Advances in Delivery Science and Technology
Padma V. Devarajan Sanyog Jain Editors
Targeted Drug Delivery: Concepts and Design
Advances in Delivery Science and Technology
Series Editor Michael J. Rathbone
More information about this series at http://www.springer.com/series/8875
Padma V. Devarajan • Sanyog Jain Editors
Targeted Drug Delivery: Concepts and Design
Editors Padma V. Devarajan Department of Pharmaceutical Sciences and Technology Institute of Chemical Technology Mumbai, India
Sanyog Jain Centre for Pharmaceutical Nanotechnology Department of Pharmaceutics National Institute of Pharmaceutical Education and Research (NIPER) Mohali, Punjab, India
ISSN 2192-6204 ISSN 2192-6212 (electronic) ISBN 978-3-319-11354-8 ISBN 978-3-319-11355-5 (eBook) DOI 10.1007/978-3-319-11355-5 Springer Cham Heidelberg New York Dordrecht London Library of Congress Control Number: 2014955161 © Controlled Release Society 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. 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. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Advances in drug delivery strategies have been phenomenal throughout the past few decades. The discovery of new drugs has been keenly matched by developments to ensure their effective delivery. Often, drugs considered hopeless have been revived through the design of drug delivery systems. Optimizing drug dosage regimens based on understanding the disease condition, developing patient-friendly systems to address compliance and other innovative approaches is the order of the day. Nevertheless the same has been challenged arduously by the development of resistance, particularly in cancer and infectious diseases. The threat today is the development of not just multidrug resistance but total drug resistance, which could spell impending doom. Targeted drug delivery presents an optimal strategy to tackle such challenges. From ensuring high drug localization at the sites of action, and hence improved therapy, to limiting drug toxicity in other organs, targeted drug delivery presents a host of opportunities to revolutionize medicine. Such delivery relies heavily on nano drug delivery systems and presents manifold opportunities. Nevertheless, targeted drug delivery using nanosystems is fraught with numerous challenges. The objective of this book is to serve as a complete reference guide for targeted drug delivery and as a ready reference for all aspects related to the theme. The book has been structured into eight sections to address the need of beginners and established researchers. Part I is an overview of the basic principles of drug targeting and possible applications therein. Part II covers the important subject of disease-based targeting with a focus on cancer and infectious diseases. Part III and IV discuss in sequence-relevant aspects related to organ-based and organelle-based targeting. Physicochemical approaches exploited for targeting are elucidated in Part V. This includes different stimuli-responsive approaches including magnetic, thermal, and pH-dependent strategies. Prodrug-based conjugates and conjugates with polymers and lipids are also highlighted in the same section. Carrier-based approaches follow in Part VI. This part details applications of various types of nanocarriers in targeted drug delivery such as functionalized lipidic carriers, inorganic nanocarriers, and carbon nanotubes, to name a few. A study of nanocarriers in targeted delivery is incomplete without characterization techniques, addressed in Part VII. The major v
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challenges in the commercial success of targeted delivery systems are the regulatory hurdles and the toxicity-related issues. This is discussed in the last part of the book, Part VIII. The book is the amalgamation of the experience and expertise of all the contributors in the field of targeted drug delivery. It is an exhaustive compilation of the multi-faceted arena of targeted drug delivery, ranging from conceptualization to product development and design and also to aspects of commercialization. Young researchers who plan to initiate research in this important field would find this book extremely relevant and handy. The book would also cater to the needs of advanced researchers in the field. The editors also take the opportunity to express their gratitude to all the contributors for their support. Special thanks are due to Prof. Michael J. Rathbone. Editors are thankful for the valuable assistance received from Dr. (Ms) Anisha D’Souza, Mr. Ashish Kumar Agrawal, and Mr. Kaushik Thanki. Finally, we wish to conclude by saying that this has been a true learning experience. Mumbai, India Mohali, India
Padma V. Devarajan Sanyog Jain
Contents
Part I 1
Targeted Drug Delivery: Basic Concepts and Advances
Targeted Drug Delivery Systems: Strategies and Challenges ............. Bhushan S. Pattni and Vladimir P. Torchilin
Part II
3
Disease-Based Targeting
2
Recent Advances in Tumor Targeting Approaches.............................. Kaushik Thanki, Varun Kushwah, and Sanyog Jain
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Infectious Diseases: Need for Targeted Drug Delivery ........................ 113 Padma V. Devarajan, Shilpa M. Dawre, and Rinku Dutta
Part III
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Organ-Based Targeting
4
Image-Guided Delivery of Therapeutics to the Brain ......................... 151 Lipa Shah, Arun K. Iyer, Meghna Talekar, and Mansoor M. Amiji
