Polymer-Drug Conjugates: Linker Chemistry, Protocols and Applications

Polymer-Drug Conjugates: Linker Chemistry, Protocols and Applications discusses important concepts, fundamentals and prospective applications of ‘Linker Chemistry’ in a clear-and-concise manner. The book provides vital information on chemical entities binding with the drug-polymer complex for targeted drug delivery systems. It highlights roles and significance, different classes and synthetic protocols as well as mechanisms of chemical bond formation in drug-polymer conjugation in drug delivery, also offering insights into the mechanism of polymer interaction with linker and drug molecules by biodegradable chemical bonding.

The protocol of binding with drug molecules is clearly explained and justified with case studies, helping researchers and advanced students in the pharmaceutical sciences understand fundamentals involved and related aspects in molecule designing for effective therapeutic benefits.

• Covers mechanism, protocol and therapeutic significance of Polymer-Drug Conjugates
• Outlines updated methods and techniques to enumerate conjugation with related case studies
• Includes comprehensive compilation of marketed and clinical trial drugs conjugated with polymers or linkers

• Language: English
• Publisher: Academic Press
• Release date: Jul 5, 2023
• ISBN: 9780323916905

Book preview

Polymer-Drug Conjugates

Editors

Jitender Madan

National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Ashish Baldi

Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India

Monika Chaudhary

GVM College of Pharmacy, Sonepat, Haryana, India

Neetu Chopra

Safety and Pharmacovigilance Specialist, Syneos Health, Gurgaon, Haryana, India

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Editors

Preface

Acknowledgment

Chapter 1. Drug delivery: The conceptual perspectives and therapeutic applications

1. Introduction

2. Basic fundamentals of targeted drug delivery systems

3. Passive targeting

4. Active targeting

5. Ligands for targeting

6. Endocytosis

7. Need of targeted drug delivery system

8. Targeted drug delivery system by oral and parenteral routes

9. Regulatory challenges of novel drug delivery system

10. Scale-up challenges of targeted drug delivery systems

11. Marketed formulation based on targeted drug delivery systems

12. Conclusion and summary

Chapter 2. Rational design of linkers in polymer–drug conjugates

1. Introduction

2. Polymer–drug conjugate

3. Linkers/spacers

4. Conclusion

Chapter 3. Exploration of polymers in drug delivery: The structural and functional considerations

1. Introduction

2. Different polymers used in linker chemistry for bioconjugation of drugs

3. Classification of polymers on the basis of their structural and physicochemical behavior

4. Role and function of different polymers used in linker chemistry

5. Selection of polymeric drug delivery system and drug release

6. Some recent developments

7. Conclusion

Chapter 4. Chemistry of conjugation in drug delivery: The prospects of biodegradable bonds in polymer–drug conjugates

1. Introduction

2. Characteristics of an ideal polymer

3. Polymer-based drug delivery system

4. Polymers used in preparation of polymer–drug conjugates

5. Drug release from polymer–drug conjugates is pH sensitive

6. Different linkages involved in polymer–drug conjugation

7. Conclusion

Chapter 5. Polymer–drug conjugation using ester and ortho-ester bond: Mechanism, protocols, and applications

1. Introduction

2. Discovery tale of polymer–drug conjugates

3. Insights into ester and orthoester bond as drug–polymer conjugate strategy

4. Ester and orthoester bond: Chemistry and cleavage

5. End group functionalities of ester and orthoester conjugation: Synthetic procedures and applications

6. Conclusion

Chapter 6. Polymer–drug linking through amide bonds: the chemistry and applications in drug delivery

List of abbreviations

1. Introduction about polymer

2. Polymer–drug conjugates

3. Various polymer–drug linking through amide bond: its chemistry

4. Application of polymer–drug linking through amide bond in drug delivery

5. Conclusion and future aspects with polymer–drug conjugate

Chapter 7. Drug–polymer conjugate tailoring by disulfide linkage for controlled and targeted drug delivery

1. Introduction

2. Basic chemistry of disulfide linkage

3. Binding with disulfide linkage

4. Drug delivery by drug–polymer sulfide linkage conjugates

5. Synthetic strategies of polymer–drug conjugates

6. New facile strategy

7. Polymer therapeutics for drug delivery

8. Applications of tailored drug–polymer conjugates by sulfide linkage

9. Failures of disulfide linkage

10. Successful disulfide linkages

11. Challenges and future projections

Chapter 8. Thioether linkage chemistry: perspectives and prospects in therapeutic designing

List of abbreviations

1. Introduction

2. Paclitaxel/gemcitabine

3. Cyclodextrin hyaluronic acid conjugates

4. Camptothecin–PEG–LHRH drug conjugate

5. BIM-23A760

6. Conclusion

Chapter 9. Drug targeting to cancer cells through stimuli-responsive imine bonds: fascinating aspects of site specificity

