the world. Sgarbura et al. performed a study with an aim to assess current PIPAC practice in terms of technique, treatment and safety protocol. Closed-ended questions were sent online to active PIPAC centres. The topics with the highest degree of consensus were safety and installation issues. Homogeneous treatment standards of new techniques are important to guarantee safe implementation and practice [37].

7 Technological Limitations of PIPAC Since many of the patients who are candidates for PIPAC have undergone one or more abdominal surgeries, safe peritoneal access can present a challenge. Inadvertent bowel injury can be a major concern, so due precaution must be taken. The equipment requirements can also be cumbersome. A smoke evacuation system, pressure injector, balloon trocars, and aerosolizer pen can pose some constraints initially. PIPAC technology is still evolving and there is a significant potential for improvement. Some technical issues are of concern such as the gravitation effect on the

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aerosol particles leading to inhomogeneity of aerosolized drug distribution during PIPAC. The addition of electrostatic precipitation (ePIPAC) may reduce the influence of gravity and may improve the homogeneity of drug distribution by applying an electrostatic gradient. In addition, it is also claimed that ePIPAC may reduce the operating time needed for the procedure. However, the above claims are yet to be proven in robust clinical trials. PIPAC performed after CRS is seen to be associated with a high incidence of bowel perforations due to unnoticed serosal lesions of the bowel thereby increasing procedure-related surgical morbidity. At present, any surgical procedure is considered a contra-indication in combination with PIPAC due to the high rate of complications in the initial experience of PIPAC treatment. PIPAC technology is still evolving and there is a significant potential for improvement. Some technical issues are of concern such as the gravitation effect on the aerosol particles leading to inhomogeneity of aerosolized drug distribution during PIPAC. The addition of electrostatic precipitation (ePIPAC) may reduce the influence of gravity and may improve the homogeneity of drug distribution by applying an electrostatic gradient. In addition, it is also claimed that ePIPAC may reduce the operating time needed for the procedure. However, the above claims are yet to be proven in robust clinical trials. To date, there is no ePIPAC study reported from India. Anatomical issues such as closed spaces within the peritoneal cavity, such as the lesser sac, are not accessible to the therapeutic aerosol. In patients in whom the lesser sac had not been opened during a previous surgery, isolated tumour progression may be observed in this closed anatomic space. Other barriers to the diffusion of the aerosol are inter-bowel and parietal adhesions, which limit the distribution of aerosols. PIPAC performed after CRS is seen to be associated with a high incidence of bowel perforations due to unnoticed serosal lesions of the bowel thereby increasing procedure-related surgical morbidity. At present, any surgical procedure is considered a contra-indication in combination with PIPAC due to the high rate of complications in the initial experience of PIPAC treatment [38, 39]. However, a recently published study (PLUS study) evaluated the feasibility and safety of PIPAC combined with additional surgical procedures. Results suggest that PIPAC can be safely combined in expert centres with additional surgeries with acceptable surgical complications [40]. Table 3 summarizes the publications involving authors from India regarding PIPAC.

8 Future Directions The two main focuses will be on technological advancements and enhanced implementation. The concept of ePIPAC, intraperitoneal immunotherapy, and PIPAC as neoadjuvant therapy are some of the concepts around the corner. Obviating the

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Table 3  Current contribution by authors from India on PIPAC The initial experiences Pressurized intraperitoneal aerosol chemotherapy Somashekhar procedure for nonresectable peritoneal carcinomatosis: et al First Indian study. Pressurized intraperitoneal aerosol chemotherapy Katdare et al (PIPAC): initial experience from Indian centers and a review of literature. Randomized control trial comparing quality of life of Somashekhar patients with end-stage peritoneal metastasis treated with et al pressurized intraperitoneal aerosol chemotherapy (PIPAC) and intravenous chemotherapy. Drug safety and efficacy studies PIPAC-OX: a phase I study of oxaliplatin-based Kim et al. pressurized intraperitoneal aerosol Chemotherapy in (Asian study) patients with peritoneal metastases. Feasibility and safety of taxane-PIPAC in patients with Mehta et al peritoneal malignancies – a retrospective bi-institutional study. PIPAC for ovarian origin PM First Indian study on pressurized intraperitoneal aerosol Somashekhar chemotherapy (PIPAC) procedure for advanced et al peritoneal carcinomatosis secondary to epithelial ovarian cancer. Randomized control trial comparing quality of life of Somashekhar patients with end-stage peritoneal metastasis treated with et al pressurized intraperitoneal aerosol chemotherapy (PIPAC) and intravenous chemotherapy PIPAC for appendicular origin PM Assessment of treatment response after PIPAC for Somashekhar appendiceal peritoneal metastases. et al PIPAC for colorectal origin PM Treatment response after PIPAC for peritoneal Hübner, et al metastases of colorectal origin. PIPAC for gastric origin PM The role of pressurized IntraPeritoneal aerosol Garg et al chemotherapy in the management of gastric cancer: a systematic review Gastric cancer with peritoneal metastasis – a Prabhu A et al comprehensive review of current intraperitoneal treatment modalities. The Indian healthcare structure and its influence on PIPAC The current status of peritoneal surface oncology in Bhatt A et al India. Practice patterns, attitudes, and knowledge among Somashekhar clinicians regarding hyperthermic intraperitoneal et al chemotherapy and pressurized intraperitoneal aerosol chemotherapy: a national survey by Indian society of peritoneal surface malignancies (ISPSM)

South Asian J 2019 Cancer Indian J Surg 2019 Oncol Pleura Peritoneum

2018

Clin Cancer Res

2021

Indian J Surg 2023 Oncol

Indian J of 2018 Gynac Oncol

Pleura Peritoneum

2018

Cancers (Basel)

2022

Annals of Surgery

2022

Pleura Peritoneum

2019

Front Oncol

2022

Indian J Surg 2019 Oncol Pleura 2020 Peritoneum

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technological limitations discussed is also the area to watch for impending breakthroughs. In order to improve the utilization of this procedure, building global evidence as well as evidence from India will contribute to more widespread acceptance of PIPAC. Training programmes have commenced in India enabling more surgeons to be certified and practice PIPAC. Strides are also being made to make this procedure more financially viable more so for middle-income countries like India.

9 Conclusion India is fast catching up with leaders in the field of PSMs. The representation of clinicians dedicated to PSO is increasing by leaps and bounds. Evidence is being generated to support the benefit of PIPAC and is contributing significantly to global data. Improved training opportunities, research methodologies, and increasing clinician interest ensure that PIPAC will gain popularity in the country just like CRS + HIPEC, thus improving patient survival and quality of life.

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surgery and HIPEC-a retrospective study by INDEPSO. Indian J Surg Oncol. 2019;10(Suppl 1):49–56. 10. Sinukumar S, Rajan F, Mehta S, Damodaran D, Zaveri S, Kammar P, et al. A comparison of outcomes following total and selective peritonectomy performed at the time of interval cytoreductive surgery for advanced serous epithelial ovarian, fallopian tube and primary peritoneal cancer – a study by INDEPSO. Eur J Surg Oncol. 2021;47(1):75–81. 11. India State-Level Disease Burden Initiative Cancer C. The burden of cancers and their variations across the states of India: the global burden of disease study 1990–2016. Lancet Oncol. 2018;19(10):1289–306. 12. Bhatt A, Goere D. Cytoreductive surgery plus HIPEC for peritoneal metastases from colorectal cancer. Indian J Surg Oncol. 2016;7(2):177–87. 13. Seshadri RA, Glehen O.  The role of hyperthermic intraperitoneal chemotherapy in gastric cancer. Indian J Surg Oncol. 2016;7(2):198–207. 14. Sarin R. Global trends in specialist training, certification, and regulation of oncology practice and its implications for the developing world. J Cancer Res Ther. 2015;11(4):675–8. 15. Bhatt A, Mehta S, Seshadri RA, Sethna K, Zaveri S, Rajan F, et al. The initial Indian experience with cytoreductive surgery and HIPEC in the treatment of peritoneal metastases. Indian J Surg Oncol. 2016;7(2):160–5. 16. Bhatt A, Mehta S, Ramakrishnan A, Pande P, Rajan F, Rangole A, et al. Setting up of the Indian HIPEC registry: a registry for Indian patients with peritoneal surface malignancies. Indian J Surg Oncol. 2017;8(4):527–32. 17. Katdare N, Prabhu R, Mishra S, Mehta S, Bhatt A. Pressurized intraperitoneal aerosol chemotherapy (PIPAC): initial experience from Indian centers and a review of literature. Indian J Surg Oncol. 2019;10(1):24–30. 18. Tempfer CB, Solass W, Buerkle B, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in a woman with pseudomyxoma peritonei: a case report. Gynecol Oncol Rep. 2014;10:32–5. 19. McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, et  al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374(9695):1105–12. 20. Baggaley AE, Lafaurie G, Tate SJ, Boshier PR, Case A, Prosser S, et al. Pressurized intraperitoneal aerosol chemotherapy (PIPAC): updated systematic review using the IDEAL framework. Br J Surg. 2022;110(1):10–8. 21. Somashekhar SP, Ashwin KR, Kumar CR, Rauthan A, Rakshit SH. Pressurized intraperitoneal aerosol chemotherapy procedure for nonresectable peritoneal carcinomatosis: first Indian study. South Asian J Cancer. 2019;8(1):27–30. 22. Somashekhar SP, Ashwin KR, Rauthan CA, Rohit KC. Randomized control trial comparing quality of life of patients with end-stage peritoneal metastasis treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) and intravenous chemotherapy. Pleura Peritoneum. 2018;3(3):20180110. 23. Kim G, Tan HL, Sundar R, Lieske B, Chee CE, Ho J, et al. PIPAC-OX: a phase I study of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy in patients with peritoneal metastases. Clin Cancer Res. 2021;27(7):1875–81. 24. Mehta S, Kammar P, Patel A, Goswami G, Shaikh S, Sukumar V, et al. Feasibility and safety of taxane-PIPAC in patients with peritoneal malignancies – a retrospective bi-institutional study. Indian J Surg Oncol. 2023;14:166–74. 25. Somashekhar SP, Ashwin K, Zaveri S, Kumar RC.  First Indian study on pressurized intraperitoneal aerosol chemotherapy (PIPAC) procedure for advanced peritoneal carcinomatosis secondary to epithelial ovarian cancer. Indian J Gynacol Oncol. 2018;16:Article number25. 26. Votanopoulos KI, Shen P, Skardal A, Levine EA. Peritoneal metastases from appendiceal cancer. Surg Oncol Clin N Am. 2018;27(3):551–61.

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HIPEC: Concept and Fundamentals in Colorectal Cancer Peritoneal Metastasis Treatment Xavier Delgadillo-Pfenninger

and Eduardo Londoño-Schimmer

Abstract  The present chapter includes a well-detailed introduction and the beginnings of HIPEC. Mechanism and role of temperature including different modalities to apply HIPEC procedure are well defined in this chapter. Special description has been done including general indications and the entire procedure step by step, with exhaustive details. Drugs used, dosage ranges in liquid and nanoparticles presentation used in HIPEC are described in a clear subject. Success and failure of HIPEC compared to clinical trials, demonstrating the limitations of the technique, are also mentioned. Finally, we got our opinion on HIPEC in colorectal cases fleshed out writing by an independent expert. We introduce with permission the concepts and the future of HIPEC with the emergence of new technology. Keywords  HIPEC (Hyperthermic intraperitoneal chemotherapy) · Factors · Colorectal cancer · CRS (Cyto-reductive surgery)

Abbreviations CRS HIPEC PCI PM EORTC

Cyto-Reductive Surgery Hyperthermic Intraperitoneal Chemotherapy Peritoneal Cancer Index Peritoneal Metastasis European Organisation of Research & Treatment of Cancer

X. Delgadillo-Pfenninger (*) Centre Médico Chirurgical Volta, Unité Spécilalisée de Chirurgie, La Chaux-de-Fonds, Switzerland E. Londoño-Schimmer Hospital Universitario Fundación Santa Fé de Bogotá, Clinical Care Center for Peritoneal Neoplasias, Universidad de los Andes, Bogotá, Colombia © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Shegokar (ed.), Exploring Drug Delivery to the Peritoneum, https://doi.org/10.1007/978-3-031-31694-4_6

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IP Intraperitoneal CRC Colorectal Carcinoma CT-Scan Computed Tomography Scan MRI Magnetic Resonance Imaging

1 Introduction In the case to face any peritoneal malignancy, it is mandatory to analyse all pathways that will bring remedy, relief and quality of life to patients treated by colorectal surgeons. To highlight, colorectal cancer has a planetary high incidence, with more than a million of new cases in the world per year, placing this entity fourth place in the row of all cancers worldwide after lung, breast and prostate cancers [1]. Mortality incidence is settled just before lung cancer. Peritoneal metastasis in patients with colorectal cancer depends on the lymph nodes resection and how high is tied the vascular ligation of main vessels. Despite good intentions during surgery, there is a lack of accuracy on cellular excision, and beyond this description, the theory of peritoneal implants follows a cellular exfoliation of tumour cells followed by a host’s molecular capture [1, 2]. After this initial phase, peritoneal metastasis, considered as implants themselves, with the respective peritoneal invasion, they move under the epithelial floor and other aspects and planes, finalizing their progression on true peritoneal metastasis, all susceptible to chemotherapeutic substances. All chemotherapeutic substances can be delivered in different molecular sizes and different states like liquid, micro or nano-particles, all under high-temperature or electrostatic solutions [2]. Improving the management of colorectal peritoneal metastases, we had to determine if the range of 25% of all microscopic peritoneal implants are already enclosed at the moment of the diagnosis or during the time of surgery. We underline that there are almost 8% of synchronous peritoneal implants, and almost 19% of metastasis affect the liver [3]. Late in 2006, Kopper et al. reported during forensic autopsies, the presence of macroscopic peritoneal metastases of colorectal origin in the range of 40–80% (5.7% from the colon and 1.7% from the rectum) [4]. Sugarbaker was the first to describe properly the Cyto-Reductive Surgery (CRS) technique, as a complicated surgical procedure including the peritoneal excision and almost full visceral resection. Since his initial publication about 25 years ago, multiple aspects of the procedure have been published in detail, and some aspects of the technique have been modified and sophisticated by other surgeons as well [5]. It has been demonstrated that the best way to understand and learn CRS is to be trained by expert surgeons at expert centres; nevertheless, every surgeon faces many variated and difficult situations during the meantime of the learning curve and even thenceforward. It has been established that achieving a comprehensive analysis of the rationale, the patient selection, and the technique for CRS reported on the literature survey is mandatory.

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We consider it important, to evaluate conscientiously all published experiences of key opinion leaders in CRS. Literature survey would guide surgeons on the way to whereby the target organs “to resect”, when to do it, in which patients and finally, the way to conduct the patient’s evolution thereafter. Adequate learning of peritoneal neoplasms spreading physiopathology is a fundamental requirement to provide CRS as an innovative therapy for peritoneal metastasis [6]. To understand CRS fundamentals, we have to go back early in the 1950s, when Meigs et al. published the first descriptions of peritoneal resection surgery in cases of ovarian peritoneal metastasis, [7] then, 20  years later, the Japanese surgical school described the first reports on hyperthermic peritoneal chemotherapy followed late in the 1990s by the well-known author, Sugarbaker’s first descriptions about a large peritoneal excision procedure [3, 5], actually known as HIPEC (Hyperthermic Intraperitoneal Chemotherapy). More recently in 2020, the National Comprehensive Cancer Network [8] has described new guidelines in colorectal cancer and following the initial descriptions of the American Joint Committee on Cancer, they had definitely enunciated that, … A complete excision surgery associated to intraperitoneal chemotherapy can be considered in experienced centres, for selected patients, with limited peritoneal metastasis and R0 resections, a very good option that can be achieved by CRS…

2 Peritoneal Cancer Index Actually, the metastatic extension of neoplasms is estimated by different radiological methods, mostly performed by CT-Scan (computed tomography) or magnetic resonance imaging (MRI). Another way to evaluate the metastatic extension of a tumour is by an exploratory laparoscopy. However, there are no extensive accepted standard references for imaging or surgical exploratory procedures in case of peritoneal metastasis [9]. The concept of Peritoneal Cancer Index (PCI) was initially proposed by Jaquet and Sugarbaker [3, 5] with the aim to describe peritoneal carcinomatosis initially for colorectal cancer and/or mesothelioma neoplasms. In colorectal cancer cases, PCI has been established as a leading prognostic factor, demonstrating a linear link with overall survival (Fig. 1). Peritoneal Cancer Index diagram of the grading score, following Sugarbaker’s description. Actually, there is no consensus on the discontinuation of the value for treatment. However, it has been determined that surgery is not recommended for patients who have colorectal conditions marked by the production of an overwhelming number of metastasized carcinomatous cells throughout the peritoneum with a PCI higher than 20. A wide variety of cut-offs concerning the total PCI have been tested on the research about the possibility of a complete tumour resection and survival in colorectal cancer. Encompassing these outcomes, most studies have proposed PCI cut-offs range from 10 to 15. Moreover, it has been proposed that instead of

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Fig. 1  The tissue and organ location targeted by HIPEC therapy

applying the total PCI score, selected PCI regions, such as the small bowel and the hepatoduodenal ligaments, are better predictors for the possibility of the mentioned concept of a complete tumour resection and survival [4, 10]. Regrettably, the small bowel and the hepatoduodenal ligament areas are very difficult to evaluate by preoperative CT-Scan or MRI, especially regarding disseminated carcinomatosis on the bowel. If the information about the tumour bundle from PCI were adequately estimated preoperatively, it could be used in selected patients for primary surgery. In the attempt for achieving this, the former PCI score has been used for the interpretation of images. Currently, it is not known whether the PCI cut-off score for colorectal cancer can also be applied for many other types of cancer directly [4, 8].

3 Eindhoven Index Regimens It has been reported by Simkens et al. an alternative concept about the development of a prognostic nomogram for patients with peritoneal metastasized colorectal cancer treated with CRS and HIPEC at the Catharina University Hospital in Eindhoven, in Holland [11]. It consists of the current practice of CRS associated with a standard HIPEC procedure for colorectal peritoneal metastases, which has been published in detail in 2018 with the PSOGI (Peritoneal Surface Oncology Group International) results of a worldwide web-based survey regimens [12].

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Most of these regimens have been based on the extrapolation of systemic chemotherapy data. Since 2020, an urgent need for more standardization of the intraperitoneal chemotherapy modalities is needed and it is important to underline to review the rationale, variables, and modalities of intraperitoneal chemotherapy [13]. It is important to offer guidance on the current intraperitoneal chemotherapy regimens and potential directions towards more standardization to surgeons that want to initialize in HIPEC or CRS. The pre-operative evaluation with multidisciplinary tumour board, standard thoracic CT scan, abdominal-pelvic CT scan and in selected cases, PET scan and exploratory laparoscopy are fundamentally mandatory [12].

4 HIPEC Contraindications If the pulmonary metastases are not accessible for surgical removal or if their removal could potentially harm the lungs, alternative treatment options need to be considered. These options may include systemic chemotherapy, targeted therapy, radiation therapy, or other treatments that are more suitable for managing metastatic lung disease. The selection of the most appropriate treatment approach should be determined based on various factors, including the type and extent of the cancer, the patient’s overall health status, and the potential risks and benefits of the different treatment options. In cases where the pulmonary metastases are extensive or inaccessible for safe removal, the focus of treatment may shift towards controlling the progression of the disease, improving the patient’s quality of life, and providing supportive care to manage symptoms and complications associated with advanced cancer. It is crucial for patients with advanced cancer, including those with pulmonary metastases, to receive comprehensive and individualized care from a multidisciplinary team of healthcare professionals, including medical oncologists, surgeons, radiation oncologists, and other specialists. The treatment plan should be tailored to the specific needs and circumstances of each patient, taking into account the stage of the cancer, the presence of metastases, and the overall health and preferences of the patient [12]. The concept of proactive management of peritoneal metastasis consists of the prevention of a disease process that has always been superior to the treatment of the same disease throughout the history of medicine and surgery. It is well known that local recurrence and peritoneal metastases appear in approximately 9% of colonic cancer patients and 25% in rectal cancer patients, this situation should be definitely avoided [14]. The most important strategies to prevent local recurrence and peritoneal metastases in colorectal cancer patients include definitely CRS and HIPEC procedures. These strategies can be used at the time of primary colon or rectal cancer resection if the HIPEC is available. In the case, where HIPEC is not available in a defined institution, it is mandatory to proceed with the treatment of the primary malignancy,

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then an exploratory surgery can be scheduled later on to evaluate the possibility to perform CRS [15]. Multiple phase II studies strongly support the proactive approach mentioned before. If peritoneal metastases were treated alone, with the primary colonic resection, an improved 5-year survival rate should be seen and these results should be superior to the results of the treatment after peritoneal metastases develop as recurrence itself [16]. Also, the prophylactic CRS and HIPEC procedures improved survival with T3 – 4 T mucinous or signet ring colon cancers. A second look has shown to be effective in two published manuscripts. Unpublished data from one of those manuscripts arises from the MedStar Washington Cancer Institute, which has also produced favourable data in cases of rectal cancer with peritoneal metastases, despite that may not be so effectively treated [17]. Performing a systematic second-look surgery associated with a HIPEC procedure in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis has been described by Elias et al., early in 2011 [18]. The author analysed the impact of the procedure 1 year after complete resection of the primary tumour in asymptomatic patients, considered as high-risk patients for developing peritoneal carcinomatosis (PC). The study described in a period of 10 years, all patients that had a primary tumour resection without any sign of recurrence clinically or by radiology studies, that underwent a second-look surgery. The patients were studied to be treated under very limited and earlier PC, a procedure allowing them to be operated on more easily. This second-look strategy treated peritoneal carcinomatosis preventively or at early stages, yielding promising results [19]. More recently, the BIG-RENAPE Group (Réseau National de prise en charge des Tumeurs Rares du Péritoine, in French) proposed the diagnosis and treatment of colorectal peritoneal metastases in early stages, before the onset of signs that could improve patient survival. They had compared the survival benefit of systematic second-­look surgery associated with HIPEC, under surveillance, in patients at high risk for developing colorectal peritoneal metastases. Their conclusions were that systematic second-look surgery plus oxaliplatin-­ HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes, and this has made a break in forward HIPEC racing [20].

5 HIPEC Mechanisms and Role of the Temperature The peritoneal route of drug delivery has been proposed and used since the eighteenth century, when an English surgeon, D. Warrick, in 1744 instilled a mixture of “Bristol water” and Bordeaux wine in the peritoneal cavity to treat intractable ascites in one of his patients [21].

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Table 1  Summary table of drugs used in peritoneal carcinomatosis (PMID: 27065705) Drug 5-Fluououracil Carboplatin Cisplatin Docetaxel Doxorubicin Etoposide Floxuridine Gemcitabine Irinotecan Melphalan Mitomycin C Mitoxantrone Oxaliplatin Paclitaxel Pemetrexed

Molecular weight 130.08 371.25 300.10 861.90 579.99 588.58 246.20 299.50 677.19 305.20 334.30 517.41 397.90 853.90 597.49

AUC ratio 250 10 7.8 552 230 65 75 500 N/A 93 23.5 115–255 16 1000 40.8

Many years later, during the first part of the twentieth century, the administration of radioactive gold (198Au) and radioactive chromic phosphate (P32Cr3+) were used as adjuvant chemotherapy in the treatment of ovarian cancer, but very high morbidity was encountered and the distribution of the drug was non-homogenous [22, 23]. In 1978, Dedrick and co-workers proposed a theoretical advantage for the use of intraperitoneal (IP) drug delivery based on the pharmacokinetic advantage that results from the fact that systemic drug clearance is much faster compared to peritoneal clearance. Thus, IP therapy can be administered at higher doses with low systemic exposure and toxicity [24]. Dedrick described the tissue penetration depth as very limited. The use of concomitant hyperthermia (as HIPEC does) and the IP distribution of liquids were the first studied in the animal model by Euler and co-­ workers in 1974 [25]. Spratt et al. reported in 1980 the first HIPEC clinical use of the combination of warm Thiotepa in a patient with Pseudomixoma Peritonei [26]. IP drug delivery permits more elevated drug concentrations (Table 1), but this effect depends on the target tissue concentration. Several studies consider tumour tissue as a homogenous (isotropic) porous medium. Two major mechanisms determine the transport of solutions into the tumour concentration: convection or bulk fluid flow, which depends on a pressure gradient, and basal diffusion, resulting from the concentration gradient. By the other and, other procedures, applying nebulized chemotherapy has been developed recently, and we present a comparative table between HIPEC drug regimens in front of doses in other types of procedures like PIPAC. The ratio of connective transport over diffusive transport is quantified as the de Péclet number. This number is low for small molecules (diffusion dominates) and higher for large compounds such as antibodies or nanoparticles, for which tissue penetration depends on a difference in pressure.