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Inhalation Therapy for Pulmonary Tuberculosis ................................ 179 Keiji Hirota, Keishiro Tomoda, Kimiko Makino, and Hiroshi Terada
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Hepatic Targeting: Physiological Basis and Design Strategy .............. 197 Anisha A. D’Souza, Vishvesh M. Joshi, and Padma V. Devarajan
Part IV
Cell- and Cell Organelle–Based Targeting
7
Targeted Drug Delivery to the Mitochondria ....................................... 241 Udita Agrawal, Rajeev Sharma, and Suresh P. Vyas
8
Targeted Delivery of Nucleic Acid Therapeutics via Nonviral Vectors ................................................................................ 271 Mamta Kapoor and Diane J. Burgess
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Contents
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Mucosal Vaccine Delivery and M Cell Targeting ................................. 313 Prem N. Gupta
Part V
Physicochemical Approaches for Targeting
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Stimuli Responsive Carriers: Magnetically, Thermally and pH Assisted Drug Delivery.............................................................. 341 Eameema Muntimadugu, Anjali Jain, and Wahid Khan
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Prodrug Conjugate Strategies in Targeted Anticancer Drug Delivery Systems............................................................................ 367 Shashwat Banerjee, Kiran Todkar, Govind Chate, and Jayant Khandare
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Polymer–Drug Conjugates for Targeted Drug Delivery...................... 389 Anjan Kumar Mohanty, Fahima Dilnawaz, Guru Prasad Mohanta, and Sanjeeb Kumar Sahoo
Part VI
Carrier-Based Approaches for Targeted Drug Delivery
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Functionalized Lipid Particulates in Targeted Drug Delivery ............ 411 Mangal S. Nagarsenker, Ankitkumar S. Jain, and Sanket M. Shah
14
Nanoemulsion in Drug Targeting .......................................................... 433 Sushama Talegaonkar and Lalit Mohan Negi
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Multifunctional Polymeric Nano-Carriers in Targeted Drug Delivery ...................................................................... 461 Ashish Kumar Agrawal, Dileep Urimi, and Sanyog Jain
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Polymeric Micelles in Targeted Drug Delivery..................................... 501 Rayasa S. Ramachandra Murthy
17
Dendritic Polymers in Targeted Drug Delivery .................................... 543 Sumati Bhatia and Rainer Haag
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Inorganic Nanoparticles in Targeted Drug Delivery and Imaging ............................................................................................. 571 Hélder A. Santos, Luis M. Bimbo, Leena Peltonen, and Jouni Hirvonen
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Carbon-Based Nanomaterials for Targeted Drug Delivery and Imaging ............................................................................................. 615 Vivek S. Thakare, D’Arcy Prendergast, Giorgia Pastorin, and Sanyog Jain
Contents
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Part VII Advanced Characterization Techniques for Nanocarriers 20
Physical and Biophysical Characteristics of Nanoparticles: Potential Impact on Targeted Drug Delivery ....................................... 649 Chiranjeevi Peetla and Vinod Labhasetwar
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In Vivo Imaging Techniques of the Nanocarriers Used for Targeted Drug Delivery ........................................................... 667 Sudha Rana, Amit Tyagi, Nabo Kumar Chaudhury, and Rakesh Kumar Sharma
Part VIII
Nanotoxicology and Regulatory Issues
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Evaluation of Lung Toxicity of Biodegradable Nanoparticles ............ 689 Nadège Grabowski, Hervé Hillaireau, Juliette Vergnaud, and Elias Fattal
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Nanotoxicology: Contemporary Issues and Future Directions........... 733 Chandraiah Godugu, Raman Preet Singh, and Ramarao Poduri
Index ................................................................................................................. 783
List of Contributors
Ashish Kumar Agrawal Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Udita Agrawal Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H.S. Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India Mansoor M. Amiji Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA Shashwat Banerjee Actorius Innovations and Research (AIR), Pune, India Sumati Bhatia Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany Luis M. Bimbo Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland Diane J. Burgess School of Pharmacy, University of Connecticut, Storrs, CT, USA Govind Chate Maharashtra Institute of Pharmacy, MIT Campus, Pune, India Nabo Kumar Chaudhury Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India Anisha A. D’Souza Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (Elite status), Deemed University, Mumbai, India Shilpa M. Dawre Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (Elite status), Deemed University, Mumbai, India Padma V. Devarajan Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India Fahima Dilnawaz Laboratory of Nanomedicine, Institute of Life Sciences, Chandrasekharpur, Odisha, India