1. Introduction

2. Polymeric drug delivery system

3. Shell-sheddable nanoassemblies

4. Core-degradable backbone-multicleavable nanoassemblies

5. Core-degradable pendant-multicleavable nanoassemblies

6. Stimuli-responsive/pH-responsive drug–polymer conjugates for cancer chemotherapy

7. Mechanism of formation of imine bond

8. In vivo fate of pH-responsive drug–polymer conjugates with imine and hydrazone linker

9. Drawbacks of imine and hydrazone linker bond in development of drug–polymer conjugate

10. Applications

11. Polymeric nanoparticles

12. Hydrogels

13. Drug–polymer conjugate (polymeric prodrugs)

14. Polymeric micelles

Chapter 10. Carbamate–drug conjugates in drug delivery: structural and mechanistic considerations

1. Introduction

2. Chemistry

3. Methodologies for carbamate bond formation

4. Applications of carbamates in pharmaceutical field

Chapter 11. Bonding through phosphodiester moiety: Its implications in pharmaceutical modifications

1. Introduction

2. Phosphodiester-containing biomolecules

3. Chemistry of phosphodiester bond

4. Role of phospholipids in drug delivery

5. Oligonucleotide–phosphodiester conjugates

6. siRNA oligonucleotide conjugates

7. Conclusion

Chapter 12. Enzymatically degradable linkers

1. Introduction

2. Chemotherapeutic agents and their therapeutic limitations

3. Concept of cancer targeted polymer–drug conjugates

4. Components of polymer–drug conjugates

5. Design and development of enzyme sensitive nanocarrier–mediated anticancer drug delivery system

6. Conclusion

Chapter 13. Dendrimer–drug conjugates

List of abbreviations

1. Dendrimers-based drug delivery systems

2. Advantages of dendrimer–drug conjugates

3. Prerequisites for dendrimer–drug conjugates

4. Synthesis strategies of dendrimer–drug conjugates

5. Dendrimer prodrugs with spacers

6. Applications of dendrimer–drug conjugates

7. Dendrimer–drug conjugates in cancer therapeutics

8. Dendrimer–drug conjugates in inflammatory diseases

9. Conclusion and perspective of developing dendrimer–drug conjugates

Chapter 14. Antibody–drug conjugate: Emerging trend for targeted treatment

1. Introduction

2. Antibody–drug conjugates design and its chemistry

3. Conjugation mechanism

4. Mechanism of action

5. Antibody–drug conjugate strategies for treatment of diseases

6. Limitation and potency enhancement of antibody–drug conjugates

7. Clinical implication of ADC

8. Conclusion and future perspective

Chapter 15. Drug–polymer conjugates: Challenges, opportunities, and future prospects in clinical trials

1. Introduction

2. Types of polymer–drug conjugates

3. Polymers used in PDC

4. Polymer protein conjugates

5. Preparation of PDCs

6. Analytical methodology

7. Advantages of PDC

8. Applications of PDC

9. Polymer–drug conjugates as a concept for combination therapy

10. Polymer conjugates for new molecular targets are being developed

11. Drug distribution

12. PDC in clinical trials

13. Conclusion and future prospects

Index

Copyright

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Dedication

This book is dedicated to all the researchers, physicians, nurses, pharmacists, and other health workers, who worked day and night to surmount the pandemic COVID-19.

Contributors

Mansour H. Almatarneh,     Department of Chemistry, University of Jordan, Amman, Jordan

Rajendra Awasthi,     Department of Pharmaceutical Sciences, School of Health Sciences & Technology, University of Petroleum and Energy Studies (UPES), Dehradun, Uttarakhand, India

Neha Bajwa

Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Panjab Technical University, Bathinda, Punjab, India

University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India

Ashish Baldi,     Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Panjab Technical University, Bathinda, Punjab, India

Pallavi Bassi,     School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences & Technology, Baddi, Himachal Pradesh, India

Adeel Masood Butt,     Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Punjab, Pakistan

Jasmine Chaudhary,     MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, India

Monika Chaudhary,     Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India

Neetu Chopra,     Safety and Pharmacovigilance Specialist, Syneos Health, Gurgaon, Haryana, India

Dimple Sethi Chopra,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Shalki Choudhary,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Narinder Deodhar,     Research and Development, Reckitt Benckiser Health Care (UK) Limited, Hull, United Kingdom

Pawan Dewangan,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Neerupma Dhiman,     Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

Rupesh Dudhe,     School of Pharmacy, G H Raisoni University, Chhindwara, Madhya Pradesh, India

Anshu Dudhe,     School of Pharmacy, G H Raisoni University, Chhindwara, Madhya Pradesh, India

Bapi Gorain,     Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Ranchi, Jharkhand, India

Parveen Kumar Goyal,     Department of Pharmacy, Panipat Institute of Engineering and Technology, Panipat, Haryana, India

Neha Gulati,     Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India

Akash Jain,     MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, India

Keerti Jain,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow, Uttar Pradesh, India

Gaurav Joshi

School of Pharmacy, Graphic Era Hill University, Dehradun, Uttarakhand, India

Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Chauras Campus, Srinagar Garhwal, Uttarakhand, India

Kiran Jyoti,     IKG Punjab Technical University, Jalandhar, Punjab, India

Kavita,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Harsha Kharkwal,     Amity Institute of Phytomedicine and Phytochemistry, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

Swanand Kulkarni,     Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, India

Giriraj T. Kulkarni,     Gokaraju Rangaraju College of Pharmacy, Hyderabad, Telangana, India