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During HIPEC, the extent of connective drug transportation is proportional to the difference in pressure, between the fluid-filled in the peritoneal cavity and the stromal tissue pressure [27]. The hydrostatic pressure exerted by the intraperitoneal fluid pressure and measured by the intraperitoneal fluid column can be estimated as 10–20 cm H2O (7.4–14.8 mmHg). Tumour tissue has mainly three characteristics: an elevated interstitial fluid pressure caused by increased blood flow, “leaky” capillaries, and deficient lymphatic drainage [28], elevated solid stress secondary to compression forces to the surrounding tissues, swelling as a result of electrostatic repulsion between negatively charged stromal components such as hyaluronic acid [29, 30], and residual solid tissue stress, which represents the stored elastic energy which can be observed when cutting into a solid tumour. Chemotherapeutic solutions diffusion depends on the hydraulic conductivity of the target tissue, which is affected by the viscosity of the interstitial fluid and by mechanical stiffness or the increased deposition of collagen I, tumour stroma’s lysyl oxidase elevated amounts [31, 32]. Drug diffusion depends on Fick’s law, depending on the concentration gradient of the solution, temperature, physicochemical drug properties, and the stromal architecture [33]. Drug properties include molecular weight, hydrodynamic size, charge, and configuration of the solution. Stroma properties can affect drug diffusion, and that includes cellular composition, density, visco-elasticity, and geometrical fibre arrangement [34]. The penetration depth of IP drug administration is very limited, a few millimetres at the most depending on the type of drug, treatment, and tissue properties [35]. Hyperthermia (39–42 °C) has been used since long ago. Considerations for its use include being selectively lethal for malignant cells [36], the effects of heat can be synergistic with the use of chemo and radiotherapy [37] (platinum compounds and mitomycin C), it improves tissue perfusion and oxygenation, and may enhance tissue penetration, demonstrated in a rodent model of colorectal peritoneal cancer with the use of Cisplatin [38]. Helderman et al. have reported in a series of in-vitro studies, different replications of clinical scenarios (38°-43° Celsius for 60 minutes) in several 2D and 3D human colorectal cancer cultures, demonstrating that hyperthermia enhanced cytotoxicity depending on the cell line and the drug used. A positive effect was evidenced when using oxaliplatin and cisplatin, but not with mitomycin C, carboplatin, or 5FU [39]. Hyperthermia may diminish the systemic toxicity of some drugs, such as doxorubicin and cyclophosphamide [40]. Another factor, besides the drug chosen, when using hyperthermia, is the length of exposure. Forsythe demonstrated using organoids from colorectal cancer that a low dose of heated oxaliplatin (200 mg/m2) for 200 min appeared to be more effective in terms of cytotoxicity than a higher dose of oxaliplatin (460 mg/m2) for only 30 min [41]. The ideal target temperature of HIPEC is not yet known. In vitro, DNA repair is inhibited at a temperature of >41 °C, unfortunately in vivo, this has not been proven.

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Hyperthermia elicits the expression of heat shock proteins, which exert anti-­ apoptotic and proliferative effects and induce resistance to chemotherapy [42, 43]. Applied temperature above 41° Celsius degrees may cause burn injury to the peritoneum [44]. Hyperthermia leads to immunogenic cell death by secretion of damage-associated molecular patterns including calreticulin, ATP, high mobility group B1, and heat shock proteins 90 and 70. The effect mediated by T cell’s immune response, may also reverse the “cold” tumour environment observed in presence of peritoneal metastasis, sensitizing the tumour to immune inhibition [45].

6 Types of HIPEC The HIPEC administration procedure basically consists of a system of in-flow delivery tubes, and another system of outflow drainage tubes, both connected to a distribution engine that heats chemotherapeutic solution compounds and delivers them as a fluid, with constant monitoring via temperature probes in the peritoneal cavity connected to the delivery tubes. Many different types of heating machines have been developed and many are available commercially. Unfortunately, there is heterogeneity in the procedural parameters including drugs used, dose regimen, carrier solution, target temperature, treatment duration, and delivery technique. Standardization is sparse [46, 47]. Chemotherapeutic drugs for HIPEC should have a favourable PK profile, no cell cycle specificity, and an absence of local peritoneal toxicity. There is still debate on the use of oxaliplatin versus mitomycin C for colorectal peritoneal metastases (PM) [48]. Sugarbaker prefers mitomycin C (personal interview, August 2020). The use of a combination of agents, though appealing, has shown to have higher morbidity and no benefit in recurrence-free or free survival in colorectal PM [49]. Perfusion of HIPEC can be performed via open or closed techniques. The open technique, also known as the “coliseum” procedure, consists in leaving the extensive laparotomy incision open, fixating sutures of polypropylene 0/0 are distributed along the skin and subcutaneous tissues, exposing the entire cavity and its organs. This technique permits that the abdominal contents to be stirred manually ensuring homogenous drug solution and temperature distribution. The also well-described closed technique consists on the closure of the fascia layer or the skin after the cytoreductive procedure is finished, connecting the delivery system well placed before, or placed under laparoscopic vision when the procedure is performed by this method [50]. It prevents OR environment contamination and heat loss and may enhance convection-driven tumour chemotherapy penetration due to increased intraperitoneal pressure [51, 52].

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7 HIPEC Procedure Patients are thoroughly evaluated according to a pre-established protocol, all patients are evaluated by a Clinical Care Centre for Peritoneal Neoplasias. Patient’s details, administrative data, radiological files, present and past clinic history are discussed and argued in a multidisciplinary staff meeting, and the best treatment and oncological-surgical attitude is decided and finally undertaken. Generally, the patient is admitted at the referral hospital at least 72 h before the procedure, time during which clinical and a full work-up is performed and complementary examination, blood tests or imaging examinations are updated. The proposed technique we use, basically follows, Sugarbaker’s descriptions and we follow the classic steps of the procedure described by the author early in the 1990s [53–56]. The chosen day for surgery, the patient is under general anaesthesia, fully monitored according to the referral hospital protocols, placed in the modified lithotomy Lloyd-Davies position (initially described by St Marks Hospital, London), positioning which allows excellent exposure and approach to the perineum. Frequently, CRS combined with HIPEC procedure are time consuming operations, where the expected average performance time, variates from five to seven hours. Silicone foam pads are placed over the operating table protecting the patient’s skin and yellow-fins® stirrups are used for lower extremities protection also. The weight of the legs must be directed to the bottom of the feet by positioning the footrests so that minimal weight is borne by the calf muscles avoiding compartmental syndrome (Sugarbaker) and eventually muscular necrosis [57]. Lower extremities compression anti-shock thighs are placed on the legs and feet. A warming blanket is placed under the patient and a warming device is placed covering patient’s head, chest and both arms [58]. Skin preparation and disinfection is carried out from the medial chest (an imaginary line between nipples) to the knees. The perineum is also prepped, and urinary Foley’s catheter is placed. In some selected cases, ureteral catheters are placed endoscopically, especially when difficult dissection of the ureters is foreseen, and a large bore nasogastric tube is placed in the stomach. A time-out checklist and verifications by the whole surgical team are performed, and a median xipho-pubic incision is performed. Fixing Polypropylene 0/0 sutures are placed on the edge of the skin and the subcutaneous tissue margins along the median incision, previously protected by an antiseptic-protective foam (3M-Ioband©).

8 1st Stage of a HIPEC Procedure Once the access to the peritoneal cavity is set, an abdominal Self-Retaining Retractor is placed and fixed on (Thompson® Surgical Instruments, Inc., Traverse City, MI, USA). This manoeuvre permits a wide exposure of the abdominal cavity, its organs

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and the peritoneum to treat. At this time of the surgery, an electrosurgical blunt tip hand piece (ValleyLab©, Boulder, CO, USA) is used for dissection, along with a scalpel dissection where required due to firm adhesions or surgeon’s preferences. Frequently, large volumes of plume of smoke can be generated during dissection, this condition is due to carbonization of tissues dissected by the electrosurgical blunt tip handpiece. In order to preserve a smoke-free operating room, protecting all people involved, a smoke filtration unit is used (Smoke Shark Bovie®) and a laminar flux is available and functioning at the OR. Ascites are a frequent finding during cyto-reductive surgery, and they must be drained and a sample sent to cytological study. The operation is pursued with the complete greater omental resection. For this purpose, it is useful to perform the excision using a bipolar instrument such as LigaSure® System (710 Medtronic Covidien Parkway, Minneapolis, MN, 55432-5604, USA). CRS follows with the exposure of the transverse colon, opening the greater sac, showing the anterior aspect of the pancreas. Gastroepiploic vessels found on the greater curvature of the stomach are ligated along with the short gastric vessels. If the tumour is compromising the spleen, the anterior fascia of the pancreas is elevated, it is mandatory to proceed to the exposure of the splenic vessels, and perform a double ligature with Polypropilene 2-0, followed by the application of the LigaSure®, vessel sealing system. A complete mobilization of the spleen is accomplished and after freeing its attachments, splenectomy is completed. Further on, a complete mobilization of the gastric greater curvature is achieved, the left upper quadrant anatomical structures are exposed (No. 3 on the PCI diagram), and the peritoneal, and the peritoneal stripping begins at the edge of the abdominal incision, off the posterior rectal sheath, placing Kelly’s clamps along the edge of the peritoneum and using the ValleyLab® electrosurgical device. A very smooth traction of the peritoneum permits the dissection and stripping of its entire structure without thorns, this manoeuvre permits the progression of the dissection and a complete resection of the peritoneum exposes the left hemi-diaphragm muscle, the left adrenal gland, the superior aspect of the pancreas and the peri-renal fascia described by Gerota. Then, complete mobilization of the splenic flexure of the colon is performed, through a double plane dissection with the separation of Toldt’s fascia (a discrete layer of connective tissue containing lymphatic channels, placed between the two mesothelial layers, which separate the mesocolon from the underlying retroperitoneum), medial mobilization of the transverse colon is completed. Haemostasis should be meticulous and must be assured. Continuing with the excision in one fold of the peritoneum membrane, dissection is achieved at the upper abdominal quadrant. Kelly’s clamps are placed on the specimen and gentle traction is applied to continue progressing with the peritoneal dissection. Adequate exposure of the diaphragm muscle is done under very careful haemostasis. From this point, the dissection is carried out until achieving access of the supra-­ hepatic veins, they should be identified precisely. Tumours on the anterior surface of the liver are frequently encountered and an electro-vaporization is needed applying the ball-tip electrosurgical device (Valley Lab, Boulder, CO, USA) for complete

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and definitive resection, associating the total excision of the Falciform ligament, a ligament that attaches the liver to the front body wall, and separates the left lobe of the liver into the left medial lobe and left lateral lobe. Then it is important to excise the round ligament deep in the umbilical fissure of the liver. According to findings and tumour compromise, complete excision of the peritoneum of the upper right quadrant and the infra-hepatic space is performed, “en block” exposing Gerota’s fascia, which covers the right kidney, the resection of this part of the peritoneum is completed by the stripping off Morrison’s pouch. The infra-hepatic portion of the inferior vena cava is identified and preserved, and the caudate lobe of the liver is exposed. The previous manoeuvre precedes the mobilization of the hepatic flexure of the colon, exposing oddly the duodenum. At this point, if needed, a classic Kocher’s manoeuvre can be performed.

9 2nd Stage of a HIPEC Procedure In some cases, the tumour might be firmly adherent to the tendinous portion of the left or right hemi diaphragm, and resection of this tissue must be accomplished. Suture of the defect should be done, and a thoracic drainage tube should be placed. At this point, an antegrade cholecystectomy can be performed, without cholangiography. If the neoplasia is widely present at the level of the portal vein, this tissue should be dissected and stripped off from its place. Special care should be observed to the vascular structures such as the blood supply to the caudate lobe and the left hepatic artery that can arise from the left gastric artery and cross the hepatic-gastric fissure. Progressively the surgeon dissects in a clockwise direction along the lesser curvature of the stomach, the two major branches of the left gastric artery are identified and preserved, ensuring blood supply to the stomach. In certain cases, if indicated according to the pathology being treated (gastric cancer) partial or total gastrectomy is performed. Once haemostasis is assured, a complete review of the small bowel is done, if any implants are found on the free side of the bowel or the mesentery, they should be excised. In case of any small bowel resection, a classic “cone” excision of lesions should be practised. The surgical continuity is followed by the anastomotic achievement with the reestablishment of the continuity of the bowel tube, this procedure is completed by suturing in one or two planes, using absorbable sutures, or using staple techniques. Surgeons try to be as conservative as possible, and in the vast majority of cases, resection of serosal implants is performed without segmental resection of the bowel. In our centre, the second team of surgeons starts from this point and performs radical excision of the peritoneum placed on the right lower quadrant, stripping the peritoneum in the same way, described before. We approach then the pelvis from the right side of the abdominal cavity, progressively identifying the deep epigastric vessels, spermatic vessels, the ductus deferens in men, or the round ligament in women.

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At this time of the operation, gentle traction is exercised after placing Kelly’s clamps along the peritoneal edge, and progressively, the right ureter and gonadal vessels are preserved in men, in women high ligation of the gonadal vessels should be accomplished, followed by the stripping of the peritoneum on the medial aspect of the peritoneal cavity. Once the right mesocolon is well identified, and the ileocecal valve mobilized, a radical right hemicolectomy, if indicated, with complete mobilization of the mesenteries, and a complete mesocolon excision are performed. This procedure includes a high tie of the pedicles and closure of the ends of the ileum and proximal transverse with staplers. Lymph nodes harvesting should be as extensive as possible. Peritonectomy continues in a counterclockwise direction, with the stripping of the peritoneum from the bladder dome and its posterior wall, until the anterior wall of the rectum. Then, the peritoneum placed at its own peritoneal reflection should be gently stripped and completely excised. Beware not to injure the rectal wall., identification is crucial. It is important to underline that the dissection of the right ureter is carried up to the bladder, a lot of care should be taken with the aim, of not compromising its own vascularity. In women, exposure and dissection of the right uterine vessels must be accomplished. At this point, the gynaecological surgical team arrives on the field, and hysterectomy is performed.

10 3rd Stage of a HIPEC Procedure The procedure continues on the abdominal cavity’s left side, peritoneum membrane excision is accomplished in the same way, as achieved at the beginning of the dissection, at the level of the umbilicus, the stripping of the peritoneum continues medially until the mesosigmoid and the mesocolon (by descending goitres), both should be well dissected and complete mobilization of this structures is performed. Peritonectomy continues on both lateral aspects of the rectum, and the peritoneal membranes are stripped and completed on this site. In women, with the onco-­ gynaecological team, a radical hysterectomy and bilateral salpingo-oophorectomy are performed, and in most cases the bladder, once the peritonectomy of its posterior wall is completed, is totally lifted off until the cervix appears on. Then, the anterior wall of the vagina is opened, and then the posterior wall is visualized and well-­ identified, at this point, it should be opened and the anterior wall of the rectum is exposed. At this moment a complete stripping of Douglas cul-de-sac of the peritoneum is concluded. The vaginal cuff is closed using a running 2/0 Polygalactin 910® suture. Through a rigorous review of haemostasis, this stage is carried out. In most cases, the rectum can be spared with meticulous stripping of the peritoneum assuring an R-0 resection. If needed, or if indicated, a standard radical anterior resection of the rectum is performed, with high tight ligation of the mesenteric artery, high ligation of the inferior mesenteric vein beneath the duodenum, finished by a complete

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mobilization of the left colon prepared for a tension-free classic colorectal anastomosis. An end to end, stapled anastomosis can be executed, verifying the anastomotic rings that must be complete and circular. Sealing of the anastomosis should be tested by air insufflation through the anus by one of the surgeons, while the other verifies patency when the pelvis has been filled with a saline solution and confirmation of an air-tight anastomosis is done. In most of the cases, we consider reinforcing the anastomotic stapler line with interrupted 4/0 Polydioxanone (PDS II®) a synthetic, absorbable, monofilament suture made from a polymer. If a right hemicolectomy or a small bowel resection has to be associated with the procedure, we always consider performing our anastomosis using stapler devices. Lateral to lateral (L-L) or lateral to end (L-E) stapler anastomotic lines are always reinforced using interrupted seromuscular 4-0 PDS II separated stitches. Finally, the mesentery closure is achieved by a running suture of absorbable lines. Both surgical teams continue the procedure, and a complete review of haemostasis should be achieved, a procedure that should be done after the abdominal cavity is washed with 6 L of normal saline solution. Al liquids are aspirated and drained.

11 Last Stage of a HIPEC Procedure HIPEC can be performed with an open or closed abdomen. Actually, we had chosen to perform the HIPEC Closed Delivery Technique. For this purpose, we install two inflow tubes and two outflow tubes, placed through the abdominal incision. A sealing closure of the skin and subcutaneous tissue is achieved using a running 0 Polygalactin 910® suture. It is important to set at least 3 thermometers attached to the tubes with the purpose for monitoring temperature in the abdominal cavity. Then, all tubes are connected to a specially designed delivery machine (ThermaSolution®, ThermoChem HT-2000, White Bear Lake, MN, USA), machine operated by a dedicated perfusion-nurse (technician) under the surveillance of our clinic oncologist, both placed in front of the control panel. The abdominal cavity is ready for a continuous perfusion with cytostatic solutions heated to 41° to 43° Celsius degrees through a drainage system consisting of inlet and outlet catheters, propelled and suck by 2 pumps. Then the hyperthermic intraperitoneal chemotherapy with the cytostatic solutions and compounds can be started. It is mandatory to observe the rigorous occupational safety of all health personnel and surgical individuals involved with the procedure, directly or indirectly. Once HIPEC is completed, the incision is opened, tubes are removed, full wash-out of the cavity is done with 1.5% dextrose dialysis solution (Dianeal®, Abbott Laboratories), full revision and assurance of haemostasis is carried out, use of fibrin sealant (Tisseel®, Baxter laboratories) is sprayed in the pelvis, body and tail of the pancreas, gallbladder’s bed of the liver and around an anastomosis if it has been performed, drains are placed in each of the four quadrants

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of the abdomen, secured by purse-string sutures to the skin with 2–0 polypropylene, the aponeurosis is closed with a double 1 PDS II suture, a subcutaneous drain is placed and secured, and the skin is closed with a running 3–0  V-loc® suture (Medtronic). Bilateral thoracic drainage tubes (if indicated) should be placed and secured. Once the procedure is finished and before transfer of the patient to the ICU, the urinary Foley’s catheter is changed by a new one, if at the beginning of the procedure ureteral catheters where placed, and there is no indication for them to stay, they are removed at this moment. Complete review of the patient’s posterior skin is mandatory, to verify that no accidental injuries or skin lesions developed during the operation. The patient is transferred to the intensive care unit (ICU) for postoperative care.

12 Final Assessment of Classic HIPEC for Colorectal Cancer Peritoneal Metastasis After mature reflection and relevant advice of facts, and discussing with other experts in America and Europe, we had retained the concepts proposed by W. Ceelen, from Belgium, referring also, to concepts of the first trial published in 2003, as a randomized clinical trial that had showed HIPEC and CRS using 90  min, Mitomycin-C 35 mg/m2, that improved survival in patients with colorectal peritoneal metastases as compared to palliative surgery and systemic treatment alone (2 years versus 1 year respectively) [59]. Despite these relevant doses, palliative concepts, and quality of life proposals, many non-controlled studies have shown that long-term survival can be obtained with HIPEC and CRS which demonstrates the median survivals ranging from 14.6 to 60.1 months according to last Ceelen’s published review, late in 2021, and this is very encouraging for the treatment of PM. However, the treatment-related mortality in other trials concerned demonstrated that it was as high as 8%. These values have diminished significantly with increasing team’s experience and actually it oscillates from 1% to 2% in most experienced units, around the world [60]. Actually, a recent French multicentre study published had compared CRS alone with CRS combined with short duration (half an hour) Oxaliplatin (460 mg/m2)based HIPEC in colorectal peritoneal metastasis (PRODIGE 7/ACCORD 15, NCT00769405). Thought-provoking, HIPEC did not enhance overall survival in this trial, but did increase 3-month morbidity. These results, had questioned the rising values concerning CRC resistance, despite that 2021 – Cancer Journal rep­orts to 16 the value of HIPEC in addition to complete a CRS in colorectal cancer peritoneal metastasis [59, 60]. As mentioned before, Ceelen et al. [59] had recently underlined orally in Rome’s latest ISSPP meeting 2021:

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... a possible explanation for the lack of efficacy of the oxaliplatin-based regimen in the PRODIGE 7 trial may be the selection of patients as these were only included after a minimum of 6 months of systemic therapy...

Such therapy was: Oxaliplatin-based in the majority of patients and this may have resulted in an acquired resistance of the peritoneal metastases against IP Oxaliplatin as it was demonstrated in pre-clinical studies. Also, patient-derived organoids from colorectal peritoneal metastases appear to be resistant to heated Oxaliplatin in a dosage similar to the one used in the PRODIGE7 protocol. Another topic of debate is whether systemic treatment, either neo-adjuvant, adjuvant or both should be part of the initial treatment strategy. Although peri-operative treatment was part of the PRODIGE7 study protocol and is practised widely around the world, high-level evidence to support this practice is currently lacking. Ceelen’s publications also indicated that recent retrospective comparative cohort studies had no beneficial effect of peri-operative systemic therapy as shown after complete CRS followed by HIPEC, as proposed by other Belgian authors, as Repullo et al. early in 2021 [60]. In contrast, a large population-based study including almost 400 patients undergoing HIPEC and CRS revealed a benefit of adjuvant systemic treatment as compared to standard follow-up alone after propensity score matching. The value of perioperative chemotherapy is currently investigated in the international multicentre randomized CAIRO6 trial. Besides a role of the Hyperthermic Intraperitoneal Chemotherapy in the treatment of established peritoneal metastasis, also the mentioned role as “prophylaxy”, two randomized trials have evaluated the use of HIPEC with Oxaliplatin in patients at high risk of peritoneal recurrence (i.e., pT4 tumours, perforated tumours, minimal PM resected at the time of primary surgery, and ovarian (Krukenberg) metastases) [59, 60]. Both the French ProphyloChip (NCT01226394) and the Dutch COLOPEC (NCT02231086) randomized trials did not meet their primary endpoint (three-year disease-free survival and peritoneal metastasis free-survival at 18 months, respectively) although long-term results are awaited. As also in these trials a short course (half an hour) high-dosed Oxaliplatin HIPEC regimen was used, and questions were raised concerning the efficacy of IP Oxaliplatin using this regimen. A similar study of prophylactic HIPEC by the National Cancer Institute (NCT01095523) has been withdrawn.

13 Futuristic Electro – HIPEC Recent treatment of tumours with heated electrochemotherapy had emerged over the past 5 years. It is due to a transient cell membrane permeabilization induced by short electric pulses used by heated electrochemotherapy exposing cancer cells to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity [61].

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Initially described in Europe, this proposal is actually taking a broad diffusion of the procedure, and since then, the progressive clinical experience, together with the emerging technologies, has extended the range of its application. Entities like the European Standard Operating Procedures (ESOPE) had proposed initial guidelines and discussed the emerging clinical data on the new electric-chemotherapy models, indications and proposed trials to demonstrate real efficacy (Cordis Project) [62]. Nevertheless, all new technical developments have not completely changed the HIPEC fundamentals and need very improved equipment, with specialized electrode probes and dedicated tools supporting individual treatment planning in anatomically challenging tumours. The feasibility has not been definitively established in deep-seated tumours, liver malignancies, colorectal metastasis, and pancreatic cancer. Moreover, pioneering studies advance early and new combination strategies with immunotherapy, gene electro transferrin and micro-radiotherapy [61, 63]. Many clinical studies are completed using HIPEC as treatment and can be referred on clinical.gov. Finally, we have to underline that CRS and HIPEC are nowadays being used as valuable treatment options in highly selected patients with metastatic colorectal spread to the peritoneal cavity. Outcomes of therapy vary with the primary disease histology and the survival advantage varies also, from a few years in the case of PC of colorectal origin, compared to controls.

14 Conclusion Actually, data clearly show that CRS and HIPEC are associated with better outcomes when a complete cytoreduction is achieved. Considering the significant cost and morbidity of the procedures, a precise patient selection should be emphasized. In very selected patients, it can result in long-term survival and possibly a cure for PC from colorectal metastasis. Currently, there is no standard protocol for CRS, the efficacy of HIPEC is being evaluated in multiple ongoing RCTs, and we eagerly look forward to the results of these studies.

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Peritoneal Implants and Drug Delivery Muhammad Ali Syed, Muhammad Irfan, Ameer Fawad Zahoor, Haroon Khalid Syed, Shahid Shah, Muhammad Ajmal Shah, Nayyer Islam, and Sana Hanif

Abstract  Peritoneal cavity owing to its physiological and anatomical features offers perfused capillaries to facilitate permeation for systemic delivery, dosage form retention, and an ideal site for delivering depot of therapeutic substance to the visceral organs. Pathologies of tumor or infectious origin are more to be treated through the peritoneal route since oral administration requires heavy dose to achieve local drug concentration. Hydrogels, nanocarriers, peritoneal implants, and nanofibrillates have been the dosage of interest for the researchers delivering intraperitoneal technological products for diagnosis as well as treatment. Hydrogels, however, present the non-particulate form of delivery that can retain on to the membrane of the peritoneum as well as not to be uptaken or permeated through the membrane. A prerequisite for depot delivery is the possibility of cytotoxicity due to polymer which is however been not observed especially when delivered with albumin-based

M. A. Syed Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, Government College University, Faisalabad, Pakistan Faculty of Pharmacy, Department of Pharmaceutics, The University of Lahore, Lahore, Pakistan Department of Pharmacy, Government College University, Lahore, Pakistan M. Irfan (*) · H. K. Syed · N. Islam Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, Government College University, Faisalabad, Pakistan A. F. Zahoor Department of Chemistry, Government College University, Faisalabad, Pakistan S. Shah Faculty of Pharmaceutical Sciences, Department of Pharmacy Practice, Government College University, Faisalabad, Pakistan M. A. Shah Faculty of Pharmaceutical Sciences, Department of Pharmacognosy, Government College University, Faisalabad, Pakistan S. Hanif Faculty of Pharmacy, Department of Pharmaceutics, The University of Lahore, Lahore, Pakistan © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Shegokar (ed.), Exploring Drug Delivery to the Peritoneum, https://doi.org/10.1007/978-3-031-31694-4_7

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biodegradable substances. These dosage forms have unique perspective in delivering drug molecules, genes, and peptide molecules as therapeutic moieties. Formulation strategies have focused on the safe portal of medicament, and various methodologies characterized the in vitro and in vivo behavior of formulations while also confirming the aim of therapeutic strategy. The advantage of the therapy can be manifested by shrinkage in the size of tumor through confocal imaging techniques. The human trials depot peritoneal delivery reflects the efficacy of the dosage to treat cancer with fewer adverse effects. Researchers should focus on targeting the drugs to the organs of abdomen through antibody-drug complex or direct targeting of drug to the tumor tissues. Keywords  Peritoneal delivery · Depot formulation · siRNA · Cancer therapeutics · Hydrogels · Nanotechnology · Xenograft mice · Cancer animal model

1 Introduction Peritoneal membrane composes vital tissue of the body that serves to filter solutes from the interstitial fluid. That is why it is an alternative natural device for the body to filter body fluids when kidneys are unable to filter blood. Delivery of drug across peritoneal membrane can be executed through skin transdermal route, catheterization, or peritoneal implant [3]. For transdermal drug delivery, the drug has direct access to the systemic circulation through permeation, however, distribution of the therapeutic moiety cannot be confined or localized to physiological organ [47]. Even if the transdermal delivery is on to the abdominal region, the drug will not traverse to the peritoneal region only, rather is distributed systemically to the whole body compartments. So, technically when transdermal delivery is assessed, the non-­ specific release of drug is associated with continual contact of the dosage form which is sometimes, or as the case may be associated with irritancy or inflammation posed to the epidermal layers. While in the catheter, there is no doubt that the direct contact with the peritoneal region is established; nevertheless, the chances of infections and risks are always on top [15]. However, there are certain clinical instances in which the surgical placement of dosage form as depot is reasonable and justified especially when there is direct access to the cavity during surgical procedure. A number of dosage forms are present through which drug can be released in to the peritoneal cavity for action, e.g., devices, coextrudates, microsphere, administration of implant through injection, aerosolized drug delivery, catheter, nanofibrillates, and other depicting time-dependent release [3, 52, 58]. For depot preparation, the reservoir will be directly inserted into the cavity after surgical incision. Distinguished features for peritoneal implant include effective local concentration achieved for drugs, delayed absorption of drugs, and the possibility of delivering biological substances through it [44]. Surgical placement of depot is the practical procedure for administration of depot or sustained delivery of the dosage, so it is very important to produce a prolonged therapeutic effect with depot formulation.

