Novel Drug Delivery Systems E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
This book serves as a unique resource on the field of novel drug delivery systems (NDDSs), catering to both academic audiences (researchers, teachers, students) and industry professionals (pharmaceutical policymakers, managers, R&D, regulatory, business development, and marketing) involved in NDDSs.
The evolving nature of diseases and the emergence of new health complications have driven a significant shift in drug therapy. Coupled with changes in human lifestyles and economic conditions, these factors have compelled the pharmaceutical industry to develop novel, efficient, and affordable drug products. The rise of promising technologies aimed at enhancing therapeutic performance further underscores the importance of novel drug delivery systems (NDDSs), making this field one of the most dynamic in pharmaceutical sciences today.
This book offers a comprehensive exploration of NDDS applications, catering to both academic and industry professionals. It is designed to be both user-friendly and thorough, meeting the needs of diverse readers—from those seeking practical insights to those delving deeply into the field’s various sectors. The content has been meticulously compiled, organized, and analyzed by a team of experts to ensure accuracy, relevance, and currency. The book provides up-to-date information suitable for a broad audience, reflecting the wide scope of the NDDS field.
The first section covers the foundational principles of NDDS, including their scientific and therapeutic basis, as well as the epidemiological and economic trends driving their development. Subsequent sections explore market-oriented aspects, such as global trends and projections. Chapters 3 to 12 present a taxonomy of NDDS categorized by their routes of administration. The book concludes with a forward-looking report on the potential future directions of NDDS.
Written in clear, concise language, the book is accessible to non-native English readers, ensuring broad usability. Original figures, created by experts with scientific and graphic design expertise, enhance the reading experience and aid in understanding complex concepts.
Audience
A wide variety of professional readers from universities and other research institutions to health industries (industrial pharmaceutical and related), to the relevant high-tech startups to health and pharma policymakers and managers will be among the audiences of this book.
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Veröffentlichungsjahr: 2024
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Table of Contents
Cover
Table of Contents
Series Page
Title Page
Copyright Page
Preface
1 Introduction to Novel Drug Delivery Systems
1.1 Historical Background
1.2 Definition, Terminology, and Taxonomy
1.3 Novel Drug Delivery Systems: Why, How, and What to Deliver?
References
2 Novel Drug Delivery Systems: Approach to the Market
2.1 Introduction
2.2 Novel Drug Delivery Systems Global Market
2.3 Emerging Diseases, Emerging Technologies
2.4 New Development Areas
References
3 Intraoral Novel Drug Delivery Systems
3.1 Introduction
3.2 Anatomy and Physiology
3.3 Factors Affecting Intraoral Drug Delivery
3.4 Challenges and Opportunities
3.5 Classification and Formulation Considerations
3.6 Pharmacokinetics
3.7 Products in the Market
References
4 Oral Novel Drug Delivery Systems
4.1 Introduction
4.2 Anatomy and Physiology of Gastrointestinal Tract
4.3 Barriers to Oral Drug Delivery
4.4 Factors Affecting Oral Drug Delivery
4.5 Challenges and Opportunities of Oral Drug Delivery
4.6 Classification of Oral Novel Drug Delivery Systems
4.7 Pharmacokinetics
4.8 Products in the Market
References
5 Rectal Novel Drug Delivery Systems
5.1 Introduction
5.2 Anatomy and Physiology
5.3 Barriers to Rectal Drug Delivery
5.4 Factors Affecting Rectal Drug Delivery
5.5 Formulation Considerations
5.6 Challenges and Opportunities of Rectal Drug Delivery
5.7 Classification of Rectal Novel Drug Delivery Systems
5.8 Pharmacokinetics
5.9 Products in the Market
References
6 Injectable Novel Drug Delivery Systems
6.1 Introduction
6.2 Anatomy and Physiology
6.3 Parenteral Administration Routes
6.4 Classification
6.5 Formulation Considerations
6.6 Pharmacokinetics
6.7 Products in the Market
References
7 Implantable Drug Delivery Systems
7.1 Introduction
7.2 Anatomy and Physiology
7.3 Classification and Formulation Considerations
7.4 Challenges and Opportunities
7.5 Pharmacokinetics
7.6 Products in the Market
References
8 Inhalable Novel Drug Delivery Systems
8.1 Introduction
8.2 Anatomy and Physiology
8.3 Factors Affecting Pulmonary Drug Delivery
8.4 Challenges and Opportunities
8.5 Classification and Formulation Considerations
8.6 Pharmacokinetics
8.7 Products in the Market
References
9 Intranasal Novel Drug Delivery Systems
9.1 Introduction
9.2 Anatomy and Physiology
9.3 Factors Affecting Intranasal Drug Delivery
9.4 Challenges and Opportunities
9.5 Classification and Formulation Considerations
9.6 Pharmacokinetics
9.7 Products in the Market
References
10 Dermal and Transdermal Novel Drug Delivery Systems
10.1 Introduction
10.2 Anatomy and Physiology
10.3 Barriers to Transdermal Drug Delivery
10.4 Factors Affecting Dermal/Transdermal Drug Delivery
10.5 Challenges and Opportunities
10.6 Classification and Formulation Considerations
10.7 Pharmacokinetics
10.8 Products in the Market
References
11 Ocular Novel Drug Delivery Systems
11.1 Introduction
11.2 Anatomy and Physiology
11.3 Barriers to Ocular Drug Delivery
11.4 Challenges and Opportunities
11.5 Formulation Considerations
11.6 Classification
11.7 Pharmacokinetics
11.8 Products in the Market
References
12 Vaginal Novel Drug Delivery Systems
12.1 Introduction
12.2 Anatomy and Physiology
12.3 Barriers to Vaginal Drug Delivery
12.4 Formulation Considerations
12.5 Classification
12.6 Pharmacokinetics
12.7 Products in the Market
References
13 Future of Novel Drug Delivery Systems
13.1 Introduction
13.2 Drug Delivery Challenges to be Overcome in the Future
13.3 Drug Delivery Opportunities to be Seized in the Future
13.4 Concluding Remarks
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 List of internationally marketed nanomedicines approved by the FDA a...