Asim Kumar,     Amity Institute of Pharmacy, Amity University Haryana, Gurgaon, Haryana, India

Shom Prakash Kushwaha,     Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India

Jitender Madan,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Shipra Mahal,     Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India

Garima Malik,     MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, India

Jayashree Mayuren,     Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Ravinesh Mishra,     School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences & Technology, Baddi, Himachal Pradesh, India

Arun Mittal,     Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India

Atul Mourya,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Kamta Prasad Namdeo,     Department of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur, India

Manisha Pandey,     Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Anchal Pathak,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow, Uttar Pradesh, India

Prateek Pathak,     Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia

Akashdeep Singh Pathania,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Dinesh Puri,     School of Pharmacy, Graphic Era Hill University, Dehradun, Uttarakhand, India

Roobal,     School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences & Technology, Baddi, Himachal Pradesh, India

Satish Sardana,     Amity Institute of Pharmacy, Amity University Haryana, Gurgaon, Haryana, India

Sheshank Sethi,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Ramanpreet Shah,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Rupali Sharma,     Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India

Shekhar Sharma,     Llyod Institute of Pharmacy, Llyod Group of Institutions, Greater Noida, Uttar Pradesh, India

Bhupesh Sharma,     Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

Rahul Sharma,     Hindu College of Pharmacy, Sonepat, Haryana, India

Shivani,     School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences & Technology, Baddi, Himachal Pradesh, India

Yogesh Singh,     Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, India

Pankaj Kumar Singh,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Jatinder Singh,     Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, United States

Dhandeep Singh,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Nirmal Singh,     Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Preet Amol Singh,     Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Panjab Technical University, Bathinda, Punjab, India

Kamlinder Kaur Singh,     School of Pharmacy and Biomedical Sciences, Central University of Lancashire, Preston, United Kingdom

Ram Sarup Singh,     Chandigarh University, Ghuran, Mohali, Punjab, India

Shashi Bala Singh,     Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India

Shabnam Thakur,     Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India

Suresh Thareja,     Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda, Punjab, India

Rohit Tripathi

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh, India

Faculty of Pharmacy, Kamla Nehru Institute of Management and Technology, Sultanpur, Uttar Pradesh, India

Renu Tushir,     Hindu College of Pharmacy, Sonipat, Haryana, India

Sandeep Vats,     Product Development (R & D), Ohm Laboratories Inc., New Brunswick, NJ, United States

Amita Verma,     Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh, India

Jagat Pal Yadav

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh, India

Faculty of Pharmacy, Kamla Nehru Institute of Management and Technology, Sultanpur, Uttar Pradesh, India

Editors

Dr. Jitender Madan is currently working as an Associate Professor in the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India. He earned his MPharm from Dr. Hari Singh Gour University, Sagar, and Ph.D. from Bundelkhand University, Jhansi, and Postdoc from the Department of Biology, Georgia State University, Atlanta, Georgia, United States. Recently, he had received highest acclaim of featuring among Top 2% Scientists across the World in the field of Pharmacy and Pharmacology for the year 2022 by Stanford University, USA. His major research area includes self-assembled supramolecular systems, namely, liposomes, niosomes, cyclodextrin, nano- and microparticles, and solid–lipid nanoparticles. The focus is centered on the exploitation of US FDA–approved biomaterials in combination with other potential lipids and polymers to develop the innovative dosage forms and drug delivery systems in order to improve the bioavailability, stability, safety (tolerance), and patient-compliance. He has authored more than 125 peer-reviewed publications in reputed international journals, and more than 18 book chapter contributions. He has several patents to his credit on composition and improving therapeutic efficacy. He guided Ph.D. (Pharmaceutics) and MS/MPharm students for their dissertations/research projects. He is a peer reviewer of various international journals and publishers. He recently published two edited books Clinical Perspectives and Targeted Therapies in Apoptosis: Drug Discovery, Drug Delivery, and Disease Prevention (Elsevier) and Multifunctional Nanocarriers (Elsevier) in addition to few other books. He has completed several industry and government-sponsored research projects.

Dr. Ashish Baldi, alumni of Dr. Hari Singh Gour University and Indian Institute of Technology Delhi, is presently working as a Professor, Department of Pharmaceutical Sciences and Technology and Dean Research and Development Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India. Recently, he had received highest acclaim of featuring among Top 2% Scientists across the World in the field of Pharmacy and Pharmacology for the year 2019, 2020, and 2021 by Stanford University, USA. With over 20 years of experience, 3 patents filed, 4 design Patents, 9 other IPRs, 10 books, 4 special issues, over 140 national and international publications, 22 book chapters, over 70 invited lectures, several popular articles, more than 170 papers at conferences/seminars in India and abroad, and several best paper awards to his credit, he is an active researcher in various facets of pharmaceutical sciences and biotechnology. He is supervising/completed 15 research projects granted by various government agencies like the Ministry of AYUSH, DST, ICSSR, ICMR, FITM, PSCST, AICTE, etc., and transferred two technologies to leading pharmaceutical industries. He has been featured in Who's Who of the World as one of the most outstanding scientists across the world in 2011 edition and Best 200 Scientific Intellectuals of the World by Cambridge Society, UK. He had also received eight research awards including ‘MRSPTU Best Researcher Award’ at university level. Presently, he is also Fellow/Life member of more than 10 scientific societies worldwide including Fellow of world's oldest scientific society, the Linnean Society, London, and serving as advisory/editorial board member in more than 20 journals of high impact.