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Few important points of discussion arise when there is a need to deliver the moiety through the peritoneal cavity. It includes the need for localization of the medicament, molecular weight of the medicament, biological nature of the molecule, the intended duration of drug release, and local or system drug effects. For instance, the peritoneal delivery of insulin molecule showed promising antidiabetic superiority over the transdermal route in diabetic rats [56].

2 Physiological and Anatomical Considerations Anatomically, the membrane constitutes a monolayer of closed flattened epithelial cells and the squamous mesothelial tissues, having a depth of up to 2 μm with several microvilli-like structure [50]. The region below the membrane is supplied with reasonable blood perfusion and lymphatics, which are responsible for the permeation of substances across the membrane. Anatomically, it is a continuous thin translucent serous membrane comprised majorly of the visceral peritoneum (covering visceral organs) and the abdominal peritoneum as it covers the inner side of the abdomen [17]. Similarly, structures like adipose tissues, collagen, and vascular cellular components like lymphocytes, fibroblasts, and macrophages are also found in the membrane tissue layer [34]. The blood flow to the peritoneal membrane is approximately 100–150 mL/min in healthy individuals as it relatively covers a surface area of about 1 m2 and the unfiltered surface area of the diffused capillary network is nearly twice the membrane area [24, 50, 51]. The compact area of the abdominal peritoneum is almost 50 μm; however, it varies with the clinical situations as it can reach up to the value of 500 μm with chronic dialysis patients [59]. Peritoneal membrane is responsible of different functions in the body, out of which protecting and continuously lubricating the visceral organs of the body are the important ones. The secretory cells of mesothelial tissues produce hyaluronic acid, proteoglycans, and lamellar vesicles encapsulating phosphatidylcholine that generates a resistance-free movement of abdominal organs during body movement, respiration, and peristaltic movement of gastrointestinal tract. These secretory substances are responsible to reduce tumor adhesion and dissemination across the peritoneum. Some other body functions performed by this membrane include displaying antigen, coagulation, tissue control, breakdown of fibrin, control of tissue inflammation (Fig. 1) as well as repair and coagulation [9, 31]. Cells in the mesothelial region generate both tissue and urokinase forms plasminogen activators (tPA and uPA). These proteases in turn contribute to fibrinolysis, by changing plasminogen to plasmin (Fig. 1). This conversion can be reduced by glycoproteins plasminogen activator, which is also generated from mesothelial cells. Similarly, the cells also regulate the active uptake of pinocytic vesicles [57]. The anatomical perspective of the capillaries in the membrane displays non-­ fenestrated regions, which contains a transport protein for the movement of water as well as numerous solute substance across the membrane. The mesothelial layer hence served for dialyzing the body fluid when kidneys fail to respond for the

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Fig. 1  Diagram numbering different functions of the peritoneum. (1) The mesothelial cells mediating the role of plasmin activity and production through plasminogen activator and inhibitor to control fibrin level; (2) Transportation of ionic and solute substances; (3) Friction-free surface by glycocalyx to prevent the attachment of tumor cells; (4) Antigen-presenting function of mesothelial cells to mediate inflammation; (5) Inflammatory response of peritoneum through monocytes mainly; and (6) Tissue reparation mechanism. (Reproduced from [57])

process of filtration [19, 43]. Moreover, peritoneum region is undoubtedly an active research area for drug delivery to cure infections, tumors, inflammatory disorder, and other diseases pertaining to the visceral organs [8, 26, 41, 42].

3 Permeation Through Peritoneal Membrane While designing a dosage form to a local region into the body, it is important to know the physiological conditions and the associated factors that can affect the degradation or clearance of the drug after administration [22]. Apart from biopharmaceutical considerations, the physiological and anatomical surfaces of the peritoneal cavity support the release of the drug [49]. The throughout leaky capillary network especially due to non-fenestrated structures supports the perfusion and exit of therapeutic moiety to deliver dug to the ovarian region, large intestine or for localized effect to treat tumors or infections [25]. Many times, the delivery is assessed in order to serve depot release [1]. Nevertheless, the peritoneal cavity is an opportunistic region for kidney failure patients and the membrane is applied to filter

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the dialysis solution for purification of the blood. The three-pore model theory of the peritoneal cavity supports the simulation of the cavity as comparative to the renal tissues for innate filtration of blood [46]. These findings portray that the extent of permeation of substances such as ionic or solute form can permeate through the peritoneal region. Strategies should be however designed in order to retain the formulation in the peritoneal region if localized action is required. Normally, material-­ based targeting to the peritoneal cavity is considered effective compared to the high dose of chemotherapy. It is because the nanoparticles are easily taken up in to the tumor cells by endocytosis (Fig. 2). It can eventually lead to the release of the therapeutic moiety inside the cytoplasmic region of the cell. However, the release of the drug from the dosage form is related to triggering factors like ATP-mediated pathways or pH sensitivity [23]. Nonetheless, the peritoneal cavity not only can provide targeting of the delivery for local action as well as it is a depot site for systemic delivery of proteinomics and drugs [55, 69]. As discussed, the perfusion of the capillary region in the peritoneal membrane is quite high compared to its surface. The synergistic factors, that boost the absorption and ultimate clearance of drug from its dosage form, are the single-layer thickened (50 μm) parietal cells [59]. So, when micro or nano particulate, intraperitoneal solution injection, hydrogel or solid composites are designed, it is very important to retain the delivery at the administrative site for localized effect. It would be beneficial for treating postoperative pathologies, infections and tumors present in the proximity of the abdomen. Studies have shown that strategies pertaining to cancers associated with colorectal, gastric hepatocellular, endometrial as well peritoneum have been successfully depicted in animal models [7, 45, 62, 69]. Peritoneal cavity is controlled through nerves connected with the overlying muscles that originated in the region T7 – L1. The visceral region of the peritoneum is

Fig. 2  Mechanism of targeted intracellular particles for drug depot into peritoneal cells. (Reprinted with permission [12])

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stimulated to pain associated with stretch. This sensation is detected by the body through the vagus nerves. While the autonomic nerves control the peritoneal region above the mesentery. For pathology, the sensation however appears to be a dull umbilicus [4]. Histologically, the peritoneal layer is a single layer of flattened squamous cells (stratified). Lower to it persists a thick layer of connective tissues that may vary considerably throughout the region. There are microvilli present in between the mesothelium cells. Parietal and visceral peritoneum are separated by small volume of fluid, approximately 50–100 mL in an adult. However, the volume may vary during the menstrual cycle. The turnover time of fluid is about 5 mL/24 h [6, 30].

4 Drug Delivery Implants 4.1 Intraperitoneal Injection It represents the simplest form of dosage form to the peritoneal cavity. However, it is usually combined with technological strategies like for improved efficacy and stability [69]. However, adeno-associated virus has also been transduced as vector using two cassettes to control peritoneal fat. The intraperitoneal injection contained the dose of cassette at lower than the systemic dose of gene drug delivery [29].

4.2 Nanocarriers Particulate materials offer distinct advantages like better surface-volume ratio, drug loading and entrapment, surface modification, facile synthesis on the surface, tunable morphological characterization, decorating with biological amines and producing specific targeting if the carrier particle displays functionalized proteins groups or mediators (Fig. 3) that can eventually lead to better uptake into the cells. This has been especially observed when the antibody-mediated carriers are taken up by the tumor cells in the visceral organs in the nearby vicinity of depot administration [12, 16]. The nanocarriers can be multi-compartment if the loaded particles may be entrapped in a gel or if there are multiple phases in the emulsified depot delivery. Such platform can support the loading of drugs with different solubility or if the differential release of the substances is required in order to produce a desired therapeutic response. The bioadhesive behavior in nanoparticles can also be introduced aided with adhesive polymer wherein intraperitoneal delivery was developed for the treatment of female reproductive tumors using polylactic acid blocks. The polymers are hyperbranched with polyglycerol copolymers, which may be produced into “covered” non-adhesive nanoparticles that can stay in the bloodstream for a long time after peritoneal injection [16]. While a list of some polymers has been tabulated to design the dosage form for a specified period of time (Table 1).

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Fig. 3  A dual-step formulation of swellable nanoparticle (a1) where the administration of unloaded nanoparticles was followed by injection of paclitaxel (a2) to tumor region as well as the entrapment of drug into the particles [12]

Table 1  List of some polymers aided to develop peritoneal depot formulation

Polymer Chitosan Avidin/biotin Mesoporous silica and polystyrene Pluronic F68 Nanofibrillated bacterial cellulose Polydimethylsiloxane and poly(ethylene-co-vinyl acetate)-based membrane Poly(e-caprolactone)

Release/ Exposure time/ Form Diffusion Chitosan siRNA NPs 14 days Liposomes 22 h Mesoporous silica NPs 6 days NPs 24 h Nanofibers 24 h Drug controlling device 60 days

Microspheres in thermosensitive hydrogels

14 h

References [28] [66] [27] [32] [2] [33]

[37]

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Fig. 4  Preparation of liposomal peritoneal depot [1]

4.3 Liposomes Liposomes represent the entrapped delivery of therapeutic substances that is usually prepared by dissolving the lipid layer first and then is either self-emulsified or converted to lamellar lipid layer in the presence of hydrophilic solvent. Alternatively, a thin lipid layer is formed by heating the ingredients to be encapsulated in a round bottom flask under controlled temperature. The dried layer is followed by the addition of aqueous or hydrophilic phase, which can form interface based on engulfed drug particles. It is stirred at high speed to form liposomes as found in a study where the diameter of 100 nm was obtained with PEGylated liposomes [14]. Multivascular lamellar particles have also been reported for the delivery of oxaliplatin to cure colorectal tumor using the double emulsion technique [1]. Briefly, the drug and cyclodextrin was dissolved in water-based solution and added dropwise in the same volume of lipid solution at around 17,500 rpm for 0.25 h. After drying the organic solvent from the lipid phase with heat and 6000  rpm, it was then re-­ emulsified to form multiple emulsion as multilamellar vesicles (Fig. 4).

4.4 Hydrogels Hydrogel offers properties of forming three-dimensional network in the peritoneal region and loading high dose of drug in gelatinous polymeric network using a controlled release mechanism (Fig. 10a) [69]. The drug can be loaded in the form of nanoparticles/nanofibers for further impact on the residence of the therapeutic substance for stability, sustainability, and formation of depots for intraperitoneal release or uptake by immune cells (Fig. 5) [69]. Additionally, the nanofibers-loaded drug can also assemble under experimental conditions to hydrogels (Fig. 8a). Moreover, it can offer a platform to load particulate drug delivery like nanoparticles and liposomes [1]. Wherein, the thermosensitive gels offer more specificity to temperature, which means that the dosage form will remain adhered to the inflammatory tissues in the cavity, and has been observed for chitosan-hyaluronic acid-based intraperitoneal depot for chemotherapy [10].

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Fig. 5  Assembling of peptides to form nanofibers [21].

Example of few thermosensitive and non-thermosensitive hydrogel-based polymers for peritoneal delivery have been summarized in Table 2.

4.5 Nanofibers Fibers of nano scale composed of self-assembling peptides were prepared in a study by Mora-Solano and coworkers for addressing tissue necrosis factor-mediated inflammation [40] using a sequential method of cleaving and dual coupling of peptide bonds. The bonding was converted into fibers either by dry powders or by

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Table 2  List of some hydrogel-based polymers for evaluating peritoneal drug delivery Polymers Peptide amphiphile C16-N

Properties Fmoc-Asp(OtBu)-Wang resin and Fmoc-protected amino acids Cross-linkable hyaluronic acid hydrogels Nominal weights 1.36 MDa and 490 kDa Polyethylene glycol and Polycaprolactone PEG, Mn = 1000 and 2000 N-isopropylacrylamide and mercaptoacetic acid – Thermosensitive poly-(D,L-lactide-co-­ PLGA-b-PEG-b-PLGA glycolide)-block-poly-(ethylene (1500-b-1000-b-1500) and glycol)-block-poly-(D,L-lactide-co-glycolide) PEG-b-PLA (4000-b2000) Hyaluronic acid HA, 20 kDa and 500 kDa Polyethylene glycol-modified bovine serum Polyethylene glycol, molecular albumin encapsulating red blood cells already weight = 200 loaded with paclitaxel

References [69] [63] [22] [10] [39]

[54] [48]

dissolving in water to assemble and propagate using different N-terminal ligands to form profibrils (Fig.  5) which eventually formed nanofibrinates using functional fibrils [21].

4.6 3D Printed Thermosensitive Disks and Thermosensitive Sol-Gels With the advancement in formulation options, the researchers have managed to treat ovarian cancer using 3D printing technology. Pretreated with multiple solvents for freeze-drying (lyophilization), the thermosensitive poloxamer-based solution of paclitaxel and rifampicin was printed to disks with nanostructuring. The conversion of solution to gelation form was influenced under the stimulus of body temperature. The solution of the drug and the polymer was lyophilized initially utilizing lyophilization using the conditions as reported [39]. Thermosensitive disks were then fabricated using 3D technology utilizing a Hyrel system. This technology has the fair advantage of ease of injecting in situ fluid into the peritoneal cavity from where it can form a sustained depot formulation to treat ovarian cancer. Moreover, the human ovarian cells xenograft in mice exhibited a reduction in the cancer cell load when treated with either 3D printed disks (Fig.  6) and its sol-gel premature solution form [11].

Fig. 6  Depiction of a nanogel disk for treating ovarian cancer from 3D printing [11]

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4.7 Nanotextiles Nanotextile is comparatively an emerging field to conventional depot formulations which uses the technique of electrospun biodegradable polymeric yarns woven into suturable nanotextiles (Fig. 7). Comparatively, when paclitaxel-loaded electrospun sutures were introduced to the orthotopic mice model, there was ~600 times reduction in the vascular endothelial growth factor (VEGF) pertaining to tumor concentrations in the dosage form treated mice model as compared with the control group. Moreover, the peritoneal concentration of VEGF was ~300 times in peritoneal non-­ textile delivery in solution which suggests its potential in the peritoneal depot to treat abdominal tumors [45] (Fig. 8).

Fig. 7  Scanning electron microscopic (SEM) images of paclitaxel-loaded polydioxanone yarn and woven nanotextile implant [45]

Fig. 8  An overview of different therapeutic deliveries for peritoneal depot delivery. PIPAC: pressurized intraperitoneal aerosol chemotherapy; HIPEC: hyperthermic intraperitoneal chemotherapy [13]

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5 Methodologies for Evaluating Peritoneal Depots 5.1 Particle Size and Entrapment Efficiency The size of the particle is of prime importance when the dosage is concerned relevant to the delivery of the peptides or ribonucleic acid fragments. Because the naked nucleotides are unstable in the stressful environment of the peritoneal fluid and do not have the capability to reach to intracellular organelles, the RNA fragments are safely packed in nanoparticles meant for intracellular delivery. The liposomal-based nanocarriers for the delivery of transforming growth factor (TGF) β1 siRNAs in the encapsulated form in C57BL/6 male mice models [64] were delivered to fibroblast cells. The efficacy of the nanoparticles will be considered when the intact NPs are delivered to the intracellular regions successively. It was found that the developed system was effective in delivering the genes to induced fibroblast cells in mice and was confirmed using reverse transcriptase polymerase chain reaction. The size of the particle should be fine enough that it may easily be engulfed by the specific type of cells into its cytoplasmic components [61].

5.2 In Vitro Drug Release Once the formulation is injected or surgically adjusted in the parietal peritoneum, the release of the active substance should be released out of the polymeric system. For thermosensitive gels, the injected sol-gel transition is achieved to control the release of the medicament. In case of silencing or siRNA, the nanoparticulate material must be protected from the peritoneal biological fluid until it is engulfed intracellularly in its intact form. It is then eventually released near the nucleus so that it can be safely taken inside the nucleus. In depot formulation, the antitumor must be loaded in a safer and controlled way inside the drug delivery. The processing of polymer in the dosage form will govern the local or systemic release of the active substance [35].

5.3 Permeation Studies Permeation study reflects the capacity of dosage form to allow effective movement of drug across the peritoneal membrane. Sometimes, the drug has to permeate in any abdominal organ where any pathology lies. It is, however, evaluated by estimating the amount of drug entered into the recipient compartment from the donor compartment. The excised mucosal tissues of the model membrane are used to estimate the efficiency of depot formulation ex vivo [60].

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5.4 Microscopy Using a wide angle CCD camera, layer to layer appearance of the formulations is evaluated. It provides the arrangement of polymer composites and integrity of the particulate delivery [69]. The integrity is especially a critical determinant when chromatin material is encapsulated or retained in the polymeric compartment. Similarly, it can provide useful information with respect to the cross-linking of the polymer in the meshwork [36].

5.5 Fluorescent Testing Fluorescence microscopic imaging employs wide-field laser illumination. The technique uses a speedy and sensitive CCD camera to save high-speed movies of individual diffusing particles in biological fluids. So, when the dosage form tagged with fluorescent material is introduced into the peritoneal cavity of the testing subject, the image is produced using visual algorithm through motion trajectories of the nanoparticles in the abdomen. The attained image is presented as a contour plot (Fig. 9) for the motion pathways of carriers administered. These pathways are then Fig. 9 Fluorescent imaging of the peritoneal cavity of mice depicting the retention of hydrogels in the region [69]

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used to analyze the intercellular transport of substances which in turn can provide useful information with respect to the diffusion coefficients of the nanocarriers. It can precisely quantitate the diffusion of individual particle. Finally, the distribution of diffusion coefficients is obtained which is expressed as size distribution with the help of Stokes–Einstein equation [5]. The estimation of the equation, however, may necessitate the knowledge of viscosity and temperature of the peritoneal fluid after the administration of nanocarriers. The obtained images from this technique can be applied to understand the kinetics of the nanocarriers, attachment of the carriers to cell-mediated receptors, and uptake of the fluorescent carriers by the tumor cells. It can also give valuable information for any examining biological polymer and its affinity to be uptaken by specific types of immunomodulatory cells [53]. The depot formulations are evaluated in terms of cytotoxicity for pathological tissues as well as for normal human cells, which is suspected to occur when exposed to drug delivery. Briefly, the defined IC50 dose of the preparation is added to the specified cell culture in plate wells. It is incubated under specified conditions of cell homeostasis for a defined time. Conclusively, the impact of the ingredients, the concentration of drug and dosage form or alternatively the method of preparation is analyzed in terms of chances of toxicity [11]. The hepatocellular cytotoxic studies of triptolide-based hydrogels were evaluated using the MTT method with an incubation time of 72 h (Fig. 10b), in which fetal hepatocytes were exposed. In the next

Fig. 10  Diagram describing (a) formulation of hydrogels loaded nanofibers containing triptolide and (b) orthotropic hepatocellular carcinoma model of mice for intraperitoneal delivery [69]

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phase, cytoreduction load of hepatocellular carcinoma cells (HCC) were determined and the growth inhibition of HCC was found [69].

5.6 Peritoneal Concentration and Pharmacokinetic Estimation Concisely, the dosage form is injected either if it is a solution form or is placed surgically in the peritoneum of the testing animal. In a study, the peritoneum depot was administered in the adult male rats after anesthetizing the animals, while blood sample was collected from the retro-orbital plexus aided with heparinized capillary tube in order to determine the blood concentration of oxaliplatin by running the sample on the chromatographic machine. After processing the sample, the amount of drug per milliliter of plasma was determined on the basis of pharmacokinetic estimation of parameters like maximum plasma concentration (Cmax), time to reach peak concentration (tmax), area under the curve (AUC), and mean residence time (MRT) with the help of non-compartmental analysis. In this way, the respective concentration of plasma can be correlated with the efficacy of the regime as well as expected adverse effects [1].

6 Peritoneal Depot Portal as Therapeutic Alternative Because the peritoneal cavity is continuous with the abdominal layer as well as the visceral organs, it is more reasonable to consider the peritoneal region as a site for drug delivery (Table 3). The injection or surgical administration of the drug is however required in order to safely portal the dosage regime. It is up to the severity of these diseases as well as the treatment plan that the dosage form can be designed [65]. In order to produce a sustained delivery of the active medicament, the choice of dosage form, for instance, hydrogel, microspheres, nano-particulate, or surgical drug implants is considered. Foremost, the cavity is used for curing major clinical complaints like chronic local inflammatory disorders and peritoneal carcinoma. However, the rapid absorption of drugs for systemic hazards presents an issue, which needs to be considered [20]. It is usually overcome by injecting the drug or introducing biological products such as amino acids or genes inside the tumor cells [25]. Alternatively, the depot drug implant administered in the peritoneal region and near the vicinity of the tumor can provide direct availability of antitumor drugs [7, 38, 67]. The multivascular vesicles (MLV)-encapsulated anticancer drug (oxaliplatin) was delivered through the depot form due to the shorter half-life of the drug. For effective and prolonged colorectal therapy, the lipid components such as cholesterol, triolein, and phospholipids were used to produce a size range of 1–20 μm as well as drug loading of >96%. The MLV nanoparticles exhibited an early burst release of the drug followed by slow release of oxaliplatin and with persistent

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Table 3  Application of peritoneal depot formulations for local and systemic therapies Pathology Pancreatic peritoneal carcinomatosis Colorectal cancer

Depot Expansible nanoparticles

Active Paclitaxel

Model Tumor-bearing mice

References

Multi liposomal vesicle Supramolecular peptide hydrogel

Oxaliplatin

Nude rats

[1]

Triptolide

Tumor-bearing mice

[69]

Recombinant lectin Transforming growth factor as siRNA Paclitaxel

Xenograft mice

Orthotopic hepatocellular carcinoma Diagnosing Nanoprobe and ovarian tumor nanocarriers Peritoneal fibrosis Nanoparticles

Ovarian cancer

Nanotextiles

Peritoneal carcinoma Post-operative residual peritoneal tumors Ovarian cancer

Micelle-loaded hydrogels Thermosensitive hydrogels

Colorectal peritoneal carcinomatosis

3D printed nanogels

Paclitaxel Doxorubicin

Paclitaxel and rapamycin Docetaxel in micelles; Docetaxel and Oxaliplatin-loaded in oxaliplatin situ hydrogels

Tumor-bearing mice

[64]

Syngeneic and orthotopic mice model Tumor-bearing mice Peritoneal carcinomatosis mice Xenograft mice

[45]

Tumor-bearing mice

[35]

[22] [10]

[11]

erosion of particulate formulation. The preclinical pharmacokinetic findings in rats for the formulated MLV demonstrated the maximum concentration to be 9.33 μg/ mL at 12 h (tmax), compared with peritoneal injection solution to be 75.21 μg/mL at 0.25 h. It clearly depicted that the MLV possessed better sustainability and could pose less toxicity to the experimental animal [1]. The nanoparticles depicted better stability at 4 °C as compared with 25 °C when they were evaluated for 21 days of storage. Almost half of the drug contents were leaked from the MLV and after the stated time period, the remnants of the lipid phase of MLV were observed, which shows instability after 21 days at the stated temperature. Treating hepatic carcinoma tumors with systemic therapy may present a lower response rate and generalized higher-­grade toxicity to the patients may cause poor output. When triptolide was evaluated on human hepatocellular carcinoma in vitro cell cultures against sorafenib and doxorubicin, it was found superior. The anticancer efficacy of triptolide, however, was poor probably due to limited drug exposure and severe systemic toxicity. Therefore, it was evaluated as an intraperitoneal depot as peptide nanofibers-based hydrogels loaded with triptolide for prolonged release and targeted drug delivery.