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Rinku Dutta Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (Elite status), Deemed University, Mumbai, India Elias Fattal Faculty of Pharmacy, Institut Galien, University of Paris-Sud, Châtenay-Malabry, France Chandraiah Godugu National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Andhra Pradesh, India Nadège Grabowski Faculty of Pharmacy, Institut Galien Paris-Sud, University of Paris-Sud, Châtenay-Malabry, France Prem N. Gupta Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India Rainer Haag Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany Hervé Hillaireau Faculty of Pharmacy, Institut Galien Paris-Sud, University of Paris-Sud, Châtenay-Malabry, France Keiji Hirota Center for Drug Delivery Research, Faculty of Pharmaceutical Sciences, and Japan Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan Jouni Hirvonen Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland Arun K. Iyer Department of Pharmaceutical Sciences, Applebaum College of Pharmacy of Pharmacy, Wayne State University, Detroit, MI Anjali Jain Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India Sanyog Jain Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Ankitkumar S. Jain Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India Vishvesh M. Joshi Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (Elite status), Deemed University, Mumbai, India Mamta Kapoor Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Wahid Khan Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India Jayant Khandare Maharashtra Institute of Pharmacy, MIT Campus, Pune, India
List of Contributors
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Varun Kushwah Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Vinod Labhasetwar Department of Biomedical Engineering, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Kimiko Makino Center for Drug Delivery Research, Faculty of Pharmaceutical Sciences, and Japan Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan Guru Prasad Mohanta Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu, India Anjan Kumar Mohanty Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu, India Eameema Muntimadugu Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India Rayasa S. Ramachandra Murthy Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India Sumukha Green Ville, Sarvabhauma Nagara, Bilekahalli, Bangalore, India Mangal S. Nagarsenker Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India Lalit Mohan Negi Department of Pharmaceutics, Jamia Hamdard, New Delhi, India Giorgia Pastorin Department of Pharmacy, National University of Singapore, Singapore, Singapore Bhushan S. Pattni Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA Chiranjeevi Peetla Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Leena Peltonen Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland Ramarao Poduri Centre for Chemical and Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, India D’Arcy Prendergast Department of Pharmacy, National University of Singapore, Singapore, Singapore Sudha Rana Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India
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List of Contributors
Sanjeeb Kumar Sahoo Laboratory of Nanomedicine, Institute of Life Sciences, Chandrasekharpur, Odisha, India Hélder A. Santos Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland Sanket M. Shah Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India Lipa Shah Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA Rakesh Kumar Sharma Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India Rajeev Sharma Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H.S. Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India Raman Preet Singh Evaluserve SEZ (Gurgaon) Pvt. Ltd., Gurgaon, India Sushama Talegaonkar Department of Pharmaceutics, Jamia Hamdard, New Delhi, India Meghna Talekar Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA Hiroshi Terada Center for Drug Delivery Research, Faculty of Pharmaceutical Sciences, and Japan Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan Vivek S. Thakare Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Kaushik Thanki Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Kiran Todkar Actorius Innovations and Research (AIR), Pune, India Keishiro Tomoda Center for Drug Delivery Research, Faculty of Pharmaceutical Sciences, and Japan Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan Vladimir P. Torchilin Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA Amit Tyagi Division of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India
List of Contributors
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Dileep Urimi Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India Juliette Vergnaud Faculty of Pharmacy, Institut Galien Paris-Sud, University of Paris-Sud, Châtenay-Malabry, France Suresh P. Vyas Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H.S. Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India
About the Editors