Dr. Monika Chaudhary is an Associate Professor in the Department of Pharmaceutical Chemistry, GVM College of Pharmacy, Sonepat, Haryana, India. She has completed doctoral studies in Pharmaceutical Sciences from IKGPTU, Jalandhar, after completing master’s (Pharmaceutical Chemistry) and bachelor’s program in Pharmacy. The main focus of her work is polymeric drug delivery systems comprising natural and synthetic polymers which can be utilized to formulate US FDA–approved drugs into marketed products. The goal is to design and develop different classes of polymer–drug conjugates, including polymer–protein and polymer–small molecule drug conjugates, dendrimers, polymer nanoparticles, and multifunctional systems so that the current obstacles hampering the clinical translation of polymer–drug conjugate therapeutics can be overcome. She has published numerous research and review papers in international journals of Elsevier, Springer, Taylor Francis, and Bentham Sciences. She has guided many graduate and undergraduate student for their thesis work. She is a peer reviewer of various international journals and publishers.

Dr. Neetu Chopra is a Drug Safety Specialist in Pharmacovigilance at Syneos Health, Gurgaon, India. She had more than 10 years of teaching and research experience. She worked as an Assistant Professor at the Department of Pharmaceutical Chemistry, Chandigarh College of Pharmacy, Landran, Mohali. Her core area of research covers design of drug molecules by using drug designing software like AutoDock, VLife Sciences, Schrodinger, computational chemistry, synthesis of drug molecules, purification of drug molecules by using column chromatography, chemical libraries, computational chemistry, drug delivery, drug discovery and development, lead optimization, screening of drug molecules, and identification of drug molecules by using different spectral analysis techniques. She has made major contributions in research paper in reputed national and international journals and books/book chapters. Moreover, she is working on the safety of postmarketed drugs and clinical trials.

Preface

In the existing scenario, interdisciplinary research collaboration is generally favored by the scientists to provide a valuable outcome in a short span of time. Therefore, most of the researchers refer those study materials which curtail basic as well as advanced information about the subject. However, limited material is available in a complied form which fulfills the needs of the scientific community. Maintaining these thrust areas in Polymer –Drug Conjugates, we have done our best to surmount to compile the different segments of linker chemistry in a single creel. This book covers interesting concepts, fundamentals, and prospective applications of ‘Linker Chemistry’ in lucid and simplified manner. The content highlights the role and significance, different classes, synthetic protocols, as well as mechanism of chemical bond formation in polymer–drug conjugation in the field of drug delivery. The theme of the proposed book offers to bestow knowledge about the interaction of the chemical bond with the drug–polymer conjugate and the drug delivery at the site of action. Additionally, this book comprehends the synthetic protocols for drug–polymer conjugation and their therapeutic applications. This book is enclosing the chapters in three ways including mechanism of polymer–drug Conjugation, protocol of conjugation, and therapeutic significance of this interaction. However, none of the books available is covering all three aspects. Moreover, this book covers the course curriculum of undergraduates like BSc and BS in Life Sciences and Applied Sciences, as well as MS programs in addition to medical graduate students, pharmaceutical, and biomedical R&D sector, including pharmaceutical and biotechnology industry. Postgraduate courses specializing in pharmacy, biotechnology, biomedical sciences, medicinal chemistry, and biology will also be benefitted from its contents. Students and faculty members from postgraduate courses viz. MPharm, MS Biotechnology, MS Biomedical Engineering, MSc Biotechnology, MBBS, MSc Chemistry/Organic Chemistry/Medicinal Chemistry, etc., undergraduate courses viz. BPharm, BSc, BTech in Biochemical/Biomedical Engineering, BS Biotechnology, etc., and research fellows working in these areas will be specifically benefitted from this book.

Editors

Jitender Madan, PhD

Ashish Baldi, PhD

Monika Chaudhary, PhD

Neetu Chopra, PhD

Acknowledgment

To our family and friends for their consistent support and encouragement for editing this book.

Chapter 1: Drug delivery: The conceptual perspectives and therapeutic applications

Pawan Dewangan ¹ , Atul Mourya ¹ , Pankaj Kumar Singh ¹ , Monika Chaudhary ² , Rahul Sharma ³ , Neha Bajwa ⁴ , Ashish Baldi ⁴ , Kamlinder Kaur Singh ⁵ , Shashi Bala Singh ⁶ , Jitender Madan ¹ , and Kamta Prasad Namdeo ⁷       ¹ Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India      ² Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India      ³ Hindu College of Pharmacy, Sonepat, Haryana, India      ⁴ Pharma Innovation Lab, Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India      ⁵ School of Pharmacy and Biomedical Sciences, Central University of Lancashire, Preston, United Kingdom      ⁶ Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India      ⁷ Department of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur, India