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The results depicted over 2 weeks of drug release with better cytotoxicity against HCC Bel-7402 cells in vitro while the in vivo inhibition of cell growth was found over 99.7% over 13 days in mice after intraperitoneal injection. The average survival level of experimental animal was improved from 19 to 43 days [69]. It denotes the possibility and success of peptide-based nanocarriers for anticancer drug effectively. While targeting through depot delivery, the antitumor activity of paclitaxel was evaluated when loaded into pH-dependent expansile nanoparticle delivery studied in the xenograft mice model for pancreatic peritoneal carcinoma. The outcome of the therapy was measured in terms of the recovery of the animal from the xenograft tumor and the survival of the mice after the xenograft. The nanoparticles labeled with fluorescent rhodamine exhibited retention of the dosage form at micro and macro tumor loci in the peritoneal cavity of xenograft mice. Almost the same in anticancer efficacy, but the paclitaxel-loaded nanoparticles depicted superior with less side effects than paclitaxel solution injection [23]. These findings support the superiority of peritoneal delivery over oral and injection formulations for peritoneal membrane carcinoma. The frequency at which the protein after peritoneal injection was permeating to the central compartment was almost similar to the isotonic solution that is injected to the peritoneal cavity [18]. Similarly, nanoparticles encapsulated tumor growth factor recombined siRNA was delivered to mice peritoneum to treat fibrosis in animal model. The liposome NPs based thrice a week administration in dialysis media for two consecutive weeks resulted in significant downregulation of fibrotic changes in the peritoneum [64]. The siRNA has also been delivered for hepatocellular carcinoma (Table  4). Recently, the biodegradable form of textiles area gained importance to treat metastatic ovarian cancer through the peritoneal route. Concisely, paclitaxel-loaded electrospun decomposable polymeric yarns intertwined and suturable nanotextile delivery was attempted by Padmakumar et al. [45]. The textile depot was transplanted to tumor-bearing syngeneic mice after the safety of dosage form was established during in vitro epithelial ovarian cells [45]. Significant efficacy was observed in nanotextile-bearing mice and subsequent 35 days, the tumor nodules disappeared in the treatment group. Furthermore, the vascular endothelial growth factor pertaining to the progression of the disease was found quite low in the peritoneal fluid as compared to the treatment group with paclitaxel solution. It signifies the efficacy and promising context of the nanotextiles in the field of peritoneal depot implant.

Table 4  Example of siRNA delivered through intraperitoneal route for regional pathologies Si RNA Sustained and targeted delivery of siRNA/DP7-C

Disease Hepatocellular carcinoma

References [68]

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7 Conclusion When therapeutic moieties are concerned, the peritoneal plant has proven as an effective alternative to parenteral and oral route as it produced effective local and abdominal visceral organ drug concentration. It was, in fact, mandatory to treat certain local lesions, cancers, infectious atrocities, and related clinical manifestations. Patients suffering from septic situations of the peritoneal cavity may be treated with depot release of local antiseptic, anesthetics, anti-inflammatory, and analgesic substances in addition to target anticancer molecules for organ targeting. Moreover, extending the targeting of DNA, siRNA nanocarriers delivery through intraperitoneal injection can abate the tumor-associated condition in the abdomen. While observing the pharmaceutical strategies, the gel delivery has been an attractive strategy as bolus form in order to retain the dosage form in the cavity. However, the complexity of the gel can be enhanced to multi-compartment particulate form when strategies are designed for homing purpose or intracellular uptaking of particles. It would be challenging to produce stability of peptide-based gel delivery or drug loading on to the peptide-based nanofibers because the fibers can eventually be cleared from the reservoir once the drug is released from the point of peritoneal administration. Undoubtedly, the peptide delivery exposes stability constraints but biological molecule-based delivery can be the challenge of the future. The peptide-­ based nanofibers of particles can be decorated on the surface with molecules like pro-inflammatory mediators, hyaluronic acid, and such others in order to effectively target regional body tissues. Similarly, the 3D-printed polymeric peritoneal mucoadhesive delivery can provide an opportunity for the researchers to build a platform to deliver drugs. The 3D approach can offer scaling up the production of the dosage form in microneedle-based delivery. However, challenges will remain there for the researchers to produce microneedles through this technique. Nevertheless, microneedles and nanotextiles have good potential in designing therapeutics for peritoneal implants. Research fields like solid peritoneal implants wherein co-­ crystals can pave way to the investigators to access the stability of substances especially the amino acids form of theranostics are of great interest.

References 1. Abuzar SM, Park EJ, Seo Y, Lee J, Baik SH, Hwang S-J. Preparation and evaluation of intraperitoneal long-acting oxaliplatin-loaded multi-vesicular liposomal depot for colorectal cancer treatment. Pharmaceutics. 2020;12(8):736. 2. Akagi S, Ando H, Fujita K, Shimizu T, Ishima Y, Tajima K, et al. Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model. Int J Biol Macromol. 2021;174:494–501. 3. Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8. 4. Blackburn SC, Stanton MP. Anatomy and physiology of the peritoneum. Paper presented at the Seminars in pediatric surgery; 2014. 5. Braet H, Rahimi-Gorji M, Debbaut C, Ghorbaniasl G, Van Walleghem T, Cornelis S, et  al. Exploring high pressure nebulization of Pluronic F127 hydrogels for intraperitoneal drug delivery. Eur J Pharm Biopharm. 2021;169:134–43.

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Importance of Computational Models in the Development of Intraperitoneal Administration-Based Drug Delivery Systems for Solid Tumors M. Soltani, Mohammad Masoud Momeni, Anahita Piranfar, Mohsen Rezaeian, Saptarshi Kar, and Farshad Moradi Kashkooli Abstract  It is hoped that injectional-based intraperitoneal (IP) chemotherapy can help treat peritoneal metastases and abdominal tumors in cancer patients. Nevertheless, drug penetration into the tumor with IP injection in many cases is insufficient. Therefore, it is essential to improve our understanding of the mechanisms and parameters affecting drug penetration to optimize treatment, introduce new treatment methods, and minimize drug toxicity. Computational models, due to their highly controllable features compared to laboratory experiments, allow for the investigation of many biological phenomena and mechanisms during regular and IP chemotherapy of various anticancer drugs. Computational models are comprehensive and are able to reasonably replicate tumor behavior, drug delivery, and estimate important drug biotransport-based parameters within the tumor microenvironment. Computational models have provided healthcare professionals with extremely Mohammad Masoud Momeni and Anahita Piranfar contributed equally with all other contributors.

M. Soltani (*) Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON, Canada Centre for Biotechnology and Bioengineering (CBB), University of Waterloo, Waterloo, ON, Canada Advanced Bioengineering Initiative Center, Multidisciplinary International Complex, K. N. Toosi University of Technology, Tehran, Iran M. M. Momeni · A. Piranfar · M. Rezaeian · F. M. Kashkooli Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran S. Kar College of Engineering and Technology, American University of the Middle East, Kuwait City, Kuwait © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Shegokar (ed.), Exploring Drug Delivery to the Peritoneum, https://doi.org/10.1007/978-3-031-31694-4_8

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useful and valuable information by taking into account the essential mechanisms ­modulating drug transport and interaction in tumor tissue including blood flow, diffusion and convection processes, distribution of the drug in the interstitial space, binding of drugs to receptors on the cell surface, internalization of the drug into tumor cells and release/excretion of the drug, on a variety of length and time scales. In general, these models provide more precise forecasts of the effectiveness of treatment. The present study investigates drug delivery during IP chemotherapy, examines barriers to IP delivery, and evaluates the importance of computational models. These models can be used to examine how drugs reach tumors in the abdominal cavity, such as ovarian and colorectal cancers. Finally, modeling approach of nanosized drug delivery systems (e.g., using magnetic nanoparticles and thermosensitive liposomes) is investigated and discussed in detail. Keywords  Intraperitoneal chemotherapy · Computational modeling · Drug delivery · Solid tumor

1 Introduction Peritoneal metastases (PM) are prominent cancerous lesions in the peritoneal cavity of the abdomen that may be caused by gynecological disorders such as ovarian cancer, upper gastrointestinal/colon malignancies, and metastases from the lungs and lobular breast [1, 2]. Treatment of patients with PM is critical since the incidence of PM is reported to significantly reduce mid- to long-term survival outcome in cancer patients. More specifically, ovarian cancer is reported to reduce the likelihood of 5-year survival rate from 90% (early stage diagnosis) to approximately 30% (late stage diagnosis) [3]. Additionally, there is an average overall survival of 5–24 months for PM in the colon and 4–8 months in patients with PM of gastric origin [1, 4, 5]. In the past three decades, PM management approaches have undergone numerous changes. In general, as clinicians become more conscious of the risks of this disease, the advancement of PM treatment methods is necessary to reduce the considerable burden on existing healthcare systems. Several decades earlier, Dedrick et al. [6] suggested that the low permeability of hydrophilic anticancer drugs through the peritoneum-plasma barrier may be exploited to provide an effective method for improving the survival outcome in patients with tumors and cancerous lesions located in the peritoneum such as PM. Studies using cytotoxic drugs have reported that the peritoneum restricted the absorption of these drugs into the systemic circulation when the medicine was delivered directly into the peritoneal cavity [6–8]. In such cases, drug concentrations are locally elevated around the tumor site while systemic adverse effects are significantly minimized as reported in many studies [9, 10]. Enabling drug penetration from the tumor surface, this approach is also effective in treating tumors that are almost avascular or in the early stages of angiogenesis [10]. Additionally, some peritoneal tumors are avascular, which makes drug delivery to them more

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challenging through IV chemotherapy. Direct exposure of tumors to drugs via IP injetion can be particularly beneficial for these tumors [7]. This study primarily reviews models that simulate the transport and biochemical interactions of anticancer drugs within the tumor tissue in the peritoneal cavity following intraperitoneal delivery of chemotherapy drugs. The following sections will present transport mechanisms, the various barriers to efficient IP chemotherapy, and the corresponding mathematical modeling for fluid flow and drug transport.

2 Transport Mechanisms in IP Drug Delivery The physical mechanisms of convection and diffusion are involved in drug distribution after injecting the recommended dosage into the abdominal cavity [1, 11, 12]. Drugs are delivered to the tumor surface due to interaction of convection, passive diffusion (conduction), and osmosis mechanisms. When the drug permeates into the tumor tissues, hydraulic conduction is exerted [1]. Interstitial fluid pressure (IFP) is one of the most important characteristics in drug delivery [13]. It is influenced by various factors such as fibrosis, the vascular and lymphatic system architecture (the lymphatic system of the tumor is almost ineffective), and carrier fluid properties such as osmolarity and carrier solution volume [14]. The volume of carrier fluid in the peritoneal cavity controls the hydrostatic pressure, which is used to drive the convective momentum of the carrier fluid throughout the peritoneum [15]. In the peritoneal cavity, the concentration gradient and the quantity of inward diffusive flow are determined by the drug’s residual concentration in the carrier fluid at any given time [16]. In addition to IP drug delivery, more effective therapies, innovative combinations, and effective procedures have been developed in recent years including cytoreductive surgery (CRS) [17]. In many cases the only treatment option available to patients with PM is cytoreductive surgery, which removes the macroscopic tumors [18]. Despite this, some cancer cells and small tumor nodules may still remain in the peritoneum and cause recurrences [19]. For this reason, in recent years, CRS combined with hyperthermic intraperitoneal chemotherapy (HIPEC), or the use of nanoparticles for certain cases has demonstrated a highly successful survival rate that in some cases can even lead to an effective and complete cure [20–25]. IP chemotherapy can be optimized using computational models by providing unique insights into various biological processes. Additionally, computational models can be used to assess the impact of different physiological and physical parameters on drug penetration into the tumor tissue. The results generated from computational models can aid in the development of new approaches to enhance the therapeutic effectiveness of chemotherapy drugs without the need to resort to expensive and risky clinical trials. In this study, we have provided a detailed overview of different computational models that were developed to simulate drug transport during IP chemotherapy.

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3 Different Barriers against IP Delivery IP chemotherapy is a well-supported treatment approach. However, the effectiveness of this procedure is highly restricted due to the insufficient penetration of the drug into the tumor tissue [10, 26–28]. The movement of the drug through the tumor tissue is a complicated mass transport phenomenon, which is affected by several factors other than the chemical/transport properties of the cytotoxic drug including molecular weight, electrical charge of the therapeutic molecule, pH variation within the tumor microenvironment including vasculature, diffusivity, and osmotic reflection coefficient [10, 29]. These factors include the anatomical characteristics of the tumor tissue such as vascular structure, interstitial fluid pressure (IFP), cellular density, the composition of the extracellular matrix (ECM), and permeability [30–33]. Pathologically elevated IFP has been observed in malignant and peritoneal tumors, which restricts convective drug transport [34]. Animal and human studies have shown that interstitial hypertension impairs therapy response and survival outcomes [34]. The rapid proliferation of tumor cells, impaired lymphatic drainage, and hyperpermeable microvessels cause elevated interstitial pressure [30, 34]. IFP gradient in the outer edge of the tumor causes a radially outward convective flow which is an obstacle for drug entry in IP administration of chemotherapy [10, 35, 36]. Therefore, diffusion remains as the major factor boosting drug penetration into the tumor tissue [37]. Another effective parameter modulating drug penetration is necrosis [13, 34, 35]. In rapidly growing tumors, the balance between oxygen and nutrients is disrupted, resulting in a necrotic core with no viable cellular units. Additionally, there is no functioning vascular system, which prevents any blood flow or drug uptake. Additionally, a portion of the drug administered to the tissue will be reabsorbed by the tumor vasculature and convectively distributed all over the circulatory system. Finally, the remaining portion of the administered drug may be diminished owing to adherence to the tumor cell ECM [10, 38]. Drug penetration in tumor tissue is also modulated by treatment regime-based parameters including dose, temperature, and carrier fluid volume, to name a few [39]. Currently, IP is delivered by implementing an “open” or “closed” abdomen technique [40]. During IP injection, the peritoneal surface is exposed to a limited extent. This necessitates the use of an open abdomen approach so that the drug may be mixed, and this issue is a major concern [41, 42]. The drawbacks of this approach are the risks it poses to surgical personnel, the high level of skill required, and the inability to repeat IP cycles [41]. As opposed to open IP approaches, closed IP procedures use in- and outflow catheters in the abdominal cavity before the abdominal wall is sealed in a water-tight manner. Toxicity in healthy tissues may arise from less homogenous drug dispersion in the open abdominal setup compared to closed IP approaches. On the other hand, temperature control is more difficult in closed IP methods [39]. An important first step in developing more effective treatments is identifying potential therapeutic targets that may be changed by altering the physical transport processes involved in IP chemotherapy. Following the discovery of probable targets,

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in vitro or in vivo investigations are often required to prove the research hypotheses, which is expensive and time-consuming. As a result, the use of computational models provides a quick and reliable strategy to assess the impact of different factors that are reported to affect drug transport and delivery into tumor tissue. It is possible to evaluate alternative procedures or medications without the need to resort to in vivo experiments by using computational modeling to get new insights into the drug transport obstacles encountered in IP chemotherapy.

4 Computational Models As a consequence of its relative simplicity and low cost, computational modeling related to drug distribution in tumor tissue has increased in relevance as a tool for cancer researchers since the 1960s [43, 44]. Since drug transport modeling permits the change of single parameters throughout an extensive range of values, it is ideal for determining the comparative impact of variables regarding the treatment outcomes with no need for expensive and time-consuming experimental and clinical research [10]. Additionally, computational models can provide a foundational platform for devising strategies to enhance the efficacy of IP chemotherapy. The computational models for simulating IP are described in this article, along with a review of past research in this area.

4.1 Compartment Models Compartmental models are popular for explaining data related to IP, as these models permit evaluation of both biochemical and physiological effects. These models split the human body into a series of linked compartments, each representing several organs, tissues, and areas with a homogenous drug concentration [26, 45]. Single-­ compartment models treat the entire human body as a single unit, while two-­ compartment models divide the human body into two distinct compartments: a core compartment and a peripheral compartment [10]. Dedrick et al. [6] proposed the first two-compartment model for IP in 1978. They postulated that the peritoneal-­ plasma barrier, hitherto seen as an impediment to drug transport, might yield a new therapeutic option for subjects with peritoneal malignancies [6]. According to Fig.  1, two main compartments were considered for IP modeling. The systemic compartment encompasses the intra- and extravascular, as well as intra- and extracellular regions (water that makes up the entire human body). It is defined by a drug distribution volume and a systemic concentration, and drugs are eliminated from this compartment at a rate determined by the clearance ratio Ke (m3 s−1) [10, 39]. The second compartment is called as the peritoneal compartment. It is determined by the drug’s concentration and a peritoneal distribution volume. This model explains that, the drug transport across the peritoneal barrier (between two compartments) is controlled by tumor-related properties (e.g.,  permeability), geometry

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Fig. 1  (left) Two-compartment model of IP. Ke (m3/s) represents the rate of elimination of the drug by systemic circulation [6]. (right). An illustration of the model with three components. In the IP cavity, K12 (s−1) represents the rate constant for drug transport between serum and tissue. K13 (s−1) represents the rate constant for the distribution of the drug from the serum to the peripheral tissue. K1e (s−1) represents the removal ratio from the serum compartment, and the ratio from the IP cavity to the serum is represented by K21 (s−1) [8]

(e.g., the distribution volume of the two compartments), and drug-related parameters (e.g., the clearance ratio (Ke)). A three-compartment model was developed in 2005 by Miyagi et al. [8]. In this model, peritoneal cavity, serum, and peripheral tissue were considered to be independent compartments. In addition to a plasma elimination factor, there were four inter-compartmental clearances present. An analysis of the area under the curves (AUC) obtained after carboplatin delivery intravenously and intraperitoneally was performed. The three-compartment model could successfully predict both IP and plasma AUC. So far, models with multiple compartments have been developed to represent chemotherapeutic data. Figure  2 illustrates the structure and connectivity of the 4-compartment model. Mathematically, the 4-compartment model can be represented in the form of the following ordinary differential equations: dC f

dt

 k1C p   k2  k3  C f  k4Cb

(1)



dCb  k3C f   k4  k5  Cb dt (2)



dCi = k5Cb dt (3)

The parameters k1 [s−1] and k2 [s−1] are exchange rates between the plasma and free drug in extracellular space, k3 [s−1] and k4 [s−1] are transport constant of drug binding and unbinding rates to the cell surface receptors. k5 [s−1] is the rate of drug

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Fig. 2  The 4-compartmental model of simple IP delivery

internalization into the cell. Cp [mol m−3] is the plasma concentration of the drug, Cf [mol m−3] is the free drug concentration in the extracellular region, Cb [mol m−3] is the concentration of the drug bound to the cell surface, and Ci [mol m−3] is the intracellular concentration of the drug. To study the delivery of drugs in IP, researchers have considered different numbers and combinations of compartments, which are listed in Table 1. One of the advantages of compartmental models is their ability to calculate relationships that predict changes in drug concentrations in each compartment, including peritoneal, plasma, intracellular, and extracellular regions based on drug data available in different databases [39]. In other words, these models enable the calculation of drug amounts contained within specific compartments after drug transfer. Despite these advantages, there are limitations to these models. In general, there is the assumption that each compartment is a homogeneous entity that is well-mixed. Consequently, it is difficult to calculate concentration gradients within a specific compartment utilizing a lumped parameter model [39]. Additionally, these lumped parameters approximate the integrated consequences of numerous physiological influences, making it hard to obtain a detailed understanding of the underlying mechanisms modulating the transport and biochemical interactions of the drug. This limitation associated with compartmental models can be overcome by the use of spatio-temporal distribution models (SDMs), which can mimic the total distribution of drugs over time and space.

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Table 1  Summary of previous studies Authors El-Kareh and Secomb [46]

Mathematical model Compartmental (extracellular and intracellular)

Shah Compartmental et al. [47] (five tumor layers)

Colin Compartmental et al. [48] (PKPD)

Feifan Xie [49]

Compartmental (PKPD)

Royer [26]

PK model

Feifan Xie [50]

Compartmental (PKPD)

Important factors influencing Validation metric 1-There is reversibility AUC in the compartment exchange 2-DNA-bound intracellular 3-Consider three different cancer cell lines

1-Combined antiangiogenic therapy (it will reduce drug elimination, increase drug concentration in target tumors, and increase IP efficacy) Paclitaxel administered intraperitoneally and its effects

Drug concentration, P-value

Findings The approach might explain why, in certain sample data, cell death corresponds well with the area under the extracellular concentration-time curve, but not in all cases After IP, antiangiogenic treatment would result in enhanced drug exposure in peritoneal tumors

AUC

Authors showed saturable absorption into tumors created a non-linear dose-­ response relationship Concentration The optimal dose -PTX blood profiles concentrations range for PTXnano-­ -Survival data GP-­MS is 7.5– 15 mg/kg, which strikes a balance between efficacy and safety -Individual PK P-value A drastic reduction in parameters renal toxicity was achieved by administration of epinephrine Researchers collected -Concentration-­ In comparison to data about intact normothermic IPEC, time chart cisplatin perfusate and -Sampling hyperthermic drug plasma concentrations, Importance delivery has a leukocyte counts, and Resampling (SIR) moderate influence serum creatinine, -Relative standard on cisplatin’s PK using a randomized while having no error design. additional side effects (continued)

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Table 1 (continued) Mathematical Authors model Loke [51] Heat compartment model

Park [52] PBPK

Zhu et al. PBPK [53]

Important factors influencing The model considered the dynamic flow, temperature, and drug distribution during oxaliplatin-based HIPEC The comparison of different doses with the corresponding PK datasets -Consider tumor growth -Combined gemcitabine and birinapant -Using PK dataset

Validation metric The parameter values such as concentration, velocity, temperature Concentration-­ time chart

Concentration-­ time chart

Findings HIPEC treatment planning in humans can be improved by utilizing the model to optimize treatment-­ specific parameters It was shown that cisplatin parameters are similar between rats and humans using a PBPK model The authors developed complete PBPK model that characterizes medicinal PK at both the action and toxicity sites

4.2 Spatiotemporal Distribution Models SDMs are a category of computational models that are often utilized to investigate the influence of different biological features on drug delivery in the treatment of solid tumors [37]. These models incorporate processes of convection, diffusion, and reaction [54]. In contrast to other mathematical modeling techniques such as the compartmental models, partial differential equations (PDEs) are employed in SDMs to describe the total drug distribution through time and space [13, 37, 55]. SDMs make the assumption that the drug concentration in the extracellular space is spatially linked through diffusion and convection mechanisms. Figure 3 illustrates the spatio-temporal distribution model. The basic approach for drug transport and biochemical interactions in tissue comprises of diffusive and convective transport in the interstitial space, transport rate through blood vessels due to diffusion and convection processes, and additional mechanisms including drug response and binding to cells [56, 57]. These models are able to analyze the effect of mechanisms that are reported to increase drug delivery in IP, such as the effect of temperature, and addition of biological and non-biological carriers [30, 58]. In contrast to ODEs commonly employed to model drug kinetics (compartment model), the SDM approach relies on PDEs, which makes it possible to estimate a drug’s concentration distribution over time as well as over space [37]. The solution strategy in SDMs is based on first solving Darcy’s equation to model the steady-state interstitial fluid flow within

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Fig. 3  SDM of IP drug transport. Diffusion and convection are also included in the SDM, and various transport parameters are explained as contributions to transport rate constants (L1–L5 rate constants)

the tumor, which predicts the spatial distribution of IFP and IFV in the tumor. The resulting IFP and IFV distribution is then used as input for a mass transport solver to calculate the spatiotemporal distribution of drug concentration in the tumor by solving the convection-diffusion-reaction (CDR) equations. Figure 4a illustrates the solution strategy in SDMs for modeling drug delivery during conventional IP chemotherapy [30]. This model will be examined in more detail in the following sections. 4.2.1 Interstitial Fluid Flow The tumor tissue is considered as a porous medium when the intercapillary distance is assumed to be (33–98μm), typically two-three orders of magnitude less, compared with the length scale of drug distribution [59, 60]. As a result, Darcy’s law was utilized to describe interstitial fluid flow in porous media as [61–63]: vi  Pi (4)



where κ [m2Pa−1 s−1] is considered the interstitium’s hydraulic conductivity, Pi [Pa] is the interstitial fluid pressure, and vi [m/s] represents the interstitial fluid velocity. ·vi  B  L (5)



ϕB [s−1] represents net blood flow into interstitial space per unit volume and ϕL[s−1] represents net lymph circulation per unit volume. According to the equations below, ϕB and ϕL were calculated using Starling’s law in microvascular walls.



B 

LP S  PB  Pi   S  B   i   V (6)

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Fig. 4  Solution strategy for: (a) Conventional IP chemotherapy [30], (b) IP chemotherapy using MNPs [5], and (c) Thermosensitive liposome-mediated IP chemotherapy [30]

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L 



LPL SL  Pi  PL  V (7)

where LP [m·Pa−1 s −1] represents hydraulic conductivity. The S/V ratio [m−1] is the surface area/volume of the vascular system. PB [Pa] represents the intravascular blood pressure. Plasma osmotic pressure and the average osmotic reflection coefficient of plasma proteins are indicated by πB[Pa] and σS, respectively. In addition, πi is the osmotic pressure of the interstitial fluid. The lymphatic vessel wall’s hydraulic conductivity is denoted by LPL [m·Pa−1 s −1], surface area/volume of the lymphatic system is indicated by SL/V [m−1], and the pressure in lymphatic vessels is referred to by PL [Pa]. 4.2.2 Mass Transport In the interstitial fluid, convection-diffusion equations with a source/sink term are used to express drug transport. The capillary system and the lymphatic system are regarded as the sink and source term, respectively. Drug transport in the convection–diffusion–reaction (CDR) system (free drug, bound drug, and drug internalized into the cell, respectively) can be modeled based on mass conservation principles with the following equations [58, 63]:



CF 1  · vCF   · D d CF   l3C_ r CF  l4C B    B   L  t  (8)



C B 1  l3Crec CF  l4C B  l5C B t  (9)



Cint  l5C B t (10)

in which, C_r [mol m−3] represents the concentration of receptors on the surface of the cell; v [m s−1] is the sum of the local and interstitial fluid velocity (vi); and Dd [m2s−1] represents the effective drug diffusion coefficient in tissue. l3 [ml nmol−1 s−1], l4 [s−1] and l5 [s−1] represent the ratio that describes the rate of drug binding to cell receptors, unbinding, and internalization of the drug into the cell via the receptors, respectively. ϕ represents the volume fraction of tumor accessible to the drug. ΦB [mol m−3 s−1] denotes the drug exchange rate between capillaries and the interstitium, while ΦL [mol m−3 s−1] represents the drug exchange rate between the interstitium and the lymphatic system. To compute the rate of transvascular movement of drug from the capillary wall, the Patlak model [58] is used. As a result, the rate of solute transfer from capillaries to the interstitium and the lymphatic system can be mathematically represented as follows [64–66]:

Importance of Computational Models in the Development of Intraperitoneal…



 B   B 1   f  CP 



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PS Pe CP  CF  Pe V e  1 (11)

 L   L CF (12)

where σf represents the coefficient of filtration reflection across the capillary wall, P [m s−1] represents the capillary permeability, and CP [mol m−3] represents the plasma drug concentration. The Peclet number is denoted by Pe and represents the ratio of drug convection rate to capillary wall diffusion.