Prof. Padma V. Devarajan is Professor in Pharmacy and Head of the Department of Pharmaceutical Sciences and Technology at the Institute of Chemical Technology (ICT), Mumbai, India. She obtained her PhD (Tech) in Pharmaceutics from the Department of Chemical Technology, University of Mumbai, India. Her research interests include nanocarriers for targeted delivery in cancer and infectious diseases, scale-up of nano drug delivery systems (DDS), bioenhancement strategies, and mucosal DDS as alternatives to parenteral administration for protein and nucleic acid delivery. Prof. Devarajan has supervised more than 100 master’s and doctoral candidates. Her research is funded by the Government of India and the national and international pharmaceutical industry. She is an author of several book chapters and has publications in peer-reviewed high-impact journals. She has a number of granted patents, with four licensed to the industry. Prof. Devarajan has served as board member, member on the Board of Scientific Advisors, and Chair of the Young Scientist Mentor Protégé Sub-committee of the Controlled Release Society. She is a recipient of the American Association of Indian Pharmaceutical Scientists (AAiPS) Distinguished Educator and Researcher Award, the VASVIK award for Industrial Research to Women, and the Association of Pharmaceutical Teachers of India–C.J. Shishoo Award for Research in Pharmaceutical Sciences, and she is a nominated Fellow of the Maharashtra Academy of Sciences, India. Dr. Sanyog Jain is currently Associate Professor at the Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali (Punjab), India. He obtained his Ph.D. in Pharmaceutics from Dr. Hari Singh Gour University, Sagar (MP), India. His key research interests include exploring nano drug delivery systems for various biomedical applications including targeted anticancer drug delivery, oral delivery of vaccines, peptides and therapeutics, topical and transdermal drug delivery, gene delivery, and carbon nanotubes. He has patented several nanotechnology-based drug delivery platforms and licensed Tamoxifen-SEDDS Technology for improved breast cancer therapy to industry for commercialization. He has authored several book chapters
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and published research papers in high-impact journals. Dr. Jain has won several prestigious awards including Bharat Jyoti (The Glory of India) Award, Alkyl Amine Young Scientist Award, Indian National Science Academy (INSA) Medal for Young Scientists, OPPI Young Scientist Award, and Punjab State Young Scientist Award for outstanding research in the field of drug delivery systems. He has supervised more than 50 master’s and doctoral students and a post doc. His research is well funded by various government agencies and pharmaceutical industries. Jain is a widely travelled scientist and has delivered invited talks at numerous prestigious platforms.
Part I
Targeted Drug Delivery: Basic Concepts and Advances
Chapter 1
Targeted Drug Delivery Systems: Strategies and Challenges Bhushan S. Pattni and Vladimir P. Torchilin
Abbreviations DDS TDDS HIV AIDS BBB RES PEG MNP SPION ADEPT GDEPT DNA RNA HSV EPR SLN FDA siRNA RNAi TNF-α WHO
Drug delivery system Targeted drug delivery system Human immunodeficiency virus Acquired immunodeficiency syndrome Blood–brain barrier Reticuloendothelial system Poly(ethylene) glycol Magnetic nanoparticles Superparamagnetic iron oxide nanoparticles Antibody-directed enzyme prodrug therapy Gene-directed enzyme prodrug therapy Deoxyribonucleic acid Ribonucleic acid Herpes simplex virus Enhanced permeability and retention Solid lipid nanoparticle Food and Drug Administration Small inhibiting RNA RNA interference Tumor necrosis factor alpha World Health Organization
B.S. Pattni • V.P. Torchilin (*) Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Room 211/214, 360 Huntington Avenue, Boston, MA 02115, USA e-mail:
[email protected];
[email protected] © Controlled Release Society 2015 P.V. Devarajan, S. Jain (eds.), Targeted Drug Delivery: Concepts and Design, Advances in Delivery Science and Technology, DOI 10.1007/978-3-319-11355-5_1
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B.S. Pattni and V.P. Torchilin
TB MSNP PEI CNS RBC PLA HAART MDR AZT BCSFB CMT RME AME APO E LDL CSSS PLGA BRB RPE P-gp PepT IBD IBS CDDS GIT RISC CPPs
1.1
Tuberculosis Mesoporous silica nanoparticles Polyethyleneimine Central nervous system Red blood cells Poly (D,L-lactide) Highly active antiretroviral therapy Multidrug resistance Azidothymidine Blood–cerebrospinal fluid barrier Carrier-mediated transport Receptor-mediated endocytosis Absorptive-mediated endocytosis Apolipoprotein E Low density lipoprotein Cyanoacrylate skin surface stripping Poly (DL-lactide-co-glycolide) Blood–retinal barrier Retinal pigmented epithelium P-glycoprotein Peptide transporters Inflammatory bowel diseases Irritable bowel syndrome Colon targeted drug delivery systems Gastrointestinal tract RNA-induced silencing complex Cell penetrating peptides
Introduction
In this complex and ever-evolving world of medicine it has become increasingly important to address the issues of the drug development involving the delivery of specific drugs to their site of action in therapeutically acceptable doses. With the advancement of the pharmaceutical sciences, the industry has certainly observed discovery of several new drug molecules ranging from small molecule drugs to macromolecules like proteins and peptides; but the ultimate goal of achieving disease-free conditions in the patients is often left hanging due to several hurdles relating to physicochemical and molecular intricacies of the “free” drugs and unapproachability and under-dosing of most of the biological/pathological targets. To improve on these situations drug delivery systems (DDS) are employed which could either be a formulation or a device that facilitate the administration of a drug to the body whilst improving its pharmacokinetic and biodistribution profiles and the efficacy and safety of the whole treatment. Targeting the drugs (and DDS) involves the improvement of the specificity of the system towards the pharmacologically relevant target in