Abstract

Poor pharmacokinetic and biopharmaceutical properties are the biggest challenges for newly discovered chemical entities as well as for existing therapeutic molecules. Although conventional formulation development remains a primary strategy for pharmaceutical industries due to its ease of manufacturing. However, these are associated with active pharmaceutical ingredient (API) access to nontargeted tissue/cells, metabolic inactivation, reticuloendothelial system (RES) uptake, low permeability, and bioavailability leading to lower therapeutic efficacy with increased chances of toxicity. In order to counteract such complications related to APIs, there is an urgent need to develop an appropriate drug delivery system that dispenses therapeutic molecules into a specific tissue or organ without any interactions with normal tissue or organs. Targeting is generally achieved via active or passive mechanisms. In passive targeting, the carrier system prolongs residence time and leads to higher bioavailability, whereas active targeting involves the selective binding of drug molecules to receptors of the targeted sites. The targeted drug delivery system is mostly applied for the treatment of cancer, parasite, neurodegenerative, cardiovascular, or infectious diseases. This chapter primarily emphasizes the mechanism and significance of active or passive targeting approaches in drug delivery with their salient features and fundamentals through different routes of administration.

Keywords

Active targeting; Bioavailability; Drug delivery; Passive targeting; Route of administration

1. Introduction

Drug delivery is described as the method or route of administration of active pharmaceutical ingredients to achieve desired therapeutic action with a minimum side effect. Any formulation or device which delivers therapeutic molecule at the specific site of the body concerning spatial and temporal is known as a drug delivery system (DDS) [1]. Drug delivery system is a diverse field that can be categorized based on the route of administration, dosage form, release profile, etc. Conventional drug delivery systems are unable to show the spatial and temporal release of therapeutic agents. Therefore, novel drug delivery systems are being explored to overcome the drawbacks of conventional delivery systems. Apart from this, they offer other advantages such as improved biological stability, controlled release, and targeted delivery [2].

In 1907, German physician Paul Ehrlich developed the concept of a magic bullet. According to him, magic bullets are comprised of two components, one of which should be able to recognize and bind the intended site, while the second should have a therapeutic effect on the target site. Despite exhaustive understanding and development of drug delivery systems to mimic the magic bullets, their applications are always challenged in the market. Targeted drug delivery systems (TDDSs) are the ones that deliver the therapeutic molecule at the site of action. The primary objective of TDDS is to confine the release of the drug at the site of action while preventing its interaction with normal organs, tissues, or cells [3]. However, only targeting is not sufficient to achieve the requisite clinical benefits as it mainly depends upon the amount of drug available at the site of action [4]. Pharmaceutical drug delivery systems are composed of a predetermined amount of therapeutic molecule along with suitable excipients meant for administration via different routes. Targeting is mainly dependent upon the affinity and sensitivity of functionalized ligand toward specific receptors which represents a particular site of the body (Fig. 1.1). The major limiting parameters observed in the formulation of TDDS are as follows [5]:

a. To find out specific target site for treatment of a particular disease

b. To identify the therapeutic agents that effectively treat disease

c. To ascertain an appropriate stable carrier exhibiting target selectivity and biocompatibility.

2. Basic fundamentals of targeted drug delivery systems

2.1. Receptors on the cell membrane

Receptors are a special type of protein situated on the surface of the cell membrane. It has been proven that cell surface receptors are prominent ports that can be successfully used to deliver the drugs, oligonucleotides, or genes to specific tissues or organs. The overexpression of particular receptors is observed in disease conditions that can be exploited to develop a targeted drug delivery with a receptor-specific ligand either attached to a drug molecule or surface engineered onto the surface of vesicular or polymeric drug delivery systems. As a result, this tailored drug delivery system penetrates the designated cell and enters the cell via receptor-mediated endocytosis, demonstrating focused effectiveness with decreased toxicity. Folate, transferrin (Tf), epidermal growth factor (EGFR), fibroblast growth factor, alpha2A-adrenergic, insulin, glucagon-like peptide-1, PPARγ, PPARα, retinoid X receptor [6], etc., are examples of overexpressed receptors in various diseases [7].

Figure 1.1  Rational of targeted drug delivery system.

2.2. Ligands as targeting tools

The identification of a carrier target is required for ligand-mediated targeting. Ligand is a specific molecule that can help to recognize, deliver a drug-loaded carrier, or conjugated drug to its predetermined receptor site. This ligand serves to interact with their specific receptor located on the cell surface. Hence, these ligands are covalently or noncovalently functionalized with therapeutic molecule–loaded nanocarriers. In this manner, exogenous or endogenous ligands exhibit the prominent potential to enhance the potency and selectivity of drug molecules toward the targeted tissue or cell. Folates, aptamers, lectins, Tf, lactoferrin, mannose derivatives, monoclonal antibodies (mAs), antibody derivatives, etc., are examples of ligands employed in targeted drug delivery systems [8].