Pe 

 B 1   f  V PS

(13)

4.2.3 Geometry There is a wide range of shapes and sizes in the tumor nodules of peritoneal carcinomatosis. In previous studies, various forms of tumors in the abdominal area have been considered [58, 62, 67, 68]. For example, Rezaeian and co-workers [30, 58] modeled the tumor as a symmetrical sphere and studied the effect of a number of important variables in a two stage  drug delivery system based on IP injection of thermosensitive liposomes (TSLs)  triggered by high-intensity focused ultrasound (HIFU), including TSL size, HIFU frequency, the pore size of the vessel wall, and size of the tumor on the fraction of killed cells and the depth of drug penetration. Steuperaert et al. [14] used spherical and elliptical geometries to mimic tumor morphology for their drug transport models. Their results showed that drug penetration was better for smaller tumors compared to larger ones. This can be possibly attributed to lower IFP in small tumors. In another study by this group [67], a complete three-dimensional model of the tumor geometry was constructed using mouse-­ specific-­based anatomical MRI images. Drug biotransport was incorporated in the model for a variety of tumor shapes and sizes. The model could evaluate the effect of changing treatment parameters such as drug type on tumor penetration efficiency.

4.3 Cell-Based Model Simulation of the dynamics of a cellular system is carried out with an agent-based cellular Potts model (CPM) [69]. The simulation of the collective behavior of cell structures based on this model is done using lattice-based computational modeling. Besides representing single cells and their compartments, generalized cells may also represent clusters of cells, which is useful in certain situations [69]. It is this

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flexible nature that makes it possible to consider different levels from intracellular to tissue-level processes and take into account their properties. The technique allows for the capture of cancer cell characteristics such as migration, growth, apoptosis, and proliferation, as well as the determination of the endothelial cell’s (EC) reaction to tumor-induced circumstances, among other things. A CPM was used by Winner et al. [70] to study the tumor penetration of two anticancer drugs when administered by IV and IP routes in disseminated ovarian cancer and also avascular and small vascular tumors. The lattices in this study represent individual cells, and during each transmission, formulas for oxygen, IL-8, the second type of growth factor, and the vascular endothelial growth factor (VEGF) are calculated. Each cell then updates its state based on the chemical concentrations in its local environment, followed by updating the cell lattice, assuming that the chemical concentrations remain constant. Results from the study demonstrated that IP delivery of chemotherapy drugs cisplatin and pertuzumab was more effective than IV delivery of chemotherapy drugs for both avascular and small vascular tumors. There was evidence that the density of the vessels affected the accumulation of the drugs in the tumor, and a sink effect was observed. There was a noticeable decrease in spatial homogeneity due to these sinks [70]. Limitations of these models include the removal of the influence of convection on the bulk interstitial fluid flow and its consequent effect on the average drug concentrations and the use of predefined concentration profiles from the literature in both the intravenous and IP routes. Additionally, it must be noted that the very high spatial and temporal resolution of such models can significantly increase simulation times to the order of days. Hence, the use of such models is computationally expensive despite the fact that the findings are accurate [10, 70].

5 Nanoparticles in Intraperitoneal Chemotherapy In previous sections, various stages of drug delivery to the tumor tissue by using IP chemotherapy method were discussed as shown in Fig. 4a. However, there are some obstacles in IP drug delivery, which decreases the fraction of killed cells (FKCs). The primary reason for this low efficiency is the presence of local microenvironmental barriers within the tumor tissue that limit deep penetration of drug particles into the tumor. Utilizing drug-loaded nanoparticles, such as TSLs or magnetic nanoparticles (MNPs), which led to significant advancements in drug delivery systems, could be a realistic approach to resolve this issue [32, 33, 71–74].

5.1 Magnetic Nanoparticle-Based IP Chemotherapy MNPs can be guided to the target tissue by subjecting the patient’s body to a permanent magnetic field [58]. This method causes a large amount of drug concentration around the cancerous area [75–81]. Due to the increased concentration of the MNPs

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around cancer cells, the drug particles can easily bind with target receptors located on the surface of these cells. The elevated binding affinity of the drug particles increases the probability of drug penetration into the cancer cells [82] resulting in fewer side effects for the patients. Computational models of IP magnetic chemotherapy are similar to models developed for conventional chemotherapy with the addition of the equations representing the magnetic field distribution and the term representing the magnetic field induced movement in the drug transport equation as shown below [58]:

  H  J (14)



.B  0 (15)

Maxwell–Ampere’s equation is used for external magnetic current and Gauss’s equation describes magnetic flux density which is zero [83], where H [A/m] is the magnetic field, J [A/m2] is the current intensity, and B [Tesla] is the magnetic flux density. For the tissue domain in the magnetic field, equation B = μ0μrH + Brem is used, where μ0 = 4π × 10−7 NA−2, the relative magnetic permeability, μr = 1000 and the remnant magnetic flux is known as Brem. The force acting on particles in the magnetic field is defined as [58]: Fm  VMNP

 T 0  H    1    x  3 (16)

 



   1 H  VMNP 0  H  2 1 3

2

(17)

where VMNP is the volume of MNPs which isequal to 4 π a 3 and ℵ  is the mag3 netic susceptibility [m3/kg] of VMNP (a = radius of nanoparticle). Under strong mag netic fields, where saturation accrues, the parameter M sat = 0.5 T , known as  T  H  saturated magnetization [A/m] is added to the equation and the term    is  x   T   H   replaced with    M sat [84–86]. The parameter M sat only affects the magnitude  x  of exerted force and does not impact on the direction of the force. Cf [mol m−3] represents the concentration of free drug which moves within the tumor blood vessels prior to entering the interstitial domain. Cb [mol m−3] represents the concentration of the bound drug to the cells’ surface receptors and Ci [mol m−3] represents the concentration of the drug internalized within the tumor cells. These three categories of drug concentration are also defined in the previous sections of this study (Eqs. 8, 9, and 10). The solution strategy for MNP-based IP chemotherapy is presented in Fig. 4b.

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Fig. 5  Schematic of HIFU-­mediated IP delivery of thermosensitive liposomal doxorubicin [69]

5.2 Thermosensitive Liposome-Mediated IP Chemotherapy One of the other solutions for classical IP chemotherapy is using TSL with hyperthermia induced by HIFU. The schematic of this process is shown in Fig. 5, based on one of our group’s work [69]. The effectiveness of TSL carriers depends on the temperature of the targeted tissue. In other words, these kinds of carriers release their drug contents at a specific temperature, which is reported to be around 40 °C [87]. Given that 40°C significantly exceeds normal body temperature, the drug may not easily release within any organ. When enough drug carriers reach targeted tissue, HIFU is employed to provide hyperthermia (HT) resulting in the release of the drug from the carrier [30]. This method can be more useful in ovarian and colorectal cancer treatment. In addition, TSLs decrease side effects by restricting drug entry into the bloodstream in the abdominal cavity [88]. This approach was investigated computationally by Rezaeian et al. [30]. Their results showed an impressive increase in drug penetration into the tumoral domain, greater treatment efficiency, as evaluated by FKCs, and relatively minimal side effects. Additionally, the effects of thermal condition on effective parameters such as TSL size, tumor permeability, and radius of tumoral domain were also investigated in this study. Mathematically, the model developed by Rezaeian et  al. [30] is similar to the conventional IP chemotherapy model and uses Darcy equation for simulating TSL transport in tissue (considered as a porous media), mass conservation [71], and CDR equations to capture spatial and temporal variation of the TSLs concentration [30]. The last equation can be shown as [89]:



CL  vi CL  DL  2CL  K EL CL   B   L t (18)

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where CL [mol m−3] represents TSL-Dox concentration, KEL [s−1] is the liposomal drug release constant, and DL [m2 s−1] is the TSL-Dox diffusion coefficient. The rest of model equations account for the transport/chemical interactions of the free drug (CF), bound drug (CB), and internalized drug (CI) and are mathematically similar to the reactive-transport equations used for modeling drug transport kinetics in conventional IP chemotherapy.



CL 1  K EL CL  vi CF  DF  2 CF  KON Crec CF  KOFF C B t  (19)



C B 1  KON Crec CF  KOFF C B  K INT C B t  (20)



CI  K INT C B t (21)

Besides, the modified Westervelt equation is employed to simulate sound propagation in thermos-viscos environment, and accounts for the effects of diffraction, absorption, and nonlinearity [90]:  2 1 2    3 p   2 p2 p       c 2 t 2  c 4 t 3  c 4 t 2  (22)



where c [m/s] is the sound speed, q [W/m3] is the sound-induced power deposition per unit volume, d [m2/s] is the acoustic diffusivity, β [kg s−2 m−1] is the nonlinearity coefficient of the medium, and p [Pa] is the acoustic pressure. Additionally, pressure-­ temperature fields are coupled follow as [88, 91]: q  2 ABS l 

2 2 ABS   p      2  c   t  

(23)

in which αABS [Np · m−1 · MHz−1] corresponds to the local absorption coefficient, I [W/m2] specifies the local acoustic intensity, and the parentheses denote time average over one acoustic cycle. The following form of the energy conservation equation is used for evaluating the local temperature distribution in the tumor tissue [92]:



t ct

Tt  K t  2Tt  DP. b cb wb  Tt  Tb   K HIFU .qt t (24)

where c [J/kg K] denotes the specific heat capacity, Kt [W/m K] is the thermal conductivity, wb [s−1] is perfusion rate of blood flow at 37 °C, and qt [W/m3] represents the heat deposition from an external source (i.e., here HIFU) in the tissue, and subscripts b and t specify the blood and tissue, respectively. In this equation, DP

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represents a reduction in the perfusion rate due to heat-induced vessel coagulation, which is assumed to be equal to 1 at normal body temperature and approaches zero by complete vascular shutdown. For modeling perfusion reduction due to coagulation, a specific form of the Arrhenius equation is employed as [93]:



E  0  RT  DP  exp    A f e   d       (25)

where the parameters Af [1/s] and ∆E [kJ/mol] are the frequency factor and the activation energy, respectively and are calculated by fitting with experimental perfusion data [94]. For reaching to appropriate amount of temperature, a PI controller is used to tune the input power based on the temperature desired in the target tumor tissue (Tset) [95, 96]:

K HIFU  K p Tset  T  t    K i  Tset  T  t   dt

(26)

in which Kp and Ki are the PI controller parameters. The duty of the last function is limiting the temperature of adjunct tissues to 43 °C to prevent from damages. The solution strategy for TSL-mediated IP chemotherapy, is presented in Fig. 4c. 

6 Discussion and Concluding Remarks In the current chapter, we have summarized the importance of computational models used for simulating different methods of IP drug delivery for the treatment of peritoneal tumors. These models were able to successfully identify the exact mechanisms responsible for low therapeutic efficiency noticed with some specific modes of IP delivery. In most of these computational models, the parameter used to quantify the therapeutic efficacy is FKCs. As discussed previously, the use of IP chemotherapy has several limitations, which decreases the overall therapeutic efficiency of the chemotherapy drug. To overcome this problem, drugs were encapsulated using nanoparticles (e.g., MNPs and liposomes) for targeted delivery. Computational models were also developed for these specialized modes of IP drug delivery and the mechanisms responsible for enhancing the drug therapeutic effectiveness were identified for these cases. Table 2 lists the research groups that are involved in computational modeling of IP injection-­ based drug delivery systems. It should be noted that no computational model has yet been developed that can capture all the complex drug transport and interaction mechanisms associated with IP drug delivery. However, by accounting for the essential mechanisms related to drug biotransport in IP delivery including blood flow, drug uptake in the carrier fluid, convective and diffusive drug transport in tumor vasculature, interstitial space and tissue regions, drug chemical interactions, binding of drug to receptors located

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Table 2  IP chemotherapy modeling research groups Authors Löke et al. Steuperaert et al.

Joanna Stachowska-­ Pietka and Jacek Waniewski Rezaeian et al.

Shamsi et al.

Area Hyperthermic IP chemotherapy IP chemotherapy

IP chemotherapy

IP injection of thermosensitive liposomal doxorubicin and MNPs IP chemotherapy & MNPs

Location University of Amsterdam

References [1, 51]

Surgery and Cancer Research Institute Ghent (CRIG) Nalecz institute of biocybernetics and biomedical engineering K. N. Toosi University of Technology & University of Waterloo University of Calgary

[10, 14, 39, 67] [11]

[30, 58]

[68]

on the tumor cell surface and drug internalization into tumor cells, computational models have provided the medical community with extremely useful and valuable information for improving treatment outcomes in patients subjected to IP chemotherapy. Each model described in this review has its own benefits and drawbacks. For example, the advantage of the compartmental models is that they can effectively fit experimental measurements and accurately predict drug concentrations on multiple scales [62]. However, the concentration gradients within various compartments cannot be reflected using compartment models [10]. Computational models used for predicting temporal and spatial distribution of drug in IP delivery were also examined in this study. These models are not suited for obtaining information at the cellular level. Nonetheless, they can accurately predict regional variations in drug concentration profile for larger tumors in a reasonable time span. It is possible to model nutrient and drug uptake in single cells with cell-level models. These models effectively capture the heterogeneous structures of cancerous tissues and provide researchers with precise, comprehensive data at a high spatial resolution. Nevertheless, they require powerful processing tools, costs and considerable processing time. Researchers have developed target-drug delivery models and combining therapies for chemotherapy to reduce the side effects of chemotherapy, minimize damage to normal tissues, and obtain the optimal dosage to kill cancer cells [58, 63, 67]. The results of computational models demonstrated that liposomes are an adaptable technology for combination therapy strategies that could be used to overcome challenges associated with conventional chemotherapy [30, 97]. Its use in conjunction with hyperthermia (to stimulate the controlled release of liposomal medicines) allows for more precise drug release [2, 30, 98, 99]. As previously pointed out, by adjusting various parameters, computational models, particularly compartmental models, can demonstrate the role and effect of various parameters, such as the frequency of the HIFU, the size of the vessel wall, and the size of the tumor, on the FKC value and the drug penetration depth. For instance,

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when TSLs are smaller than vessel wall pores, a large proportion of the drug is lost through the vessels. When these drugs reach the bloodstream, they increase the risk of chemotherapy-related side effects and reduce treatment effectiveness [30]. In conclusion, computational modeling has revealed some intriguing insights into drug biotransport during IP chemotherapy, which could lead to the development of novel methods for enhancing cancer treatment with less complications. Acknowledgments  M. Soltani and Farshad Moradi Kashkooli extend their acknowledgment to the Iran Science Elites Federation for providing partial funding.

Abbreviations

Parameters Af Brem B b C_r CB CF Cint CL CP c c Dd DL d H I J K Kp Ki KEL k1

Units [s−1] [Tesla] [Tesla] – [mol m−3] [mol m−3] [mol m−3] [mol m−3] [mol m−3] [mol m−3] [m/s] [J/kg K] [m2s−1] [m2 s−1] [m2/s] [A/m] [W/m2] [A/m2] [W/m K] – – [s−1] [s−1]

k2

[s−1]

k3 k4 k5

[s−1] [s−1] [s−1]

Description Frequency factor Remnant magnetic flux Magnetic flux density Blood The concentration of receptors on the surface of the cell Bound drug concentration Free drug concentration Internalized drug concentration TSL-Dox concentration Plasma drug concentration Sound speed Specific heat capacity Effective drug diffusion coefficient TSL-Dox diffusion coefficient Acoustic diffusivity Magnetic field Specifies the local acoustic intensity Current intensity Thermal conductivity Controller parameter (proportional term) Controller parameter (integral term) Liposomal drug release constant Exchange rates between the plasma and free drug in extracellular space Exchange rates between the plasma and free drug in extracellular space Transport constant of drug binding rate Transport constant of drug unbinding rate Rate of drug internalization into the cell

Importance of Computational Models in the Development of Intraperitoneal… Parameters κ LP LPL l1 l2 l3 l4 l5

Units [m2Pa−1 s−1] [m·Pa−1 s −1] [m·Pa−1 s −1] [s−1] [s−1] [ml nmol−1 s−1] [s−1] [s−1] [A/m]

Description Hydraulic conductivity of interstitium Hydraulic conductivity of the microvascular wall Lymphatic vessel wall’s hydraulic conductivity Rate constant )blood flow into interstitial space( Rate constant (interstitial space into vessel( Binding rate constant Unbinding rate constant Internalization rate constant Saturated magnetization of the particle

P PB Pe Pi PL p q qt S/V SL/V t VMNP v vi wb ℵ αABS

Capillary permeability Intravascular blood pressure Peclet number Interstitial fluid pressure Pressure in lymphatic vessels Acoustic pressure Ultrasound power deposition per unit volume Acoustic power deposition Surface area/volume of the vascular system Surface area/volume of the lymphatic system Tissue Volume of MNPs Sum of the local and interstitial fluid velocity Interstitial fluid velocity Perfusion rate Magnetic susceptibility of MNPs Local absorption coefficient

β ∆E μ0 μr πB πi σf σS ΦB

[m s−1] [pa] – [pa] [pa] [pa] [W/m3] [W/m3] [m−1] [m−1] – [m3] [m s−1] [m/s] [s−1] [m3/kg] [Np · m−1 · MHz−1] [kg s−2 m−1]. [J/mol] NA−2 NA−2 [Pa] [Pa] – – [mol m−3 s−1]

ΦL

[mol m−3 s−1]

ϕB ϕL ϕ

[s−1] [s−1] –

 M sat

189

Nonlinearity coefficient of the medium Activation energy Vacuum magnetic permeability Magnetic permeability Osmotic pressure of the plasma Osmotic pressure of the interstitial fluid Coefficient of filtration reflection across the capillary wall Average osmotic reflection coefficient for the plasma proteins Fluid source term or the rate of fluid flow per unit volume from blood vessels into the interstitial space Lymphatic drainage term or the rate of fluid flow per unit volume from the interstitial space into lymph vessels Net blood flow into interstitial space per unit volume Net lymph circulation per unit volume Volume fraction of tumor available to drugs

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Drug Delivery Systems to the Peritoneum: Current Status and Future Perspectives Bhavana Joshi, Tanmay Vyas, Badri Narayana Sahoo, Kamakshi Parsai, Sachin Dubey, and Abhijeet Joshi

Abstract  Intraperitoneal drug delivery systems provide a regional therapy model for the peritoneal and also relatively increase the half-life and concentration of the desired drug molecule in the peritoneum cavity. Current studies and research suggest IP delivery is a promising technique for drug delivery against peritoneal drug delivery as compared to conventional systemic administration. However, the peritoneal drug delivery system faces many challenges like premature clearance of low molecular weight molecules, lack of specific targeting, and poor penetration ability of cells. Recent studies suggest the use of different nanoparticles may improve drug targeting. These drug delivery systems have been explored in various animal models. This chapter aimed to provide an overview of various types of drug delivery systems and provide preclinical data about the animal studies used in peritoneal studies. Future studies in the chapter mainly focus on improving the clinical relevance of the experiments, standardizing the experimental study setup, and improving their methodological quality and reporting. Keywords  Peritoneal drug delivery systems · Intraperitoneal malignancies · Micro/nanoparticles · Preclinical studies

Bhavana Joshi and Tanmay Vyas contributed equally with all other contributors.

B. Joshi · T. Vyas · B. N. Sahoo · A. Joshi (*) Department of Biosciences & Biomedical Engineering, Indian Institute of Technology Indore, Simrol, MP, India K. Parsai Amity Foundation for Science, Technology and Innovation Alliances, Amity University, Noida, Uttar Pradesh, India S. Dubey (*) Analytical and Formulation Development, KBI Bioharma SA, Geneva, Switzerland © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Shegokar (ed.), Exploring Drug Delivery to the Peritoneum, https://doi.org/10.1007/978-3-031-31694-4_9

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1 Drug Delivery: Overview Drug delivery systems are technologies that are designed to provide therapeutic drugs in a targeted and/or controlled manner. It refers to the formulation, manufacturing techniques, preservation methods, and technologies involved in conveying any chemotherapeutic agent to its intended target site [1]. Nowadays, it is an emerging field for the creation of new materials or carrier systems so that the drug required curing a particular ailment could effectively be delivered to the site required. Biochemical engineers have made significant benefaction in our perception of the physical drag to effective drug delivery, like delivering drugs in the vascular system and drug progression via cells and tissues; they indeed assisted in the evolution of several new drug delivery modes that are now in clinical use [2]. Any chemotherapeutic agent should be governed properly including categories like opioid anesthetics, inhalation analgesic agents, soporific/hypnotics, muscle depressant, etc. These therapeutic agents could be dispensed into the body through multiple routes like skin, buccal, and nasal mucosal membranes [3]. As medical application systems improve, the distribution of various pharmaceuticals in the form of liquids, lotions, mixes, injectables, tablets, quick liberating capsules, and so on to cure numerous diseases is done utilizing various conventional drug delivery dosage methods. The ability to successfully deliver pharmaceuticals into patient’s bodies while minimizing negative effects has paved the way for the growth of inventive drug delivery systems. These drug delivery techniques, which include site-­ specific delivery systems, liposomes, transdermal patches, and others, offer improved therapeutic potential [3, 4]. Dispensing medications regionally rather than comprehensively (to complete body) is a typical method of reducing side effects and drug toxicity while boosting treatment effectiveness [1]. For best therapy, the dosage form at the required site should be within a treatment regimen that is intervening the minimal effective concentration (MEC) and the minimal toxic concentration (MTC). To keep drug concentrations in the therapeutic range, several aspects must be controlled, including dosing frequency, drug clearance rate, route of administration, and drug conveyance method. Drug delivery systems are classified based on their physical condition, place of delivery, and initial drug release [4, 5]. Each method has its advantages and downsides, and not all procedures are appropriate for all medications. To improve functionality and reduce drug toxicity, an advanced delivery system known as a targeted drug delivery system is devised. This medication delivery method is so exact that the drug is only released at the target site, causing no harm to the patient’s healthy cells which covers various hurdles such as selecting exact targets, developing effective and stable medication, ensuring biodegradable drug carrier, and avoiding immunogenic and non-specific interactions [6]. To be effective in curing a disease, a drug delivery system must have tumor selectivity, efficient penetration time, cellular uptake, and intracellular drug residence [2]. Recently, intraperitoneal administration of beneficial agents has been widely employed for chemotherapy in the sufferer, particularly for intra-abdominal

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malignancies such as gynecological and gastrointestinal tumors, and manifested encouraging outcomes, as it is directly injected towards the parietal peritoneal [7].

2 Anatomy of Peritoneal Cavity and Membrane The peritoneal cavity is a confined compartment in the belly which houses the abdominal organs. It evolved from the embryonic coelomic cavity. It is lined with the peritoneum, an enormous membrane in the organism with a complete surface area equivalent to skin [7]. It is made up of thin peritoneal fluid made up of water, electrolytes, cells, and chemicals from surrounding tissues. It serves to support the viscera and to provide paths for blood vessels and lymph to and from the viscera. In humans, the volume of peritoneal fluid is 50–75 ml, peritoneal fluid contains leukocytes and antibodies that aid in the fight against infection in addition to other elements, as well as plasma proteins at a concentration half that of plasma. Peritoneum also contains fibroblasts and macrophages occasionally [8]. The peritoneum is compelled of two continuous stratums: the peripheral parietal peritoneum and the beneath visceral peritoneum. Both varieties are made up of mesothelium, which are basic squamous epithelial cells with a diameter of 25 μm that covers the intra-abdominal organs [9]. Visceral peritoneum is supposed to support intra-­ abdominal organs and the mesentery, whereas parietal peritoneum is thought to line the abdominal wall, pelvic, frontal borders of retroperitoneal organs, and the diaphragm [10]. Peritoneal mesothelial cells are expected to play a pivotal part in fluid and solute conveyed beyond the membrane as well as homeostasis. Peritoneum often reduces friction and aids in movement of abdominal viscera, inhibits and limits infection, and reserves fat in the omentum area [11]. Because peritoneal fluid has a buffering capability and a pH range of 7.5–8.0, there is relatively little ionization of substances after intraperitoneal medicine administration. The omentum, ligaments, and mesentery are all contained within the peritoneal cavity. The liver, stomach, spleen, jejunum, ileum, sigmoid colon, and transverse colon are all intraperitoneal organs. The esophagus, aorta, colon, ureters, kidneys, pancreas, and adrenal glands are all located beneath the peritoneal membrane [7, 12].

3 Malignancies in Peritoneal Cavity and Current Therapy Most peritoneal malignancies begin in another section of the body. Cancers of the appendix, colon, rectum, stomach, and ovaries are all known to spread to the peritoneum. Breast cancer and other malignancies that begin outside of the abdomen, on the other hand, can spread to the peritoneal membrane. A recurrence of an abdominal malignancy is frequently manifested as peritoneal cancer. Peritoneal cancer or

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peritoneal surface malignancy occurs when a malignant cell invades the serous membrane in order that channels the coelom, viscera, and abdominal cavity [13]. As it has been documented that the majority of peritoneal malignancies grow from metastases of other tumors, it is extremely rare for peritoneal cancers and mesothelioma to develop from the peritoneum. So, the malignancy is classified as primary or secondary based on where it originated. Primary mesothelioma develops from the mesothelium of the abdomen, while secondary peritoneal cancer develops when tumor cells from other places disseminate into the peritoneal cavity. Secondary/ metastatic peritoneal carcinomatosis is caused primarily by primitive malignancies in the gastrointestinal and gynecological systems. Histologically, primary malignancies are classed as additional ovarian primary peritoneal carcinoma, visceral surface papillary carcinoma, and so on [13, 14]. Primary tumor spread is caused by the uncontrolled development of intramural cells beyond the serosal layer. Secondary seeding occurs mostly during surgical tumor resection, resulting in malignant cell spilling [14]. The most common cancers that arise in the parietal peritoneal are peritoneal carcinomas, deprecating epithelial tumors (e.g., ovarian cancer), caused by gynecological and intra-abdominal diffusion, and peritoneal carcinomas caused by diffusion of gynecological and intra-abdominal origin are hard to detect and they persist even after surgical and other treatments [2]. For long years, peritoneal surface cancers were thought to be incurable. This is due to the fact that the peritoneum covers a broad area and that these tumors tend to impact several organs. Performing surgery to remove the malignancy would be a time-consuming and complicated task. The dangers of operating on many organs were deemed insufficient in comparison to the surgery’s limited benefits. Furthermore, because the peritoneum is nearly totally separated from the bloodstream (this is known as the peritoneal-plasma barrier), chemotherapy administered via IV has limited effect in treating these tumors. Today, peritoneal tumors can be treated with a process known as cytoreductive surgery (CRS), due to advancements in surgical techniques and instruments. The surgeon uses this method to remove as many cancer cells as feasible. CRS is frequently used in conjunction with hot chemotherapy (HIPEC) given directly to the surgical site. HIPEC penetrates the peritoneal-plasma barrier, killing many of the minute cancer cells left behind after surgery [15]. The purpose of intraperitoneal chemotherapy is to get a pharmacokinetic recognition, by way of illustration higher amount and lengthy half-life of the medication in the peritoneum [16].