1 Targeted Drug Delivery Systems: Strategies and Challenges
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the body. Targeted drug delivery systems (TDDS) involve the administration of the DDS to the patient, delivery of the DDS at the target (pathological) site, release of the active ingredients in/around the target, and avoiding nonspecific toxicity in normal cells. The above concept of targeted drugs—magic bullet—was first conceived by Paul Ehrlich in early twentieth century and over the past decades several strategies have developed to achieve targeting [1, 2]. A TDDS can be broadly understood as a system that carries out the following functions: • Facilitate the therapeutic substance to reach the site of action from the site of administration where the target site can be organ, tissue, cell or even specific cell organelles. • Release the therapeutic payload in its active form in/around the target site presenting effective therapeutic levels at the site of action. • Protect the drug/gene from the detrimental effects of environmental factors such as pH, enzymes, etc. • Avoid toxicity or adverse reactions of the drug/gene on nonspecific normal cells and facilitating administration of lower doses to achieve therapeutic/diagnostic benefits. Research in the field of targeted drug delivery has given several options of carrying out the above functions: • Direct targeting to site of action, e.g., topical applications for skin diseases. • Use of external stimuli, e.g., ultrasound. • Chemical modification of the drug to make its physicochemical properties ideal for the delivery which includes prodrug approach of attaching a promoiety to the drug. • Use of nanocarriers like liposomes, polymeric micelles, polymeric nanoparticles, solid lipid nanoparticles which can be functionalized further with attachment of targeting ligands, antibodies. An efficient TDDS ideally should possess the following properties: • The drug-conjugate/drug-carrier should reach the intended site of action (organ/ tissue/cell/cell organelles) with minimal nonspecific accumulations. • The chemical conjugation or physical encapsulation of the drug/gene with the targeting ligands or carriers should not inactivate or alter the drug/gene action on the intended site of action; the TDDS should be able to protect the drug from environmental factors such as enzymatic degradation till they reach the target. • The chemical conjugation or physical encapsulation of the drug/gene with the targeting ligands or carriers should not inactivate or alter the ligand or carrier activity and function to reach the intended site of action. This chapter has been divided into sections which cover the general strategies of developing TDDS, the use of TDDS in diseases like cancer, HIV/AIDS, tuberculosis, and the use of TDDS to target specific organs and locations. While the targeted drug delivery systems require in-depth study on their own, the intentions of this chapter remain to provide only an overview of the relevant challenges and strategies.
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Targeted Drug Delivery: General Concepts
Targeted drug delivery at the site of action can be carried out by direct techniques usually involving invasiveness: direct injection, catheter [3, 4], gene-gun [5], etc. Though these systems show direct delivery, invasiveness is not patient convenient and expensive to carry out in many cases. As a result, efforts are put into developing TDDS which involve chemical, physical and biological modifications with or without the use of carriers. Changes done to improve targeting the drug include study of structure activity relationships to improve the physicochemical properties for targeting. Small-molecule drugs intended for brain delivery unable to penetrate the blood–brain barrier (BBB) may be made more lipophilic to aid penetration through the BBB, provided they have small size. Prodrugs can be made to improve the pharmacokinetics of the drugs. Small molecule drugs are chemically modified by attaching “promoeities” rendered pharmacologically inactive and are metabolically activated in vivo into active drugs only after reaching their intended target [6]. Drugs may be conjugated with antibodies, peptides, aptamers, folic acid, etc. to generate targeted prodrugs [7]. On the other hand, the drugs can be incorporated into nanocarriers or nanosystems. These include drug carrier systems like liposomes, polymeric micelles, polymeric nanoparticles, polymer–drug conjugates, nanogels, carbon nanotubes, etc. [8]. The nanosystems are a very efficient way to deliver the drugs or genes. The major advantage of using such systems is that the pharmacokinetic behavior of the drug-loaded nanocarriers depends on the nanosystems rather than the drugs or genes, which makes it easy to control with the help of further targeting. The nanoparticles described in this chapter are 10 μm are trapped at the oropharynx, whereas smaller particles of Daer