2.3. Intracellular processing of targeted drug delivery system

Intracellular transport across various receptor–ligand systems and cell types varies noticeably following the receptor-mediated endocytosis and transcytosis. This decides the destiny of drug carrier systems for selective intracellular uptake mechanism. At the next stage, the ligand–receptor is simultaneously separated leading to the movement toward the plasma membrane followed by the development of endosomes. Receptors undergo at least one of the following pathways:

a) Receptors can revert to the surface of the plasma membrane, releasing the ligand for lysosomal metabolism.

b) Receptors can travel to lysosomes along with bound ligands to share the fate of the ligand (lysosomal disposition).

c) Receptors can be recycled along with the ligand back to the site from where the receptor originated.

d) Receptors can return to a different domain of the plasma membrane (transcytosis) [9].

In most the cases, the acidic environment of the endosome encourages the dissociation of ligand from its receptors and grounds it to end up in the lysosomal disposition. Finally, the receptors are returned to the cell surface for reutilization via transport vesicles.

2.4. The epithelial membrane: A potential barrier to targeted drug delivery system

The cellular uptake process of a drug or nanocarrier system involves a highly perforated membrane with specific biomolecular interaction to overcome cell membrane permeability (Fig. 1.2). Therapeutic molecules having low molecular weight can easily flow through the biological membrane by a simple diffusion process, whereas high molecular weight compounds or surface-engineered drug delivery systems cannot easily permeate the membrane due to their bulkiness. Therefore, it utilizes the presence of receptors on the cell membrane to achieve entry into the cell using another cellular process such as receptor-mediated transport, endocytosis, etc. [10]. The process of endocytosis can be further distinguished as phagocytosis and pinocytosis. Furthermore, the lysosomal membrane may serve as a potential barrier for biological ligands and/or surface-engineered carrier systems. Hence, ligands having low molecular weight are transported into the cytoplasm produced by lysosomal degradation. This lysosomal barrier uses substrate-specific transporters for the efflux of end-products of lysosomal degradation.

2.5. Significance of targeted drug delivery system

a) The efficacy of targeted drug delivery systems is better as compared to the conventional delivery system because drug molecules reach a higher concentration at the targeted site, rather than dispersed in the whole-body system [11].

Figure 1.2  Cellular event involved in targeting.

b) The primary benefit of a targeted drug delivery system is drug safety; it does not show any adverse effects [12].

c) Targeted drug delivery exhibits higher patient compliance as well as acceptability due to its relative safety and efficacy.

d) A targeted drug delivery system is realized as a low-cost strategy for the treatment of chronic illness or disorders.

3. Passive targeting

Passive targeting is the targeting of tissues or cells with the help of the circulatory system which is primarily achieved by the body's natural reaction or physicochemical features of the drug and drug delivery system (Fig. 1.3). The word 'passive' refers to features of the drug delivery carrier system such as size, circulation time, and tumor biology such as vasculature, leakiness, and so on but does not have a ligand for the particular tissue or organ interaction. The basic mechanism underlying passive targeting is accumulation of drug or drug carriers at the target site, and prolonging the half-life of the drug in the systemic circulation. The capacity of some colloids or vesicles is engulfed by RES via the liver or spleen, so therefore it can be made with an ideal or suitable vector for passive targeting of a drug at the specific site of the body [13].

Passive targeting of the drug delivery system primarily depends on the improved impact of permeability and retention (EPR) or retention of therapeutic molecules or drug carriers at the target site as a result of inadequate lymphatic drainage. The improved penetration and retention are mainly accountable for the deposition of the drug with the carrier in a specific targeted site at higher concentration because of microenvironmental changes of the normal tissues or targeted tissue known as passive targeting. The phenomenon where drug molecules are permeated by leaky vasculature or accumulated in the surrounding of tumors is called EPR effects [14]. These targeting approaches are especially concerned with drug molecules that stay in systemic circulation for a short period. It is also called physical targeting because the drug is delivered with the help of some specific carrier and it can restrict the body by normal functions like metabolic process, excretion, phagocytosis, and opsonization. Therefore, the pegylation technique [15] can be used to achieve passive targeting. Pegylation involves surface modification of the delivery system using polyethylene glycol (PEG) to suppress the opsonization mechanism. The most commonly used coupling agent is PEG because it creates a hydrophilic surface that facilitates the long circulation of the nanocarrier system. In some pathological conditions, such as tumor cells, inflammation, or infracts, the permeability of the surrounding tissue increased, resulting in leaky vasculature. In this highly permeable area of tissue, a nanodrug delivery system such as nanoparticles, niosomes, liposomes, micelles, or polymeric nanoparticles may be deposited in higher concentrations and provide better therapeutic action [16]. Doxil is a commercially available medicine that combines doxorubicin active pharmacological components with PEG surface–coated liposomes to treat Kaposi's sarcoma, ovarian cancer, and multiple myeloma. It is an example of passive targeting, which works on the mechanism of the EPR effect [17].

Figure 1.3  Schematic representation of active and passive targeting mechanism.