4 Intraperitoneal Drug Administration Route of drug administration is the utmost requisite for determining the clinical, pharmacodynamics, pharmacokinetics, and also the toxicity created by drug moieties in an animal model. The different routes of drug administration include intravenous (IV), subcutaneous (SC), oral and intraperitoneal (IP). Out of these intraperitoneal routes of drug administration is the widely accepted route of drug

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delivery in experimental studies due to its easy and quick administration process and its low impact of stress to the animal models, in human this route is rarely used. However, there are various techniques used to administrate IP drug delivery. IP therapy is a type of locoregional drug therapy that provides longer circulation time with minimal drug clearance for a longer time due to the presence of peritoneal membrane barrier [8, 17]. The most conventional IP drug administration technique is a catheter-based drug delivery system, generally used for cancer chemotherapy of the abdomen or pelvis, in which a flexible tube structure called catheter is placed in the peritoneal cavity, the space between muscles and organs in the abdominal cavity, is diagrammatically represented in Fig. 1 [16]. The choice of drug administered through this tube reaches directly to the diseased area and promises to give better drug delivery with higher drug efficiency. This treatment modality uses high concentration dose for treatment and thus cause toxicity. Recent research on IP cancer chemotherapy for pelvis region suggests advantages of metronomic dosing over conventional catheter-based chemotherapy [8]. This metronomic dosing of chemotherapeutic compound includes continuous minimal dosage of drug in a certain interval of time which lowers the toxicity caused by chemotherapy and also improve the quality of life in cancer patients. Another technique used to deliver the drug intraperitoneally is the use of hydrogel, which is extensively explored in the recent years. Thermo-sensitive hydrogels are most widely investigated hydrogel as they are liquid in room temperature and form gel at body temperature which directly increases the drug exposure time in the body [18]. Chen et al. have explored poly(N-isopropylacrylamide)-based hydrogel (HACPH) loaded with doxorubicin (DOX) to observe the chemotherapeutic and membrane adhesion property in the animal model (BALB/c mice). These HACPH-DOX has proved to be better drug delivery system when compared to the pure drug of same concentration, based on the rate of tumor suppression, tumor

Fig. 1  Strategies used for intraperitoneal drug delivery

growth rate, and survival rate of animals [19]. Adding to this, the other technique

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used for IP drug delivery for cancer is intraoperative chemoperfusion (IPEC), which involve the hyperthermic chemoperfusion (HIPEC) generally at 42 °C, also claimed to enhance the cytotoxicity of chemotherapeutic molecule as shown in Fig. 1 [19]. However, some of the studies claim there are no significant changes or enhancement in the efficiency of chemotherapeutic in hyperthermia. The most recent technique used for IP drug delivery is pressurized intraperitoneal aerosol chemotherapy (PIPAC). In this method, the therapeutic solution is aerosolized with pressure (maximum 20 bar) and aerosols are released in the abdominal area. This method is generally performed during the laparoscopy. Based on all the above-mentioned drug administration route for IP, researchers have explored various drug-loaded nanoparticles and protein-conjugated drug delivery in peritoneum region [20, 21]. This approach is widely used because it promotes medication localization to metastatic tumors. All IP injections result in improving concentration of drug or length of drug disposure to cancer cells in the peritoneum while decreasing systemic toxicity [17]. IP administration of drugs aids in the ease and rapid reabsorption of high doses of chemotherapeutic material and is the tendered inoculation path for isotonic, sterile, and non-irritant solutions [22]. Any medicine delivered to the peritoneal tumor is delivered in two ways during IP administration. The medicine is first diffused through the interstitial, and then it is recirculated through the peritoneal cavity, where it is absorbed [12]. Diffusion, ultrafiltration, and fluid reabsorption are the processes involved in peritoneal drug transport. The drug is transported across the peritoneum by three different pore sizes: large pore with either a radius of 20–40 nm and small pore besides of 4.0–6.0 nm, for the mobility of large and small solutes, respectively, while ultra-pores (aquaporins) accompanied by virtue of radius 0.8 nm are only for the transport of water. The rate of drug transfer is influenced by a number of parameters, including time of contact, peritoneal inflammation, peritoneal blood flow, surface area, etc. [7]. Principles of IP medication administration for a successful outcome include: 1. Agents that are better adapted to being delivered intraperitoneally ought to be able to slowly leave the peritoneal cavity and be cleared easily and quickly from the circulatory system upon entering the compartment. 2. Chemotherapeutic drugs that are converted into a less toxic state when they pass through the liver are the most preferred and appealing choice for IP administration due to their high absorption from the peritoneal cavity via portal circulation. 3. The IP tumor should be as small as 0.5 cm in the larger dimensions, in that one may achieve the best results. 4. The volume of distillate used with antitumor agent is sufficient to ensure proper agent exposure and maximize the distribution of specific antitumor agent to the entire peritoneal cavity. 5. IP drug administration is carried out through a port that is directly attached to a cannulae that drifts willingly in the peritoneal cavity [23].

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IP administration is thought to be superior to conventional routes since it avoids the gastrointestinal tract and the alteration of injectable biopharmaceuticals [16]. Chemotherapeutic drugs administered intraperitoneally have demonstrated efficacy in the therapy of ovarian cancer [24]. Various experimental research has found that visceral peritoneum absorbs medium- to small-sized particles (MW   5000), blood, proteins, and immune cells. In addition, both small and big molecules migrate retrogradely from capillaries to the peritoneal cavity [24]. The peritoneal microvascular network is responsible for a number of dissolvable and fluid interchange from the parietal peritoneal to the vascular system. Solutes with a diameter of 2000  Da are absorbed from either the peritoneal cavity through capillaries by diffusion or convection. Solutes swallowed through the visceral peritoneum, mesentery, and omentum reach the portal vein, and those ingested through the parietal peritoneal blood capillaries and lymphatics enter the bloodstream. When chemicals enter portal circulation, they combine with molecules in systemic circulation as they move through the liver and are processed as a result [9].

5 Types of Peritoneal Drug Delivery Systems Several drug delivery systems have been investigated to overcome the challenges of IP therapy. IP therapy provides the advantage of high drug concentration for a longer duration but somehow small molecule drugs can surpass the membrane and clear via first pass mechanism. The penetration ability of tumor tissue is also less in IP therapy. So, to trespass all these barriers and challenges of IP therapy, drug delivery systems have been introduced. The most widely explored peritoneal drug delivery systems are explained below.

5.1 Microspheres Microspheres are free-floating, biodegradable solid spherical particles comprising proteins or synthetic polymers that range in size from 1 to 1000  m (Fig.  2). Microspheres are specially engineered to release medications gradually over time by incorporating a diverse range of biocompatible and biodegradable polymeric components. The size of the microspheres influences their stay in the peritoneum [25]. The ability to bind and release large amounts of medication is one of the benefits of utilizing microspheres. They prolong the therapeutic impact by increasing the biological half-life. They reduce dose frequency while increasing patient compliance. A number of polymeric compounds, such as biodegradable aliphatic polyesters derived mostly from hydroxyl acids as poly(lactic-co-glycolic) acids (PLGA) and related polymers, are employed for IP drug delivery [26]. The Food and Drug

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Fig. 2  Diagrammatic representation of types of drug delivery vehicles explored for peritoneal drug delivery Table 1  Different categories of IP drug delivery along with parameters Category of drug delivery Microsphere

Drug incorporated Cisplatin

Micelles

Doxorubicin

Liposomes Doxorubicin Injectable system Paclitaxel Implantable system Nanoparticles

Particle Size 19.65 μm

Cancer targeted Gastrointestinal and gynecologic 80–90 nm Abdominal and pelvic 150 nm Abdominal cavity – Abdominal

Paclitaxel

–

Ovarian cancer

Epothilone

127 nm

Ovarian cancer

Data available In-vitro

References [28]

In-vivo

[4]

In-vivo In-vivo & In-vitro In-vivo & In-vitro In-vitro

[38] [41] [12] [5]

Administration has approved them for individual use in medicine as an application for use in sensitive parts of the brain. Furthermore, these polymers are planned in such a manner that the duration for drug release can be tailored over a period of weeks to months. This PLGA degrades non-enzymatically to lactic and glycolic acid, and then to water and carbon dioxide. As a result, polymers in this class are suitable for intravenous medicine delivery [27] (Table 1).

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Cisplatin is typically encapsulated in microspheres using PLGA.  Cisplatin is hydrophilic in nature, and it is absorbed by peritoneal capillaries and transferred to the circulatory system. Diffused from the PLGA matrix till 14 days following injection, and particles remained in the abdominal cavity for lengthy periods of time before being absorbed with no side effects [5, 28]. It is highly effective chemotherapy drug for gastrointestinal and gynecologic malignancies. It is hard to predict significant and long-lasting anti-cancer effects simultaneously because it reaches the bloodstream immediately after intraperitoneal delivery and has a relatively short retention time in cancer tissue [29]. Paclitaxel-loaded microparticles are another PLGA-based drug delivery method [2]. In vitro and in vivo, these microparticles resulted in the release of paclitaxel for 8 weeks [30]. Triblock poly(−caprolactone)poly (ethylene glycol)-poly(−caprolactone) (PCL-PEG-PCL) copolymer was used to create camptothecin-loaded microspheres. These microspheres were created in such a way that they prevent camptothecin hydrolysis and improve colorectal peritoneal carcinomatosis treatment [31].

5.2 Nanoparticles Microparticles have a long-life span in the peritoneal cavity, but they would produce peritoneal adhesions and inflammatory responses, according to the previous study. As a result, nanoparticles are preferred over microparticles. According to research, nanoparticles made of lower MW polymers have a decreased risk of peritoneal adhesions and are safe to use [27, 32]. A broad variety of components are now being explored for the manufacture of nanoparticles for drug administration, ranging from biological material such as gelatin, phospholipids for liposomes and albumin, to more chemical compounds such as different composites and solid metals comprising nanoparticles. The interlinkage of nanoparticles with tissues and cells, as well as their potential toxicity, are obviously greatly reliant on the precise composition of the nanoparticle formation. Other advantages include the capacity to avoid multidrug tolerance, avoid drug efflux transporters, and achieve larger drug deposition as contrast to free medicines [26]. Because typical nanoparticles are quickly evacuated from the abdominal cavity owing to its small size, nanomaterials with stimuli like temperature, pH, light, and ultrasound are being created. pH-responsive nanoparticles loaded with paclitaxel were created for IP treatment, delivering paclitaxel intracellularly following endocytosis. This formulation employs an acrylate-based polymer to encapsulate paclitaxel, a pH-responsive polymer with the protecting group 2,4,6- trimethoxy benzaldehyde. At endosomal pH (pH  5), these nanoparticles become active and grow in volume, allowing their medication content to be released [33]. Tumor penetrating nanoparticles (TMN) loaded with paclitaxel are designed for IP medication delivery. These TMNs can be retained for a longer amount of time, have reduced toxicity, and achieve a greater therapeutic effect. According to one study, using poly iso-hexyl-cyanoacrylate (PIHCA) nanospheres to encapsulate

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doxorubicin can lower the toxicity of the medication when used free and thereby enhance the availability of the medicine in the peritoneal cavity [3, 34]. Nanoparticles injected into the peritoneal cavity enter systemic circulation, where they pass via lymph nodes and reach blood vessels. According to Kohane et al., PLGA nanoparticles with a diameter of 256 nm reach the systemic circulation from the peritoneal cavity in 2 days and end up in the liver and spleen. Nanoparticles larger than 500 nm, from the other contrary, are confined in lymph nodes. As a result, nanoparticles, relying on their size, can aid in the targeting of cancer cells [27].

5.3 Liposomes The first enclosed bilayer phospholipid structure, liposomes, was rapidly proposed as a medication delivery mechanism. Liposomes are spherical, tiny artificial vesicles comprising of cholesterol with non-toxic phospholipids as shown in Fig. 2 [35]. They are primarily employed as drug carriers for hydrophilic as well as hydrophobic medicines, but they also have the potential to be used as diagnostic agents [36]. Numerous liposome researchers’ pioneering work resulted in significant advances in technology such as remote drug loading, pultrusion for homogeneous size, long-­ circulating (PEGylated) liposomes, provoked release liposomes, nucleic acid polymer/ligand binding liposomes, and liposomes enclosing drug consolidation. These breakthroughs have resulted in a flood of clinical trials in disciplines as diverse as anti-cancer, anti-fungal, and anti-toxin conveyance, gene medicine delivery, and an aesthetic and anti-inflammatory drug administration. They have a size range of 100–1000 nm and evacuate the stomach cavity quickly. It is recommended that liposomal parameters such as lipid configuration, surface possessions, and charge be changed to improve liposomal performance and expand their maintenance period in the abdominal cavity [12]. Recent research has concentrated on the production of multipurpose liposomes capable of targeting cells and cell organelles with just a single delivery technique. According to one study, the charge of the liposome functions as a predictor of retention time [37]. Liposomes that are negatively charged are speedily captivated from the parietal peritoneal; on the other hand, positively charged liposomes are slowly absorbed [36]. There was no consequence on retention time in the abdominal region when the phospholipids type was changed; however, phosphoethyleneglycol (PEG) incorporation in the phospholipids membrane indicated a 30% increase in peritoneal retention by evading macrophages present in the peritoneal cavity [38].

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5.4 Micelles Micelles are spherical amphipathic formation having a hydrophobic center and a hydrophilic outside. The hydrophilic shell makes micelles soluble in water and aids in intraperitoneal distribution, while the hydrophobic core transports medication payloads for therapy. The hydrophilic shell and its nanoscale dimensions (less than 50  nm) shield the polymeric micelles from removal from the body while also increasing circulation and drug transport capabilities [39]. Polymeric micelles are biodegradable, long-lasting in  vitro and in  vivo, and capable of dissolving a wide range of undisposed solvable medications. This property of micelles leads to the formation of numerous forms of micelles for drug delivery [12]. Micelles target tumor cells by using the increased permeability retention (EPR) phenomenon, which allows us to create micelles out of stimuli-­responsive amphiphilic chunk copolymers, or by imbuing the micelle surface with specific targeting ligand molecules [39]. Klein et al. proposed that mixed micelles with phosphatidylserine (PS) and phosphatidylglycerol (PG) are effective alternative to liposomes since they exists naturally and have anti-inflammatory characteristics [40]. Taxol is an IP therapy for ovarian cancer that combines micellar paclitaxel with Cremophor EL (a polyetoxylated castor oil surfactant). It has a long retention time in the abdominal region than other loose unformulated paclitaxel (40.7 13.8 h vs. 7.3 2.8 h), demonstrating that encapsulating any drug molecule into a carrier molecule lengthens residence time inside the abdominal cavity. Several studies have found that using a carrier molecule is crucial for medication distribution and clearance after IP administration [12].

5.5 Injectable System They are essentially injection formulations for medications that slowly release the chemical over time. They are designed to improve the adhesion and uniformity of medicinal molecules. Depot injections are created by either changing the medication molecule or changing the method of administration [6]. Currently, an injectable depot (PoLigel) was created to ensure persistent distribution of the ovarian cancer medication docetaxel (DTX) in the peritoneal cavity. PoLigel are water-soluble derivatives of egg phosphatidylcholine (ePC) and a fatty acid analog. At physiological temperature, this mixture normally produces a gel consistency due to hydrophobic interactions with acyl chains of ePC and water-soluble chitosan. Some other type of injectable gel for IP chemotherapy is heat-sensitive hydrogel, which is formulated on the triblock copolymer PLGA-b-PEG-b-PLGA. This polymer is soluble in water at 4 °C but gels at normal body temperature to form ReGel, a water-insoluble gel. When ReGel is coupled with the drug paclitaxel (PTX), OncoGelTM is formed, which releases up to 40% of the loaded PTX during the

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initial 10 days and continues to release the burden for the following 40 days. This formulation is biocompatible because it shows no symptoms of inflammation or toxicity [41]. ReGel for IP chemotherapy was researched to combine Triogel, a combination of three medicines (PTX and two protein inhibitors). For ovarian cancer, this Triogel demonstrated higher antitumor effectiveness and lower toxicity than IP-administered PEG-b-PLA micelles [18].

5.6 Implantable System Implantable systems are a form of drug delivery technology that allows for localized and targeted drug delivery while yet achieving a significant therapeutic effect with lower drug concentrations. One significant benefit of this method is that they can be removed early if they have negative impacts on any treatment [42]. The application of non-intraperitoneal drug delivery systems that maintain peritoneal drug extent while decreasing systemic levels could provide notable enduring benefits as a patient-submissive therapeutic method. Saturable-inseminated gadgets predicated on metronomic drugging, which elutes medicine in a constant way at lower amount, might be incisionally attached after eradicating for the medication of patients with refractory epithelial ovarian cancer [20]. Paclitaxel-loaded poly-D, L-lactide, and poly(lactide)-block-poly(ethylene glycol) (PLA-b-PEG) implants are embedded in a chitosan-egg phosphatidylcholine matrix which were utilized to treat ovarian cancer patients [12].

6 Preclinical Studies Increase in peritoneal malignancies leads to the growing investigation of clinical and preclinical research of IP drug delivery systems. To investigate the impact of peritoneal drug delivery on living body various in-vitro, in-vivo, and ex-vivo study has been carried out for decades [43]. Recently, a wide range of drug delivery systems are being explored for IP chemotherapy as an alternative to postoperative chemotherapy in case of ovarian cancer. IP drug delivery has proved to be efficient as compared to intravenous drug delivery in the case of ovarian cancer. A group of 546 randomized patients has been used in the study and proved to survive longer with lower death rate when treated with intraperitoneal drug delivery of cisplatin for ovarian cancer. In spite of several developments in the mode of drug administration to peritoneal system, the severity of the disease somehow remains the same in case of regional non-specific toxicity. To avoid this, drug delivery systems have been introduced that are capable to deliver the drug in controlled manner with minimal toxicity [44]. Some of the preclinical and clinical data showing the efficiency and efficacy of drug delivery systems for peritoneal drug administration are:

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6.1 In-Vitro Model The cellular toxicity created by drug delivery systems when treated intraperitoneally is very less as compared to the pure drug intraperitoneal administration. Paclitaxel-loaded folic acid-conjugated PEGylated nanoliposomes (FA-NP) were investigated for cytotoxicity in paclitaxel-resistant SKOV3/TAX ovarian cancer cell lines. These FA-NP are able to overcome the paclitaxel resistance and increase the target efficiency causing the cell death in cancer cells [45]. Another nanoparticle investigated for peritoneal drug delivery is poly-lactic-co-glycolic acid (PLGA) nanoparticles loaded with Cannabidiol (CBD). These PLGA-CBD nanoparticles are able to internalize SKOV3 cells in 2–4  h. of incubation and show lower (IC50) inhibitory concentration than free cannabidiol [26]. Various cell lines were used for the IP delivery such as ovarian cancer cell lines (OVCAR-3, MA-148, K562, etc.), HEK293, etc.

6.2 In-Vivo Animal Model Hijaz et al. have investigated the use of folic acid-conjugated cerium oxide nanoparticles (NCe-FA) for ovarian cancer treatment in mice model. Ovarian cancer cells are reported to overexpress the folate receptor and thus these NCe-FA get attached and accumulate inside the cancer cells and inhibit the cellular proliferation. Mice treated with Cisplatin-loaded NCe-FA are found to have better tumor reduction efficiency without causing toxicity as compared to the cisplatin-loaded NCe. Selenium (Se) nanoparticles are also capable to deliver drug efficiently in peritoneal carcinomatosis [46]. Wang et al. have introduced H22 malignant hepatocarcinoma cells to the peritoneal cavity and further injected the elemental Se nanoparticles to the same peritoneal space and observed high concentration of Se nanoparticles in the cancer cells as compared to the normal cells. The cytotoxicity in cancer cells depends on the accumulation of Se nanoparticles which causes reactive oxygen species (ROS) production resulting in impairment of glutathione and thioredoxin systems [10]. Intraperitoneal delivery of mesoporous silica nanoparticles (MSN) loaded with paclitaxel facilitates prolonged retention time in the mice peritoneal tumor tissue as well as in systemic circulation. This increases the peritoneal tumor reduction efficiency of paclitaxel in the human-pancreatic carcinoma xenograft mice model. This paclitaxel-loaded MSN are able to increase the accumulation of drug in the tumor tissue by 6.5-fold as compared to the free paclitaxel, which is also confirmed by fluorescent imaging of fluorescent MSN in tumor tissues [47].

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6.3 Human Clinical Studies Some of the clinical studies have been registered which are on on-going trial. A clinical trial of paclitaxel albumin stabilized nanoparticles is registered by the US government (NCT00825201) in 2018 on a group of 27 individuals of age 19 and above to investigate the effect in intraperitoneal drug administration. Where the patients receive albumin-stabilized  paclitaxel nanoparticles on 1st, 8th and 15th days of the treatment and repeated on every 28th day and then patients were observed for 4  weeks after the treatment completion. The result of the study has not been reported yet. Sugarbakar et al. have reported doxorubicin-loaded PEGylated liposomes (PLD) for peritoneal drug delivery in patients with peritoneal metastasis. The formulations were not suitable for hyperthermic intraperitoneal chemotherapy (HIPEC) condition as the rate of PLD absorption is very slow in the presence of hyperthermia conditions whereas suitable for early postoperative intraperitoneal chemotherapy (EPIC) [48].

7 Toxicity Toxicity caused by pharmacological compound is restricted due to the barrier between the peritoneal cavity and bloodstream. In in-vivo toxicity of anthracycline via IV and IV drug administration was observed by Yeung et al. where they have reported to observe higher toxicity and lower antitumor efficiency when drug is administered peritoneally in nude mice. However, when the drug is administered via intraperitoneal route,  a  reduced  toxicity and increased biocompatibility  was observed [49]. As reported by Vassileva et  al. chitosan-egg phosphatidylcholine (ePC), an implantable drug delivery system, provides controlled drug release of paclitaxel and thus decreases the cellular toxicity created by the drug at higher concentration. They have used CD-1 mice and SKOV-3 xenograft model of ovarian cancer. Taxol encapsulated in nanocrystals of Pluronic F127 (i.e., polyethylene oxide polypropylene oxide (PEO-PPO)) is capable for faster recovery in animals, however the cytotoxicity caused by free Taxol and encapsulated Taxol is similar [50]. Albumin is an excellent drug carrier with multiple ligand binding sites and cellular receptors. A case study reported by Colby et al. has proved the pH-sensitive nanoparticles-based drug delivery system is better in drug delivery efficiency to the cancer tissues for a longer duration with minimal off-target effect and cellular toxicity as compared to the pure drug delivery. They have observed that paclitaxel-loaded expansile nanoparticles (PTX-eNPs) increase the delivery of Taxol by 10 times in 24 h and 100 times after 7 days of the treatment in mice model and also improve the survival rate of animals by decreasing the systemic toxicity. All these studies suggest the encapsulation or binding of pharmacological agents in the drug delivery system lowers the systemic cytotoxicity and increases the drug efficiency [44].

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8 Regulatory Guidelines Every drug delivery system is investigated for the impact of its toxicity on the living being to reach till the market. The process of development of a drug delivery system in the laboratory to its clinical and further to the market is set by the regulatory implications. Drug delivery systems comprised of nanoparticles, liposomes, micelles, implantable systems, and injectable systems are widely explored in their preclinical as well as in their clinical stages to check their safety and toxicity during administration [51]. The important key features of regulatory guidelines related to any drug delivery system from its raw manufactured system to its polished final product are summarized below:

8.1 Material and Manufacturing The material used for manufacturing of the drug delivery system should be non-­ toxic as to check the toxicity caused by the chemical composition of therapeutic moiety loaded in the delivery vehicle. The material and development characteristics of the delivery vehicle imply the morphological and chemical properties (size, shape, polydispersity, toxicity, solubility, hydrophilicity, hydrophobicity, surface charge density, etc.) to the drug delivery system. New technique and standards used in the production method might require to set an acceptance characteristic as it is important to check the immunogenicity and toxicity created by the drug delivery system [51, 52].

8.2 Safety To investigate and identify the impact of the drug delivery system the formulation is generally checked on the small animals like rodents and non-rodents via single dose or multiple small doses. The main key heads that are scrutinized are absorption, distribution, metabolism and excretion (ADME), toxicity, allergic reaction causing irritation and sensitization, genotoxicity, carcinogenicity, immunogenicity, and biodistribution. Biodegradation and long-term biodistribution to check the clearance or accumulation of the drug delivery vehicle in the body is also a concern that need to be identified to reduce the damage caused during the treatment and also helpful to select the route of drug administration [49, 52].

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8.3 Efficacy Most of the developed drug fails to reach the demand of the therapy in the clinical trial. The efficacy of drug delivery system depends on the amount of drug reached to the disease tissue and its bioavailability at the particular area. The route of drug administration plays the most prominent role in the efficacy of drug delivery system [50]. The considerations for developing a drug delivery system with high efficacy are: localization of the disease to plan the route of drug administration, disease progression rate to plan the therapy, immune status of the patient to counter any of the side effects caused during or after treatment and impact of angiogenesis to check the vascular permeability and accessibility to the disease tissue to plan the target therapy to reduce the off-target effects [52].