Table 2.2 Nano-formulated cancer therapeutics currently in the market [16].
Chapter 3
Table 3.1 Some commercial intraoral products.
Chapter 4
Table 4.1 Some commercialized oral novel drug delivery systems.
Chapter 5
Table 5.1 Formulation considerations of rectal dosage forms.
Table 5.2 Nano-based rectal novel drug delivery systems with completed clinica...
Chapter 6
Table 6.1 IV administration route considerations.
Table 6.2 Some micro- and nanocarriers investigated in research for parenteral...
Table 6.3 List of some novel parenteral drug delivery systems in the market.
Chapter 7
Table 7.1 Some commercialized polymeric implantable systems.
Table 7.2 Commercially available and under clinical trial osmotic implantable ...
Table 7.3 Classification and characterization of mechanical and non-mechanical...
Table 7.4 Some of FDA FDA-approved implantable drug delivery systems.
Chapter 8
Table 8.1 Novel inhalable DDS in the market.
Chapter 9
Table 9.1 Nasal mucosa enzymes.
Table 9.2 Nasal immunological agents.
Table 9.3 Different target sites and purposes pursued by intranasal drug deliv...
Table 9.4 Description of different pharmacokinetic parameters for nose-to-brai...
Table 9.5 A summarized list of commercialized products for intranasal administ...
Chapter 10
Table 10.1 List of some of dermal and transdermal products.
Chapter 11
Table 11.1 List of some novel ocular products in the market.
Chapter 12
Table 12.1 List of some marketed vaginal novel drug delivery systems.
List of Illustrations
Chapter 1
Figure 1.1 A summary of different classification systems for NDDSs.
Figure 1.2 Some types of NDDSs.
Figure 1.3 The steps of drug disposition in the body known by the acronym “LAD...
Figure 1.4 Plasma drug concentration-time curves of systems with different rel...
Figure 1.5 By affecting which phase of LADME, NDDSs improve pharmacokinetics? ...
Figure 1.6 Drug delivery barriers [9, 34, 52, 75].
Figure 1.7 Considerations to be observed for designing controlled-release drug...
Figure 1.8 How prodrugs improve therapeutic efficiency of drugs.
Figure 1.9 Considerations to be observed in design of nanocarriers.
Chapter 2
Figure 2.1 Global healthcare expenditure per capita in 2019 and projection in ...
Figure 2.2 Global medical spending (2019-2025), current and pre-COVID-19 outlo...
Figure 2.3 Total and segmental difference in medical spending (2019–2025) [2].
Figure 2.4 Per capita use of medicines varies by national income. The drug use...
Figure 2.5 Value added medicines global market 2019, by route of administratio...
Figure 2.6 Value-added injectables global market trend (2014-2019) [5].
Figure 2.7 5Y VAM injectables contribution to positive growth (2014-2019), LCU...
Figure 2.8 Value-added medicines global market size, by geographical segmentat...
Figure 2.9 Therapeutic areas dynamics [5].
Figure 2.10 Globally marketed nanomedicines by therapeutic area [17].
Figure 2.11 Selected benefits demonstrated by value added medicines [5].
Figure 2.12 New development areas in drug delivery systems.
Chapter 3
Figure 3.1 Intraoral cavity; (a) boundaries of the oral cavity (lips from the ...
Figure 3.2 Different types of oral mucosa (created with BioRender.com).
Figure 3.3 Challenges and opportunities of intraoral drug delivery.
Figure 3.4 Classification of intraoral drug delivery systems.
Figure 3.5 Different fates of intraoral nanoparticles (pink circles) containin...
Chapter 4
Figure 4.1 How the share of drugs belonging to each class of BCS is changing.