Passive targeting approaches are based on the EPR effect; EPR effect is a unique phenomenon of tumor tissue associated with their pathophysiological alteration from normal tissues. The EPR has the properties to cross the specific size of particles about 20–200 nm by leaky vasculature of tissue in the targeted site. The tissue of the tumor is heterogeneous distribution, larger in pores size and highly permeable properties than the vasculature present in normal tissues. EPR effect is predominantly utilized for passive targeting of drug molecules of molecular weight more than 40 kDa. Encapsulation of low molecular weight drugs in carriers like liposomes, nanoparticles, and polymeric micelles has made tumor-specific passive targeting efficient. The targeted drug delivery system should have a longer circulation time. Various factors influence the EPR effect, such as the size of the tumor, degree of the vasculature, and properties of the drug carrier system, which can be considered while designing a specific drug carrier system to avoid the EPR effect. The EPR effect is mainly determined by tumor biological properties like degree of perivascular tumors growth, degree of angiogenesis and lymph angiogenesis, and nature of the tumor. Therefore, drug delivery efficiency is dependent upon all these factors and the physicochemical characteristics of drug carriers. Although leakiness formed in tumor vessels affects the nanoparticles permeability, high interstitial pressure in the circulatory system restricts the accumulation of drug molecules with a carrier in the targeted site [18].

The EPR effect can be modulated mechanically or chemically to get the vasculature normalization to achieve a higher concentration of drug carrier. The EPR enhancer could be achieved chemically by nitric oxide, peroxynitrite, bradykinin, and cytokines. This type of chemical molecules temporarily enhanced the tumor perfusion and normalized the vasculature pores to achieve passive targeting. Many techniques such as radiation, hyperthermia, photo-immunotherapy, and ultrasound could be used to increase the tissue vasculature to enhance the permeability of nanocarriers [19]. To increase blood flow, the EPR effect optimizes deep tissue penetration and modifies some specific physiological modulators. Surface functionalization and outer charge of carrier play a crucial role in carrier circulation. Hydrophobic or charged particles are typically opsonized in an RES system, resulting in a water-like surface hydrophilic with a neutral or slightly charged carrier. Pegylation is mostly used for attraction or nonspecific interaction by changing the surface charge and decorating the outer surface of the drug carrier system [20].

Madan and colleagues developed noscapine solid lipid nanoparticles for very efficient targeting of glioblastoma cells present in the brain. To enhance the biological shelf life of noscapine, it was coupled with a poly(ethylene)-glycol solid lipid nanoparticle carrier, and finally, they enhanced plasma half-life 11-fold by encapsulating noscapine in solid lipid nanoparticles. Noscapine was entrapped into the core of solid lipid nanoparticles, which prevents ionization of noscapine; due to the lipidic nature of the core, it also shows a controlled release of drug and accumulation into the tumor site with improved therapeutic efficacy of a drug. Development of surface-engineered solid lipid nanoparticles with poly(ethylene)-glycol along with the lipophilic nature of lipids is eventually responsible for greater retention of the encapsulated therapeutic entity in brain tissue [21,22].

3.1. Novel carrier characteristics affect the passive approaches

Various characteristics of a carrier affect the EPR-based targeting such as the size of particles or globules, shape of carriers, outer surface of the carrier, and circulation time of carrier in the circulating system. The size, shape, surface property, and polymer composition are four critical characteristics for the efficient design of nanocarriers for targeted drug delivery [23].

The diameter and size of nanocarriers are mostly important for permeation and retention in the tumor cells and it is a specific parameter for the fenestration of tumor cell vessels. The optimum size of nanoparticles around 20–200 nm range is suitable for targeted drug delivery system. Development of pegylated and surface engineered carrier system can be employed to accomplish passive targeting while also restricting the drug's quick elimination or RES uptake [24]. The particle size of nanocarriers is important for permeation and retention in the tumor cell via passive targeting. Tumor cells take up a different size of particles than healthy normal cells due to the confluence of leaky tumor vasculature and imprecise particle screening, such as phagocytic cell uptake of large carriers, whereas the nonphagocytic cell ingests carriers of small size. Pegylated nanocarriers diminish the plasma adsorption or hepatocellular filtration because their size is smaller than 100 nm [15].

The surface charge of nanocarriers also plays a significant part in passive targeting during blood circulation and cellular internalization. Most of the time, negative charge of the nanocarrier has a circular longer period in the circulatory system, while positive surface nanocarriers are more rapidly taken up by tumor cells because of the negative surface charge of tumors cells [25].

Carrier shape is an important parameter that shows an impact on in vivo performance of nano-particles by changing their cellular uptake, the biodistribution of particles, and cellular function. Spherical particles of diameter less the 200 nm are passed through the spleen, but disk-shaped particles of diameter about 10 um are routinely passed through the spleen as well as the liver, while nonspherical particles have areas of different thickness which can be unique degradation profiles [26]. Li and colleagues compared the effect of different shapes of pegylated nanoparticles in cellular uptake of targeted drug delivery such as a sphere, rod, cube, and disk. They find out that spherical-shaped nanocarriers exhibit the quickest cellular internalization and uptake, trailed by cubic-shaped nanocarrier, then rod and disk-shaped nanocarriers. The possible reasons behind the enhanced uptake of spherical-shaped nanocarrier can be substantial membrane deformation responsible for a large free energy barrier of the membrane [27].