8.4 Pharmacokinetic-Pharmacodynamic Correlation Pharmacokinetic parameters are directly linked to the therapeutic efficiency and efficacy of the drug delivery system. Recent advancement in the clinical testing suggests the clinical pharmacokinetic status of the therapeutics in the animal models. A better understanding of pharmacokinetic and pharmacodynamic correlation enables us to identify the pathophysiology and pharmacological activity of the developed system [48]. However, it changes in every individual and case study is necessary for therapeutic evaluation and for this model should be developed for individual testing of drug delivery systems and to plan the therapeutic route and dose of administration [17].

9 Pharmacokinetic of Peritoneal Drug Delivery Even though peritoneal drug delivery system is the easiest route and also results in better and faster absorption rate than any other route of drug administration, it has certain limitations. The most important concern is its least clinical application (generally used for cancer chemotherapy of peritoneal region) and thus becomes questionable for preclinical experimental studies [53]. The main challenge of IP drug administration is first-pass metabolism as the substance absorbed via peritoneal cavity moves up to portal and vein and thus passes through the liver. Studies suggest that the small molecular therapeutic agents administered through IP show similar pharmacokinetics to the orally administered drug in terms of higher first-pass mechanism resulting in lower systemic absorption of drug. Whereas the contradictory studies suggest in case of macromolecule drug administration, it reaches systemic circulation via lymphatic vessel and shows minimal first-pass metabolism [6]. Some recombinant enzymes like neurolysin, angiotensin converting enzyme, and

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superoxide dismutase enzyme have retained their catalytic activity after reaching systemic circulation in rodents when applied intraperitoneally. The other important concern or challenge in IP drug administration is its change in efficiency with place and technique of drug administration. A human study done on healthy volunteers suggests there is about two-fold variation in absorption and reaching maximum plasma concentration of insulin based on the position of IP drug administration below and above the transverse mesocolon [53]. However, the use of higher volume of drug dosage is the advantage of IP drug administration but also a challenge, as the large volume sometime may generate abdominal pain, perforation of abdominal organs and respiratory distress. Although very less occurring inaccuracy in IP administration also suggests sub-cutaneous drug administration rather than IP due to sharp angle administration. Some studies also reported the deposition of drug and drug delivery vehicle in the peritoneal cavity including the gastrointestinal tract and urinary bladder. Continuous IP administration may also damage peritoneum and may also lead to irritation at the site of administration [54].

10 Advantages of Peritoneal Drug Delivery Intraperitoneal drug administration is the easiest and least stressful technique of drug administration. The first benefit of IP administration is: large volume (up to 10  ml/kg in rodents) of drug administration which is the utmost requirement of therapeutic agents with low solubility. IP administration is preferred over the oral route to avoid first-pass mechanism in case of macromolecules and also to avoid its potential degradation in the gastrointestinal tract or post-modifications of therapeutic moiety [54]. Among all the routes of drug administration the rate and extent of drug absorption is highest in intraperitoneal drug administration followed by intra-­ muscular, subcutaneous, and then oral. Exposure of therapeutic agents to the large surface area is the reason of higher and better drug absorption. This route of drug administration is also preferred to avoid the repetitive intravascular (IV) drug administration [2]. Studies suggest the effect of pharmacological agent in IP drug administration is similar to intravascular rather than intramuscular and subcutaneous administration, whereas the rate of drug absorption is usually half of the drug absorption in IV administration. However, this route provides prolonged retention time to the therapeutic compounds at the diseased location and thus increases the efficiency of the drug delivery system [7]. Shimada et  al. have reported to have higher concentration of docetaxel (almost 100 times) in the peritoneal administration group than in the IV administration group. They also observed the concentration of drug is higher in cancer cells and solid tumors when administered intraperitoneally without causing any severe systemic toxicity. IP chemotherapy should be considered as the prime treatment modality for peritoneal cancer for efficient tumor penetration, cellular uptake, and tumor specificity [55].

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11 Future Perspectives on IP Drug Delivery Systems The challenges of intraperitoneal drug delivery system have been somehow addressed by the development of drug delivery systems. However, major concern of the of IP drug delivery for cancer chemotherapy remains the same in the case of deep tissue penetration. Inefficiency of drug delivery system for drug penetration is due to the high interstitial pressure and low functional lymphatics. This high interstitial pressure should be addressed to avoid the barrier between the drug and the diseased tissue [54]. Targeted drug delivery system should be developed to reduce the regional toxicity created by the drug and drug delivery systems by non-specific targeting. As the peritoneal drug delivery system retains for a higher duration in the peritoneal cavity it must be non-toxic and biodegradable in nature. Another issue with peritoneal chemotherapy is its multi-drug resistance, because the multi-drug transporters can efflux the drug out of the cells even if the drug is able to locate the tumor cells [3]. Perhaps nanoparticles and other hydrogels are able to avoid the drug efflux from the cells and significantly increase the drug concentration inside the cells. As the drug delivery system is exposed in higher concentration as well as for higher duration, biocompatibility is the primary requisite for developing drug delivery system [14]. Biodegradable polymer-based nanoparticles may be a better platform for peritoneal drug delivery over hydrogels or microparticles as their small size allows an even distribution of nanoparticles in the peritoneal space and also allows a controlled release of drug but the point of concern needs to be investigated is its fast clearance due to small size [2, 50]. Thus, the use of nanoparticles, liposomes, and hydrogels can be a better drug delivery system for IP drug therapy. However, drug delivery systems need to be explored for tumor specificity and efficient tumor penetration to avoid the off-target cytotoxicity [44].

12 Conclusion Intraperitoneal drug delivery systems (IP-DDS) are the most demanding delivery systems for IP therapy due to their superior efficacy reported by the recent preclinical and clinical trials comparing IP drug delivery systems to the conventional therapy. These IP-DDS provide extreme benefits over free drug therapy. They provide high targeting specificity during the treatment with minimal cellular toxicity and higher sustained release. However, targeting of small molecules in peritoneal space needs to be explored more to reduce the clearance time. Efforts should be made to identify the pharmacokinetics and pharmacodynamics of the DDS. Promising lineaments of IP-DDS are reduction in tumor growth, delayed cellular proliferation, higher accumulation of drug inside the cancer cells, ability to target the tumor cells more efficiently, prolonged circulation time, and increased survival rate in animals. Moreover, IP-DDS has potential to target the peritoneal diseases more efficiently with least toxicity and is an easy and less time-consuming technique for

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administration than the other route of administration. However, further studies need to be done to establish and evaluate IP-DDS for their actual clinical potential.

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39. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today. 2003;8(24):1112–20. 40. Klein ME, Rieckmann M, Lucas H, Meister A, Loppnow H, Mader K.  Phosphatidylserine (PS) and phosphatidylglycerol (PG) enriched mixed micelles (MM): a new nano-drug delivery system with anti-inflammatory potential. Eur J Pharm Sci. 2020;152:105451. 41. Zentner GM, Rathi R, Shih C, McRea JC, Seo M-H, Oh H, et al. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J Control Release. 2001;72(1–3):203–15. 42. Nampoothiri DP, Subhash AK, Aboobacker F, Mohan A, Keerthana K. Biomimetic materials in Implantology. Int Oral Care Res. 2018;6(2):93–6. 43. Deng Y, Yang F, Cocco E, Song E, Zhang J, Cui J, et al. Improved Ip drug delivery with bioadhesive nanoparticles. Proc Natl Acad Sci. 2016;113(41):11453–8. 44. Colby AH, Oberlies NH, Pearce CJ, Herrera VL, Colson YL, Grinstaff M, et al. Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017;9(3):e1451. 45. Tong L, Chen W, Wu J, Li H. Folic acid-coupled nano-paclitaxel liposome reverses drug resistance in SKOV3/TAX ovarian cancer cells. Anti-Cancer Drugs. 2014;25(3):244–54. 46. Hijaz M, Das S, Mert I, Gupta A, Al-Wahab Z, Tebbe C, et al. Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer. BMC Cancer. 2016;16(1):1–14. 47. Fu Q, Hargrove D, Lu X. Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous silica nanoparticles with intraperitoneal delivery. Nanomed Nanotechnol Biol Med. 2016;12(7):1951–9. 48. Sugarbaker PH, Stuart OA.  Pharmacokinetics of the intraperitoneal nanoparticle pegylated liposomal doxorubicin in patients with peritoneal metastases. Eur J Surg Oncol. 2021;47(1):108–14. 49. Yeung T, Simmonds R, Hopewell J. The relative toxicity of intravenous and intraperitoneal doses of epirubicin. Cancer Chemother Pharmacol. 1989;24(4):211–8. 50. Vassileva V, Grant J, De Souza R, Allen C, Piquette-Miller M. Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model. Cancer Chemother Pharmacol. 2007;60(6):907–14. 51. Gaspar R, Duncan R. Polymeric carriers: preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv Drug Deliv Rev. 2009;61(13):1220–31. 52. Hort MA, Alves BD, Ramires Junior OV, Falkembach MC, Araújo GD, Fernandes CL, et  al. In vivo toxicity evaluation of nanoemulsions for drug delivery. Drug Chem Toxicol. 2021;44(6):585–94. 53. Sugarbaker PH. Intraperitoneal delivery of chemotherapeutic agents for the treatment of peritoneal metastases: current challenges and how to overcome them. Expert Opin Drug Deliv. 2019;16(12):1393–401. 54. Davies SJ.  Peritoneal dialysis  – current status and future challenges. Nat Rev Nephrol. 2013;9(7):399–408. 55. Shimada T, Nomura M, Yokogawa K, Endo Y, Sasaki T, Miyamoto K, et al. Pharmacokinetic advantage of intraperitoneal injection of docetaxel in the treatment for peritoneal dissemination of cancer in mice. J Pharm Pharmacol. 2005;57(2):177–81.

Exploring the Intraperitoneal Route in a New Way for Preclinical Testing Pralhad Wangikar, M. V. S. Sandhya, and Pradhnya Choudhari

Abstract  The peritoneum serves as the primary site for the spread of most of the intraperitoneal (IP) diseases. The available literature showed that IP drug delivery systems have prolonged the survival rate by limiting the peritoneal disease and systemic toxicity. However, to our knowledge, so far, there is no drug available in clinical practice that has been formulated specifically for IP administration. Due to significant variations in the procedures of IP drug delivery, there is a significant impact on the pharmacokinetics and pharmacodynamics; in order to get maximum benefits of its locoregional effects, there is a need to investigate the full potential of drugs administered intraperitoneally. There is a need for exploring the intraperitoneal route in a new way by using preclinical animal models, which will be rapid, reproducible, and inexpensive and will also demonstrate clinical scenario. This book chapter emphasizes on various aspects of IP drug delivery including biology of peritoneal cavity, factors affecting pharmacokinetics of drugs, systems used in IP drug delivery and animal models. This will open the new doors for successful treatment of IP disease conditions, provide clear survival advantage to patients, improve quality of life and will encourage clinicians to adopt it towards benefiting the patients. Keywords  Intraperitoneal · Carcinomatosis · Pharmacokinetics · Preclinical

1 Introduction Route of administration determines the outcome of the medication administered; it is generally classified based on the location where the medication is deposited or applied. The choice of route of administration depends upon drug’s properties and pharmacokinetics. Selection of route of administration is important for the outcome of drug, improving patient’s care and also from a convenience point of view. P. Wangikar (*) · M. V. S. Sandhya · P. Choudhari PRADO, Preclinical Research and Development Organization, Pvt., Ltd., Pune, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. Shegokar (ed.), Exploring Drug Delivery to the Peritoneum, https://doi.org/10.1007/978-3-031-31694-4_10

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Intravenous (IV), oral, subcutaneous (SC) and intramuscular (IM) routes are the main paths of drug administration both in humans and laboratory animals. Among these routes of administration, one of the most commonly used routes is the IP route where pharmacological agents are injected into the peritoneal cavity. In humans, it is applied when other routes are not found suitable to handle the situations such as replacement of large amounts of blood fluids or in case of low blood pressure or any other disease conditions including cancer that prevent the use of intravenous injection. In rodent preclinical studies, the IP route is one of the more commonly used routes of drug administration because large volume can be administered, it is quick, suitable for chronic treatments, with low impact of stress and it avoids GI tract [1]. The peritoneum serves as the primary site for spread of most of the diseases [55]. Major disorders of the peritoneal cavity include peritoneal adhesions, peritonitis, and peritoneal carcinomatosis. Where peritoneal adhesions and peritonitis are common consequences of peritoneal surgery, trauma, or infections, the peritoneal carcinomatosis is dissemination of the primary cancers of intra-abdominal malignancies from stomach, colon, pancreas, rectum or ovaries and also from the remote primary malignancies of lung or breast cancer. Abdominal adhesions occur in 67–95% of patients after laparotomy and are responsible for hospital admissions, whereas the peritoneal carcinomatosis have poor prognosis with survival rates not more than 3–4  months [98]. It is well documented that adhesions are associated with morbidity, and continue to be a significant cause of postoperative complications; however, peritoneal carcinomatosis was reported to be the most frequent cause of death in patients. It has been reported that in patients who underwent surgery for peritoneal cancers, the first recurrence site was the peritoneum (43.9%) and then a local site (32.5%) followed by the liver (16.9%). These conditions are putting so much burden on the economy of the World [97, 109, 110]. Peritoneal carcinomatosis is major and important than any other diseases or conditions of peritoneal cavity; therefore, more effective therapies are needed in the treatment of this peritoneal disease. Because of the difficulty in removing the peritoneal cancers radically, systemic chemotherapy is a commonly used treatment, as currently it is the only choice of treatment among the various treatment options for peritoneal carcinomatosis. However, it is observed that surgery, systemic chemotherapy and their combinations are the most ineffective options. Due to the development of resistance to systemic chemotherapy by peritoneal metastases, limits for the height of the dose that can be administered intravenously, myelotoxicity, futility against peritoneal metastases and confinement of these diseases to the peritoneal cavity, researchers are exploring this site for developing local therapies. Investigators are exploring the IP route where drugs can be administered directly into the peritoneal cavity. The primary concept of IP therapy is to expose the tumour tissue directly to an extremely high concentration of anticancer agents by perfusing inside the peritoneal cavity leading to improved cytotoxicity, as well as a longer half-life of the drug in the peritoneal cavity [24]. However, there is controversy over this approach, supporters of this concept argue that there are regional therapeutic advantages of

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this route when peritoneal to plasma levels are compared. A series of phase II clinical trials in patients with ovarian cancer cited this as clear activity. Whereas detractors of this concept argue that pharmacological advantages in the peritoneal compartment do not reflect the levels attained inside the tumour tissues, as the penetration of IP drugs was limited to the superficial cell layer, typically only few millimetres and many other studies using systemic chemotherapy have not demonstrated clear outcome advantage. However, extensive work by Markman et al. and other researchers on the IP chemotherapy showed a clear survival advantage of IP over IV therapy in patients with regard to prolonged survival and improved quality of life. Future results will yield additional information regarding the incorporation of different approaches to IP therapy, converting IP therapy into clinical practice and encouraging clinicians to adopt it towards benefiting the patients [24, 27, 60–64, 97]. The aim of this book chapter is to assess the IP route of drug administration, history of IP drug delivery, biology of peritoneal cavity, review of preclinical and clinical data, pharmacokinetics of drugs administered by this route, factors affecting the use of IP drug delivery systems and, various systems used for IP drug delivery. This chapter will also throw some light on our understanding of animal models of IP drug delivery system which play important role in modulating effects of treatment administered by IP route; this may help us understand how this treatment can best be deployed and combined with the newer generation of targeted agents along with future perspectives towards the use of intraperitoneal drug delivery systems.

2 History of IP Drug Delivery The earliest report of IP drug therapy dates back to 1744. Christopher Warrick, an English surgeon, injected a mixture of ‘Bristol Water’ and ‘Claret’ (a Bordeaux wine) into the peritoneal cavity of a woman suffering from intractable ascites. Thereafter, IP drug administration for the treatment of cancer reports to the late 1950s and early 1960s. Although with this route of administration, improvement was observed in cancer-related signs and symptoms, particularly in controlling re-­ accumulation of fluid in pleural effusions, the local side effects such as abdominal pain, adhesion formation, bowel obstruction and infertility were with unacceptable severity. Bleomycin, a cytotoxic agent, was used most commonly for this purpose, however success was limited. It was the classic paper presented by Dedrick et al. [9] in 1970 which mentioned the sound pharmacokinetic rationale for IP delivery of chemotherapeutic agent to control ovarian cancer. The concept behind IP chemotherapy was direct exposure of the tumours within the IP cavity to 10–1000 times higher drug concentrations compared to systemic circulations, a longer half-life of the drug, advantage of first-pass metabolism as a major route of excretion through liver, thereby reducing systemic toxicities associated with the IV route. Figure 1 depicts various steps in the development of IP drug delivery.

220 Fig. 1  History of intraperitoneal drug delivery

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Over the past 2 decades, the Gynecologic Oncology Group (GOG) in collaboration with the Southwest Oncology Group (SWOG) conducted several randomized, phase III clinical trials comparing IP (IP) versus intravenous (IV) chemotherapy (GOG 104, 114, and 172). All 3 clinical trials investigated IP cisplatin, with the last one adding IP paclitaxel. The results clearly showed superior progression-free and overall survival with IP chemotherapy compared with IV chemotherapy. Tewari et al. [97] reported exploratory analysis of two randomized phase III clinical trials towards long-term survival and evaluated factors associated with IV and IP injection chemotherapy in patients with advanced ovarian cancer, they concluded that IP therapy into clinical practice is challenging and needs further investigation towards individualizing this therapy. On the other hand, Vergote et al. [105] evaluated the role of IP chemotherapy in the management of ovarian cancer and reported that at the Consensus Conference on Ovarian Cancer of the European Society of Medical Oncology and the European Society of Gynecologic Oncology held in April 2018, it was concluded that IP chemotherapy was not a standard of care for first-line therapy. However, the discovery of BRCA genes and their key role in DNA repair have strengthened the rationale for IP drug delivery. Therefore, research is ongoing towards the selection of patients based on genomic features and focusing on the better tolerated IP carboplatin [8, 70]. While exploring the IP route, for preclinical testing, it will be interesting to review the anatomy, histophysiology, circulation dynamics, gross and histopathology of the peritoneum before looking into pharmacokinetics.

3 The Peritoneum: Anatomy and Histophysiology The peritoneum is the largest and most complexly arranged structure than a simple serous membrane in the body. Anatomy, physiology and histology of the peritoneal cavity have been explained previously in detail by Isaza-Restrepo et  al. [38] and [1]. Recently, literature on various aspects of the peritoneum is emerging indicating that peritoneal research is a dynamic field and needs more understanding from a clinical context. Viewing the abdominal cavity as a continuous space and various abdominal structures as mesenteries, ligaments, and fascia within it will help to conceptualize our understanding of the intra-abdominal spread of diseases [28, 65, 66]. Anatomically, the peritoneum is divided into the outer layer that is parietal peritoneum, which is attached to the abdominal and pelvic walls and the inner layer that is visceral peritoneum that covers the internal organs, and between these two layers is the peritoneal cavity. The organs within the peritoneal cavity may be intraperitoneal or retroperitoneal. Intraperitoneal organs are usually mobile whereas organs in the retroperitoneum are usually fixed to the posterior abdominal wall. Histologically, the peritoneal cavity is lined by a single layer of mesothelial cells which are squamous, and the majority of them are flattered type, closely connected to each other by either tight junctions, adherens junctions, gap junctions or desmosomes. The

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mesothelial cell layer is anchored onto a thin basement membrane. Apical surface of mesothelial cells has many microvilli of different length, shape and density, that increase the functional surface area of the peritoneum. The sub-mesothelial layer contains collagen, adipose tissue, lymphocytes, blood vessels as well as lymphatics. Fibroblasts and occasional macrophages are also present in this part of the peritoneum [1, 42, 52, 67, 89]. Functionally, the peritoneum provides a protective, non-adhesive, frictionless surface that allows smooth sliding of viscera by synthesizing and secreting surfactant, proteoglycans and glycosaminoglycans. Apart from proving protective surface, mesothelial cells have great variety of functions such as immune induction, modulation and inhibition by presenting antigens to T cells, participating in tissue repair by the secretion of chemokines, growth factors, ECM components, and other biological mediators, prevention of adhesion, tumoral dissemination and transcellular [38, 53, 94, 102, 111]. The ‘peritoneal–plasma barrier’ consists of peritoneal mesothelium, subserosal interstitium and capillary walls and plays an important role in the pharmacokinetics of drugs administered intraperitoneally. The peritoneal–plasma barrier may help achieving high intraperitoneal drug concentration and low systemic concentration [8, 92]. Peritoneal mesothelial cells maintain peritoneal homeostasis and support transport of fluid and solutes across. Mutsaers and Wilkosz [71], mentioned mesothelial cells as sentinel cells that can sense and respond to signals within their microenvironment. Mesothelial cells are unique as they express characteristics of epithelial cells, appropriate stimulation of these cells can undergo an epithelial to mesenchymal transition (EMT) response, losing their epithelial characteristics and adopting a more fibroblast-like phenotype. Witowski et al. [107] put forth the concept of epithelial-to-mesenchymal transition and cellular senescence explaining the role of mesothelial cells in fibrogenesis and vasculopathy that underlie peritoneal membrane dysfunction. The blood supply to the peritoneum plays an important role in pathophysiology, let us see the circulation dynamics of the peritoneum.

4 Circulation Dynamics of Peritoneum Of the total peritoneal surface, the visceral peritoneum covers 70% and parietal peritoneum accounts for about 30%. Visceral peritoneum derives its blood supply majorly from celiac, superior and inferior mesenteric arteries and drains into portal vein, whereas parietal peritoneum receives its blood supply from circumflex, iliac, lumbar, intercostal, and epigastric arteries and drains into inferior vena cava. In case of human, the total effective blood flow to the peritoneum is only 1–2% of the cardiac outflow [4, 30, 42, 86]. The compounds absorbed through the visceral peritoneum drain through the portal veins and face first-pass metabolism, whereas compounds absorbed through the parietal peritoneum bypass the liver and get into systemic circulation directly. Primarily small molecular weight compounds pass through portal circulation, because the visceral circulation area is much larger, whereas macromolecules access systemic circulation directly through parietal circulation. The second one may impact variability to the pharmacokinetics of

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intraperitoneal injections, which is much efficient but less studied by researchers [8, 11, 49, 58] (Fig. 2). Rippe [81] proposed a ‘three-pore model’ of peritoneal transport through capillary membranes, which defines solute and water transport across the peritoneal capillary through pores of three different sizes: Large, small and ultra-small pores [7]. The principal pathway is for water and water-soluble substances, accounting for 99% of exchange and can be called as ‘protein-restrictive pore pathway’. The second pathway is the exchange of proteins that occurs through large pores only, which are extremely few in number and are non-restrictive to protein transport. The third pathway is transcellular which can be called as ‘water only’ pathway and is permeable to water but impermeable to solutes [13]. The three-pore model will be helpful while developing the formulation during drug development (refer Fig. 3). The peritoneum can autoregulate its blood flow depending on its own requirements. However, there are various extrinsic and intrinsic factors which affect this autoregulation of splanchnic blood flow by the peritoneum. Regulation of the splanchnic circulation including effects of various physical, chemical, neurological, hormonal factors, drugs or molecular, have already been explained in detail previously [41, 86, 87, 112, 113]. Similar to the alterations in the blood circulation, alterations in the morphology of the peritoneal surface may impact the pharmacokinetics of the drugs administered intraperitoneally, so let us quickly review the gross and histopathology of the peritoneum.

Fig. 2  Circulation dynamics of peritoneum

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Fig. 3  Transport of drug through peritoneum

5 Gross and Histopathology of Peritoneum Morphological alteration of the peritoneum leads to functional failure including impaired ultrafiltration and peritoneal permeability. Morphological alterations of the peritoneum can be diagnosed by gross and microscopic findings and mesothelial cytology of the peritoneal effluent. Grossly there might be changes in the colour such as brown, opaque or tanned from normal pink and translucid appearance. Hamada et  al. [31] examined macroscopic morphological findings such as fibrin deposition, peritoneal turbidity, vasculopathy, adhesion and calcification in both parietal and visceral peritoneum of upper and lower peritoneal cavities in peritoneal dialysis patients at catheter removal and reported that vasculopathy in the parietal peritoneum was more serious compared with that in the visceral peritoneum [14, 16, 32, 96]. Histo-morphological alterations of peritoneum are characterized by the disappearance of mesothelial cells, sub-mesothelial fibrosis and thickening, thickening of the walls of blood vessels and neo-angiogenesis. Honda et al. [35] proposed a ‘two-hit theory’ about the development of encapsulating peritoneal sclerosis (EPS), which explains that at the first hit (exposure of bio-incompatible dialysate), peritoneum deteriorates, and the second hit causes additional deterioration. Although EPS can be developed without the second hit, can the same theory be also applicable in the case of intraperitoneal therapy (exposure of test item)? Exposure of the peritoneum to a non-physiological, therapeutic agent along with the use of HIPEC or PIPEC approach may lead to histological and

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functional changes in the peritoneum. Hence peritoneal deterioration should be considered as an important factor while designing the intraperitoneal therapy [59]. Angiopathy and neo-angiogenesis are important in the various disease conditions of the peritoneum such as inflammation, peritoneal adhesions and carcinomatosis. Dvorak [17] explained that microangiopathy and neoangiogenesis involve a sequence of events that include degradation of basement membrane of normal capillaries and venules and the formation of ‘mother vessels’ under the influence of VEGF that leads to neoangiogenesis, leaky blood vessels and thickening of blood vessels [17, 72, 73]. Thus, pathological changes including angiopathy and neo-­ angiogenesis affect the pharmacokinetics of drug given intraperitoneally. Pharmacokinetics also plays a major role in the research of finding the successful therapy for peritoneal diseases [78], so let us review the pharmacokinetics of the drug given intraperitoneally.

6 Pharmacokinetics of the Drug Given Intraperitoneally The interest in the use of IP drug delivery was transformed after a publication by Dedrick et al. [9] which is considered now as a classic paper. The authors described a sound pharmacokinetic rationale for IP drug delivery and put forth the mathematical model which suggested that direct IP administration could achieve exposure of 10–1000 times higher concentrations of the drug compared to the systemic circulation. Slower exit of drug from the peritoneal cavity and rapid removal by systemic circulation gives the better pharmacokinetic advantage. This pharmacokinetic rationale was found advantageous for the patients with peritoneal surface malignancies for applying cytostatic drugs in the peritoneal cavity. The dose–effect relationship plays an important role for most of the drugs to show their effects. For perfusion of the IP cavity, the dose will be diluted by the amount of fluid needed to fill the peritoneal cavity. Usually, an isotonic dialysis fluid is used, after a few cycles of perfusion, the concentration of the drug in perfusate reaches about 90–95% of the expected concentration by the initial dose. The concentration of the drug in perfusate decreases over time according to a one-­ compartment kinetic model with first-order elimination. At the end of perfusion, recovery of the percent of the initial dose from the perfusate indicates uptake of the total dose in the patient. A part of the absorbed drug will bind to tissue structures in the peritoneal cavity and the remaining part will pass the peritoneal plasma barrier, the plasma concentration gradually increases until the end of perfusion. The major challenges of IP chemotherapy are to optimize the contact of the drug to the entire seroperitoneal surface and to increase the penetration depth of the intraperitoneally delivered drugs. However, the IP drug delivery or the treatment modality is not yet properly or completely standardized due to significant variations in the procedures, influencing the pharmacokinetics and pharmacodynamics of intraperitoneally administered drugs. [8], explained significant pharmacokinetic and pharmacodynamic variables of IP chemotherapy in detail. It is observed that there are

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Table 1  Comparison of IP and IV administration Dose

Concentrations achieved Peritoneal– plasma barrier Drug exposure Drug clearance

Other diseases

Dose limiting toxicity Administration side effects

IP Large quantity of drug can be administered

IV Limited quantity of the dose that can be administered intravenously High intraperitoneal concentrations can be Systemic drug accomplished concentrations remain low Slow absorption of the drugs from the No such barrier for peritoneal cavity into the systemic blood systemically administered circulation (peritoneal clearance) drugs Direct contact with tumours in peritoneal Systemic drugs reach cavity, tumours by capillary flow First-pass and high renal drug clearance, Increased drug exposure to reduce systemic drug exposure and longer whole body, half-life is half life shorter hepatic diseases and concurrent metastases in Less advantage due to the lymph nodes can be treated more systemic toxicity effectively Local toxicity due to larger doses Bone marrow suppression, mucositis Patient acceptance, catheter failure, catheter Local side effects are minor infections, inflammation, irritation and pain at local site, chances of bowel obstruction

various factors that influence the IP drug delivery. Table 1 shows the factors affecting the pharmacokinetics of convention vs nanomedicines. In the following section, we will see various factors influencing pharmacokinetics and intraperitoneal drug delivery.

7 Factors Influencing Preclinical IP Route Drug Delivery 7.1 The Type of Drugs Used While considering IP therapy, the expected characteristics of drugs include the ability to effectively penetrate the peritoneal surface and the target tissues (in case of carcinomatosis, tumour nodules), in combination with its ability to eradicate microscopic residual disease within the peritoneal fluid. Various types of drugs and chemotherapeutic agents have been tested for the IP route of administration, it is observed that their potential efficacy, safety, and pharmacokinetic advantage vary with the type of drug used. Initially, the cytotoxic drugs used included alkylating agents, nitrogen mustard, thiotepa, and 5-fluorouracil. Bleomycin was the most commonly used cytotoxic agent to control pleural effusions, however success was limited. L. De Smet et al. [12] explained the ideal parameters for a chemotherapeutic agent for IP therapy and to maximize its efficacy such as cavity-to-plasma AUC

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ratio, systemic absorption, depth of tumour penetration, and intrinsic activity of the agent. Water insoluble, larger molecular weight anticancer drugs have larger peritoneal cavity: plasma drug ratio and they stays longer in the peritoneal cavity. However, such drug does not penetrate deep till the inner core of the tumour tissue. On the other hand, smaller molecular weight, water-soluble drugs have smaller peritoneal cavity: plasma drug ratio, they stay shorter in the peritoneal cavity but penetrate till the inner core of target tissue through microvasculature. Further, the small molecular weight agents which become active after liver metabolism are not suitable for IP delivery as they get drained into systemic circulation and may cause toxicity; however, the smaller molecular weight drugs which are already in active form are suitable for IP delivery [8, 10, 22, 34].

7.2 The Dose of Drug Used The doses vary with the type of drug used. The drug dosage can be calculated according to the estimated body surface area (mg/m2); however, the correlation between the actual peritoneal surface and the estimated body surface is gender dependent and found misleading. Administration of the drug with a fixed concentration or dosage in mg/kg, mg/m2/L or mg/kg/L has been tried by many others. Drugs can be administered as single high dose or in several divided doses, where single dose administered has disadvantage of fast decrease in the concentration over the time, administration in divided doses has the advantage of achieving constant and long-term drug concentration [82, 104]. Van Ruth et al. [104] opined that if dosing is based on surface area, large people tend to have a big abdomen, needing more perfusion fluid, levelling the concentration differences. The same phenomenon occurs when a fixed concentration in perfusate is used, the extra fluid needed in big people results in a higher total dose. A dangerous situation with the fixed concentration method would occur in those patients with extensive mucinous ascites (pseudomyxoma peritonei) preoperatively. Their body surface may be small in relation to the size of their peritoneal space resulting in an overdose of chemotherapy.

7.3 The Volume of Drug Larger volumes can increase the effective contact surface area for the drug administered intraperitoneally and can have increased absorption of the drugs from the peritoneal cavity, however they may lead to higher systemic toxicity and lower efficacy [18]. Sugarbaker et al. [91], studied the pharmacokinetic changes induced by the volume of chemotherapy solution in patients treated with hyperthermic IP mitomycin C and demonstrated that the volume should not be determined by the amount of

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fluid that the administration machine requires for priming or by the amount of fluid required to fill the peritoneal cavity. They found that IP and the plasma concentrations were highest in the 2-l group, less in the 4-l group, and least in the 6-l group indicating that volume of carrier solution can alter the absorption of drug into the plasma compartment. Therefore, they concluded that apart from the dose of drug, the volume of chemotherapy solution plays an important role in pharmacokinetics and the toxicity of IP chemotherapy. To reduce the experimental variables, enhance animal welfare and 3Rs, guidelines for ideal and maximum dose volumes for various routes have been researched and published [15, 25, 36, 37]. Table 2 represents the recommended dose volume for different laboratory animals by IP route.

7.4 Intra-abdominal Pressure The effect of increased intra-abdominal pressure on the pharmacokinetics of intraperitoneally administered drugs was studied in various animal models [19, 21, 40]. Esquis et al. [19] studied high-pressure closed IP chemotherapy in a murine model of peritoneal carcinomatosis of colorectal origin and found that the effect of pressure is more in the parietal peritoneum and cisplatin penetration markedly increased with improved survival. They also mentioned that the use of hyperthermia with high pressure complements each other. In another study [21], hypothesized that open techniques of hyperthermic intraperitoneal chemotherapy (HIPEC) may achieve better tissue concentrations than closed techniques and assessed the effect of high pressure and hyperthermia separately and in combination on tissue penetration of oxaliplatin in an experimental swine model. They concluded that it is possible to achieve open high-pressure HIPEC (25 cm H2O) with oxaliplatin in the pigs. The high pressure is effective in both the visceral and parietal peritoneum. Closed technique helps achieve high IP pressure, whereas, with open techniques more homogenous distribution and better penetration can be obtained [76]. Sloothaak et al. [84] and Valle et  al. [101] safely used laparoscopic HIPEC for refractory malignant ascitic patients who were not suitable for cytoreductive surgery and in patients with colorectal cancer. They successfully applied intra-abdominal pressure of 12–15 mm Hg. It is observed that increased pressure increases drug concentration in peritoneum, tissues and increases penetration in tumour tissues; however, adverse effects have been observed on respiratory and hemodynamic system.

7.5 Hyperthermia It has been reported that physiologically relevant hyperthermia (fever range) of 39.5–40  °C maintained for 6–8  hours enhances the activity of NK cells, macrophages, granulocytes, and several endpoints of innate immunity. The anti-tumour

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Table 2  Characteristics of the intraperitoneal drugs impacting pharmacokinetics

Name of drug Paclitaxil

pKa 11.9

Cisplatin

5.1

Carboplatin

Formulation Solution/liposome/ polymeric nanoparticle or suspension, etc. Dose used 135–175 mg/ Cremophor m2 (polyoxyethylated castor oil) and nanoparticle albumin-bound (NAB- paclitaxel) 20–120 mg/ Protein-based m2 nanoparticulate system 300 mg/m2 Aqueous solution biodegradable 2 mg of carboplatin in polymer polycaprolactone 3 mL of simulated (PCL) carboplatin-­ nasal fluid PCL nanoparticle 10 mg/kg Dox-quercetin conjugate

Doxorubicin pKa (strongest pKa acidic) 8.4 (strongest basic) – 10.3 2 mg/kg

Mitomycin C pKa – 10.9 0.5–2.5 mg/ mL Oxaliplatin

pKa – 5.88 5 mg/kg

Irinotecan (CPT-11)

pKa (strongest acidic) – 11.71 pKa (strongest basic) – 9.47

DOX-NPs, DOX-PDA-NPs, DOX-PDA-FA-NPs and DOX-PDA-RGD-­ NPs Mitomycin-C from chitosan nanoparticles PLGA-PEG (OXA) PLGA-PEG-FA (OXA) CPT-11-loaded DSPE-PEG 2000

Particle size 130 nm

Reference Stinchcomb [90]

≥70 nm

Das et al. [6]

Alex et al. 311.6 ± 4.7 nm [2]

–

Alrushaid et al. [3]

162.9 nm

Bi et al. [5]

140 nm

Kavaz et al. [45]

180.8– 201.3 nm

Oliveira et al. [75]

84.6 ± 1.2 nm Liu et al. [57] to 150.4 ± 0.8 nm

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Name of drug Melphalan

pKa pKa (strongest acidic) – 1.29 pKa (strongest basic) – 9.51

Dose used 50 nM

Formulation Solution/liposome/ polymeric nanoparticle or suspension, etc. Surface-modified melphalan nanoparticles

Particle size 107 ± 64 and 145 ± 54 nm

Reference Tabatabaei et al. [95]

effects of whole-body hyperthermia were correlated with increased granulocytic accumulation at the tumour site which might be mediated by L-selectin-dependent adhesion and increased respiratory burst of granulocytes [20, 43, 56]. Jacquet et al. [39] studied the effects of hyperthermia on pharmacokinetics, metabolism, and tissue distribution of IP doxorubicin in a rat model and found that hyperthermia did not affect the pharmacokinetics of IP doxorubicin; however, there was increased uptake of doxorubicin in small bowel, omentum, and spleen but not in heart tissue, suggesting the regional effects of hyperthermia without affecting the systemic toxicity of doxorubicin. The main aim of IP drug administration is to inhibit tumour growth and prolong survival. The authors suggested various mechanisms of hyperthermia supporting this principle such as acceleration of blood circulation, thereby improving local drug concentration in the tumour, even distribution of drugs, enhanced cytotoxic lymphocyte (CTL) activity, tumour cell apoptosis, stimulating production of neutrophils thereby enhancing the immune function of the body against the tumour and increased portal blood flow may help in minimizing side effects of chemotherapy. These reports hypothesized that planned design and applications of thermal therapy may assist in controlling tumour growth, improving patient quality of life by alleviating pain. However, it is necessary to carefully monitor the complications of hyperthermia treatment such as burns, and cardiopulmonary reserve as rapid rehydration process due to excessive sweating may have effects on lung and heart function [8, 33, 77, 114].

7.6 Vehicle Used Possibility of administering larger doses regionally and achieving higher plasma concentrations are the major advantage of IP therapy. Carrier solutions, in which the drug is dissolved for IP administration have an important role in the distribution, plasma absorption, chemical stability, and solubility of drug, thereby affecting its

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efficacy, tissue penetration, clearance from the peritoneal cavity to general circulation and overall toxicity. Therefore, the choice of right carrier solution is important in enhancing the performance of drug administered intraperitoneally. Mohamed et al. [69] explained the ideal characteristics of a vehicle or career solution including its capability to provide long-period exposure of cancerous surfaces within the peritoneal cavity, possible high IP volume, slow IP clearance and less toxic effects on the peritoneal membranes or other organs [8, 50, 69, 79]. Most regularly used vehicles for IP drug administration are low molecular weight solutions such as isotonic salt solutions or dextrose-based peritoneal dialysis solutions, which are rapidly absorbed from the peritoneal cavity. Whereas high molecular weight solutions such as hypertonic sodium chloride solutions have slower peritoneal fluid clearance, thereby delaying systemic absorption or excretion. It has been reported that the uptake of chemotherapeutic agents into tumour cells increases significantly when the cells are exposed to such agents in a hypotonic solution. The increased accumulation in tumour cells and the enhanced cytotoxicity of cisplatin in hypotonic solution have been confirmed in vitro. Smith and Brock [85], found that reduction in osmolarity from 300 to 240 mosmol/1 caused a three-fold increase in the uptake of drug by cells in vitro and [29] reported that reduction in osmolarity from 290 to 200 mosmol/1 increased the clonogenic cell killing. Kondo et al. [47], studied the effects of isotonic, hypotonic and hypertonic solutions of cisplatin in tumour-bearing mice when administered by IP route. They found that drug uptake by tumour cells was greater and also the survival of tumour-bearing mice was prolonged, when drug was given in hypotonic solutions, than that of isotonic and hypertonic solutions. They also reported the lowest LD50 of the drug given in hypotonic solutions compared to that of isotonic or hypertonic solutions. They correlated the increased uptake of the drug in tumour cells to cell swelling and flow of water inside the cells. The cytotoxicity was correlated with the drug-binding DNA and accumulation in the cells. Hypotonic solutions might have caused the expansion of chromatin, enhanced formation of DNA-protein cross-links and generation of free radicals, resulting in cytotoxicity [44, 99, 100]. Various reports demonstrate the augmented therapeutic efficacy of the drug when administered in hypotonic solution intraperitoneally. In summary, total drug availability depends not only on the molecular structure of the drug, but also on the carrier solution that maintains peritoneal volume [80].

7.7 Type of Carrier Solutions (Hydrophilic vs Lipophilic) The water insolubility and high molecular weight have been correlated with a high cavity-to-plasma AUC ratio and longer IP stay of the drug. The intercellular gaps of the mesothelium are larger than those in the endothelium; therefore, large molecules that cannot pass through endothelial layers do penetrate mesothelial layers. [79] evaluated comparative pharmacokinetics of lipophilic and hydrophilic carrier solutions of anticancer drugs to determine absorption rates in rat model. They concluded

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that the lipid carrier solution increases the peritoneal/plasma AUC ratio and decreases plasma absorption rates and correlated this effect of hydrophobic lipid particles that are resistant to traversing the plasma membrane of endothelial cell layers. The disadvantages explained by the same author of using lipid solutions included inadequacy of drug to recirculate into tumour core from the capillary vessels and to increase cytotoxicity and risk of formation of fat embolism. Drug penetration or transport into tumour tissue is a complex process that involves multiple parameters. There are many more factors that play important role in the pharmacokinetics of intraperitoneally administered drugs. Table 2 shows various characteristics of the drugs including pKa, dose used formulation and particle size of currently used drugs. However, it is clear from the above factors that, the peritoneal drug clearance is slower than systemic drug clearance because the peritoneal plasma barrier maintains a continuous high ratio of chemotherapeutic drug concentration between peritoneal cavity and plasma. This will help determine the most effective drug regimen for effective IP therapy [104].

8 Animal Models of IP Drug Delivery The results of IP drug delivery systems seem promising, and the use of these systems has proved in prolonging survival rate, limiting the peritoneal disease and superior pharmacology, limiting systemic toxicity and reducing risk of mortality by 12% with each cycle of IP therapy. However, this therapy could not gain popularity due to the higher incidence of adverse events [68]. To our knowledge, so far, there is no drug available in clinical practice that has been formulated specifically for IP administration. The methods used for administering drugs into the peritoneal cavity include surgery, traditional use of IP catheters, approach of combining cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) [93] and a recent development of pressurized intraperitoneal aerosol chemotherapy (PIPAC) [87]. Over the years, researchers have gained knowledge and understanding of the physiology of the peritoneal membrane, role of various cells in the transport of solute across and the necessary mechanisms influencing inflammation, peritonitis, peritoneal injury and disease transmission within the peritoneal cavity. However, the use of these methods in clinical setup is difficult due to complications and technical problems. Chemical peritonitis, pain, gastrointestinal side effects, and catheter-­ associated complications are some of the limitations preventing the clinical usefulness of this method. In order to get maximum benefits of its locoregional efficacy, to investigate the full potential and further optimize these new systems for IP drug delivery, there is a need for adequate functional preclinical and/or animal models, which will be rapid, reproducible, and inexpensive and also will demonstrate clinical scenario. Various in vitro models of the isolated peritoneal membrane were reported previously [51, 54]. These models provided information on the effect on mesothelial permeability,

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transperitoneal transport of solutes, mechanisms of dialysis fluid and modulation of cell function; however, in vitro systems do not provide information on long-term changes to the peritoneal membrane nor on peritoneal transport characteristics in humans. [83], proposed the Inverted Bovine Urinary Bladder Model (IBUB); however, it has some disadvantages such as it does not allow repeated measurements over time and there is a significant biological variability between organs. Researchers observed similarities in the transport properties of solute and pharmaceutical agents across the peritoneal membrane in humans and animal models. The literature review shows that various models have been used such as acute and chronic peritoneal dialysis models [26, 74, 103, 106], models for optimization of IP drug delivery systems [1, 12] and models used for HIPEC in tumour-bearing ­animals [46, 74, 88] described in detail the various animal models used for IP therapy, and commented on the main problems encountered while working with these models. They have also highlighted the characteristics of these animal models and mentioned the differences with those of humans. Mostly used animal models include mice (normal or genetically modified), then small laboratory animals such as rats and rabbits, although reports of use of larger animals such as dogs, sheep and even kangaroos have been found. Similarly, Spratt et al. [88] explained preclinical evaluations of surgical procedure, temperature studies, fluid dynamics, and physiology in 15 dogs. Kudo et al. [48] presented an original model of closed continuous hyperthermic peritoneal perfusion (CHPP) in mice and found to support the efficacy of intraperitoneal hyperthermia and its usefulness for the prevention of peritoneal dissemination. Our in-house experience of the conduct of pharmacokinetics and tissue distribution study of combination oncology nanoformulation in Sprague-Dawley rats by intravenous and IP routes showed that animals tolerated doses up to 1500 mg/kg when administered by IP route, however by the intravenous route the doses of 50  mg/kg and above caused immediate mortality. Further, the tissue distribution showed that concentrations of test items reached in various tissues including brain without any toxic effects. Animals administered with intravenous route showed signs of dyspnoea, frothy nasal discharge and death; however, animals receiving IP doses were normal till scheduled sacrifice up to 2 months. Thus, we could administer the maximum dose by IP route without any toxic effects and the absolute availability of drug was higher in IP vs IV route. It is possible that large dose volumes, drug properties, cytoreduction and senescence or any other cellular response may contribute to the failure of ultrafiltration and thereby pharmacokinetics of the drug administered intraperitoneally. Flessner [22] studied fluid movement into the peritoneal cavity of rats and reported that the mesothelium does not appear to be an important barrier to solute transport. In parallel, innovative pharmaceutical platforms, such as targeted agents, nanosized medicine, and drug-eluting beads, have the potential to further increase the appeal of locoregional drug delivery [53].

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9 Conclusion After the successful demonstration of improvement in the median overall survival rate in the patients receiving intraperitoneal and intravenous (IP/IV) chemotherapy by Gynecologic Oncology Group (GOG), National Cancer Institute (NCI) announced clinically encouraging IP/IV chemotherapy use and its benefits over the IV chemotherapy alone [108]. However, the investigators found that the adoption of IP combined with intravenous (IV) chemotherapy has plateaued at around 50% and is underused in clinical practice. Intraperitoneal injections are the preferred method of administration in animal experimental studies than those of humans, due to the quick onset of effects post injection and many other advantages mentioned above. Animal experimentation allows researchers to observe the effects of a drug in a shorter period of time, to study the effects of drugs on multiple organs that are in the peritoneal cavity at once, various surgical techniques can be easily established in animal models. As highlighted in this chapter, currently there are only a handful of drugs that are delivered through intraperitoneal injection for chemotherapy. There is a need of more research to be done to determine appropriate dosing and combinations of these drugs to advance intraperitoneal drug delivery. Preclinical and animal experimentation will certainly help explore IP route of administration in a new way for its potential to improve the cancer outcomes in the patients. It can be expected that the IP drug delivery by overcoming all its limitations will  open new doors for successful treatment of IP disease conditions including carcinomatosis and will provide clear survival advantage to patients with prolonged survival, improved quality of life and encourage clinicians to adopt it towards ­benefiting the patients. However, more research in this regard is required.

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Index

B Bioadhesive, 44, 89, 95, 152 C Carcinomatosis, 28, 81, 91, 92, 98, 115, 120, 127, 128, 130, 131, 162, 181, 198, 203, 207, 218, 225, 226, 228, 234 Chemotherapy, 39, 61, 93, 108, 127, 151, 171, 196, 218 Colorectal cancer, 40, 108, 109, 115, 126–141, 162, 184, 228 Continuous-infusion, 45–46 Cyto-reductive surgery (CRS), 81, 108, 111, 115, 116, 119, 121, 126–130, 135, 139–141, 171, 198, 232 D Depot formulation, 148, 153, 156–158, 160, 162 Dermatome, 19 Dialysis, 4, 26–28, 57, 138, 149, 151, 163, 224, 225, 231, 233 Drug-delivery, 130, 148, 171, 196, 219

H Hydrogels, 89, 92, 98, 99, 151, 153–156, 159–162, 199, 205, 212 Hyperthermic, 84, 92, 108, 120, 127, 138, 140, 157, 171, 176, 187, 200, 227, 232 Hyperthermic intraperitoneal chemotherapy (HIPEC), 29, 39, 84, 92, 108, 109, 111, 115, 116, 121, 127–141, 157, 171, 177, 198, 200, 208, 224, 228, 232, 233 I Implantable, 42, 45, 47, 56, 88, 89, 202, 206, 208, 209 India, 107–121 Infracolic, 11–15 Intraperitoneal (IP), 8, 39, 55, 80, 108, 127, 171, 196, 219 Intraperitoneal malignancies, 41 Intraperitoneal therapy, 86, 224, 225

E Epiploic, 9, 13, 14

L Lipid nanoparticles (LNPs), 52, 53, 55–64, 67–71 Liposomes, 44, 47, 52–55, 57–71, 85, 88, 89, 91–95, 153, 154, 163, 186, 187, 196, 202–205, 208, 209, 212

F Factors, 17, 20, 21, 26–29, 58, 64–66, 68, 72, 84, 86, 88, 92–94, 97, 99, 108, 118, 127, 132, 150, 151, 171–173, 176, 186, 188, 219, 221–223, 225–232

M Mesentery, 4, 6–10, 12–16, 27, 136–138, 152, 197, 201, 221 Mesothelium, 2, 5, 16, 17, 20, 152, 197, 198, 222, 231, 233

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242 Microparticles, v, 47, 55, 80, 87–99, 203, 212 N Nanomedicine, 86, 87, 93, 98, 226 Nanoparticles, v, 47, 53–56, 65, 66, 68, 69, 71, 80, 87–99, 126, 131, 151–155, 157–159, 162, 163, 171, 182–186, 202–204, 207, 208, 212, 229, 230 Nanotechnology, 71, 87, 88, 98 O Omentum, 6–10, 13, 14, 20, 197, 201, 230 Ovarian cancer, 9, 14, 40, 43, 56, 63, 67, 69–71, 80–99, 108–111, 115, 120, 131, 156, 162, 163, 170, 182, 198, 201, 202, 205–208, 219, 221 P Parietal, 2–9, 11, 15, 16, 18, 22, 26, 27, 54, 119, 151, 152, 158, 197, 198, 201, 204, 221, 222, 224, 228 Peritoneal delivery, 41, 149, 155, 163 Peritoneal drug delivery systems (PDDSs), 55–56, 58, 72, 201–206, 210, 212 Peritoneal surface malignancies (PSMs), 107–109, 111, 117, 118, 121, 198, 225 Peritoneal surface oncology (PSO), 108–111, 120, 121, 128 Peritoneum, 2, 38, 81, 127, 149, 170, 197, 218

Index Pharmacokinetics, 41, 52, 63–65, 68, 69, 95–98, 131, 161, 162, 198, 210–212, 217, 219, 221–223, 225–228, 230–233 PILLSID, 45 Preclinical, 69, 71, 72, 162, 206, 209, 210, 212, 217–234 Preclinical studies, 140, 206–208, 218 Pressurized intraperitoneal aerosol chemotherapy (PIPAC), 92, 107–121, 131, 157, 200, 232 R Referred, 5, 19 Retroperitoneal, 3, 6–8, 11, 12, 197, 221 S Sac, 7, 12–14, 22–24, 119, 135 Small interfering RNA (siRNA), 63, 69–71, 87, 88, 94, 95, 99, 153, 158, 162–164 Supracolic, 10, 13, 14 V Visceral, 2–4, 6–9, 11, 15, 16, 18–20, 22, 24–27, 29, 38, 39, 54, 60, 109, 126, 149–152, 161, 164, 197, 198, 201, 221, 222, 224, 228 X Xenograft mice, 94, 96, 162, 163, 207