4. Active targeting

Active targeting is defined as more accumulation of drug carrier in the target site as compared to free drugs. In active targeting, mostly nanocarriers are decorated with specific types of ligands, which bind to the particular receptors that are overexpressed on the cell surface. A major factor behind the delivery of drugs through passive targeting is affinity or binding of ligand toward the receptors; the drug-loaded carriers are bound to the receptor by endocytosis mechanism and leave the drug inside of the cells; this process is proportionate to the number of receptors present on the cell membrane or affinity of carrier molecule with the receptor site [11]. The active target is mainly used for tumor targeting because of the tumor cell surface; many receptors are overexpressed such as folate receptor [28], integrins, Tf [29], epidermal growth factor [30], fibroblast growth factors receptors [31], G protein-coupled receptors, etc.

Active targeting is a type of ligand–receptor interaction (Fig. 1.3), which occurred after binding of ligand toward specific receptors and completed extravasation process of carriers. It is mainly dependent upon the ligands which are attached to carriers or systems. Hence, various types of cross-linking can be used to achieve the active targeting approach such as protein, nucleic acid, oligonucleotides, small molecules (folic acid, carbohydrates), antibody peptides, lipoproteins, and polysaccharides [32]. Ligands are endogenous proteins that have the property of binding to specific receptors. The ligand on the surface of modified carriers exhibits binding affinity for the particular receptor. The ligands for active targeting are screened after a thorough study of receptors overexpressed on the selected target site. Nowadays, antigen fragments of antibodies are explored as a ligand for various tumor cells targeting. This includes antigen-binding fragments (Fab) and single-chain variable fragments (scFv). Various peptide ligands include cell-permeable peptides such as TAT peptides and RGD peptides expressed in tumor cells.

The active targeting approach is predominant because many of the receptors are expressed in tumor cells and can be targeted using mAs. Currently, multiple mA-based products are available in the market to limit the growth or kill the various malignant cells. For example, Rituxan is an mA used for the treatment of non-Hodgkin's lymphoma and trastuzumab (Herceptin) anti-HER2 which primarily binds to ErbB2 receptors overexpressed in breast cancer [33].

The vascular endothelium found on tumor cells is a promising strategy that can be easily targeted, as it differs in anatomy from normal tissue. Overexpressed receptors on the cell surface, such as folate receptors, LDL receptors, gonadotropin receptors, and luteinizing releasing hormone receptors, provide several sites for ligand binding [34]. The primary effect of active targeting is the alteration in the natural distribution of nanocarriers, which allows targeting of a particular organ, cell, or organelle. In contrast, passive targeting primarily depends upon physiological parameters such as EPR and blood circulation [35].

4.1. Ideal characteristic for active targeting

a) Nanocarriers have the potential to reach cancer cells or tumors.

b) The nanocarrier should have higher penetration ability at the cellular level in cancer cells.

c) Active targeting is achieved by the cellular endocytosis mechanism of a specific target site of tumor cells.

d) The drug must be reached at the target site at a therapeutic concentration in the cytosol of all target cells to achieve the therapeutic activity.

e) It must have the property to overcome multidrug resistance.

f) It must have an appropriate architecture and structure to deliver or protect entrapped drug molecules.

g) The carrier or ligand employed in the development of targeted drug delivery systems should not exhibit any kind of toxicity or undesirable effects [11].

4.2. Different levels of active targeting

The active drug targeting approaches can be classified into four different levels of targeting (Fig. 1.4).

Figure 1.4  Different levels of active targeting (A) organ level targeting—liver (B) cellular level targeting—cell (C) intracellular level targeting—mitochondria (D) intracellular level targeting—DNA and RNA.

4.2.1. First-order targeting

In first-order targeting, the drug nanocarrier is forbidden to be used or distributed to the bottom of the capillaries at the target site of an organ or tissue that is known as organ-level targeting (Fig. 1.4). It mainly involves targeting the drug carrier system that reaches a specific type of organs or tissues such as the eye, lung, liver, joints, cerebral ventricle, peritoneal cavity or lymphatic cavity, etc. In order to deliver the drug to closed arteries, the catheter-based delivery system can be employed. It involves the application of drug-eluting stents or inoculation of drug carriers into the specific peritoneal cavity or target site. Therefore, a novel vesicle system can be used to increase access to the organ affected by any disease by administering intravenous injections. The carrier is conjugated with ligands or peptides such as human serum albumin and lipoproteins, which have the potential to increase organ-specific potency. The nanocarrier has a size of about 80 nm and can reach specific organs such as the brain, kidney, and liver by intravenous injection [36].

First-order targeting is specially related to a specific organ of the body. Ghalehkhondabi and colleagues developed silibinin-encapsulated nano micelles, which effective for drug delivery in liver cancer. Silibinin was conjugated with folic acid and pluronic acid; it was encapsulated in the hydrophobic portion of the self-assembled pluronic acid nanomicelles to improve the targeting ability as well as therapeutic efficiency of silibinin against hepatic cancer. Cytotoxicity study revealed that nanomicelles containing drugs enhance the cytotoxic activity of the drug as compared to free drugs against hepatic cancer cells. The developed silibinin loaded pluronic conjugated with folic acid showed higher potential and serve as a platform for active drug delivery toward folate receptors, which overexpress in hepatocellular carcinoma [37].

4.2.2. Second-order targeting

Second-order targeting is mainly targeted at a cellular level although it refers to the targeting of drug nanocarrier