Figure 4.2 A scheme of the main and accessory organs of the human digestive sy...
Figure 4.3 Key structural features of the small intestine (created with BioRen...
Figure 4.4 Main bioavailability barriers to oral drug delivery (created with B...
Figure 4.5 Intestinal drug absorption pathways (created with BioRender.com).
Figure 4.6 Classification of drugs based on biopharmaceutics classification sy...
Figure 4.7 Common approaches to improve oral absorption of drugs belonging to ...
Figure 4.8 Considerations to be observed in designing of nanocarriers.
Figure 4.9 Corresponding challenges and opportunities of each organ for oral d...
Figure 4.10 Schematic illustration of EsoCap system; structural design, how to...
Figure 4.11 Schematic illustration of the raft (floating
in-situ
gel) forming ...
Figure 4.12 Examples of expandable systems’ geometries (based on [83, 84]) (cr...
Figure 4.13 A schematic illustration of a magnetic field-assisted system (crea...
Figure 4.14 Some lipid/surfactant-based nanocarriers used in oral drug deliver...
Figure 4.15 Some polymer-based nanocarriers used in oral drug delivery (create...
Figure 4.16 How do nanocrystals improve drug absorption? (created with BioRend...
Figure 4.17 Comparative plasma concentration-time curves of a model drug admin...
Figure 4.18 Why oral bioavailability is generally lower than 1? (created with ...
Figure 4.19 Schematic plasma concentration-time curves of different single-dos...
Chapter 5
Figure 5.1 Anatomy of the rectum as well as its venous and lymphatic drainage.
Figure 5.2 Factors affecting rectal delivery of nanocarriers.
Figure 5.3 Challenges and opportunities of the rectal drug delivery.
Figure 5.4 Classification of rectal novel drug delivery systems.
Figure 5.5 Drug absorption from a drug-suspended suppository in rectal area.
Figure 5.6 Anatomy of rectum and drug distribution in this part (created with ...
Chapter 6
Figure 6.1 Scheme of skin layers and different sites of parenteral administrat...
Figure 6.2 Some considerations for developing a new pharmaceutical dosage form...
Figure 6.3 The classification of injectable drug delivery systems.
Figure 6.4 Various pharmacokinetic profiles upon parenteral administration as ...
Chapter 7
Figure 7.1 Different implantation sites of drug delivery systems (created with...
Figure 7.2 Cross-section of the spinal cord.
Figure 7.3 Vaginal wall constituents.
Figure 7.4 Anatomy of the eye (created with BioRender.com).
Figure 7.5 Formulation factors that affect drug release from polymeric systems...
Figure 7.6 A schemeatic illustration of an osmotic pump.
Figure 7.7 Examples of two-compartment osmotic pumps.
Figure 7.8 A schematic illustration of multi-compartment Rose-Nelson osmotic p...
Figure 7.9 Infusion pump based on pressurized gas.
Figure 7.10 A schematic illustration of a peristaltic pump.
Figure 7.11 A schematic representation of SynchroMed II.
Figure 7.12 A schematic illustration of a microchip.
Figure 7.13 Challenges and opportunities of implantable drug delivery.
Chapter 8
Figure 8.1 Anatomy of the respiratory system (Created with BioRender.com).
Figure 8.2 (a) Functional division of respiratory system, (b) anatomy of the c...
Figure 8.3 Mechanisms of particles deposition in the lung (created with BioRen...
Figure 8.4 Opportunities of the respiratory tract in the development of inhala...
Figure 8.5 Pulmonary drug delivery challenges and strategies to overcome.
Figure 8.6 Schematic diagram of different devices for inhalation drug delivery...
Figure 8.7 DPI formulations (including trojan particles and strawberry particl...
Figure 8.8 A schematic representation of PRINT technology to prepare particles...
Chapter 9
Figure 9.1 Anatomy of the nose; (a) The nose bony framework and pyriform apert...
Figure 9.2 (a) Bony and cartilage structure of the nose; (b) Lateral view of t...
Figure 9.3 Factors affecting intranasal drug delivery.
Figure 9.4 General anatomy of the internal nose from front and sided view (Cre...
Figure 9.5 Opportunities, challenges and their corresponding solutions for int...
Figure 9.6 Appropriate nanocarriers for intranasal drug delivery.
Chapter 10
Figure 10.1 Schematic structure of the human skin (created with BioRender.com)...
Figure 10.2 Schematic illustration of available pathways for a drug to cross t...
Figure 10.3 Ideal physicochemical characteristics of a drug molecule to pass t...
Figure 10.4 Challenges and opportunities of (trans)dermal drug delivery.
Figure 10.5 Different approaches, strategies and systems to improve drug deliv...
Figure 10.6 Mechanism of iontophoresis to improve skin absorption of drugs (cr...
Figure 10.7 Mechanism of electroporation to improve skin absorption of drugs (...
Figure 10.8 Mechanism of sonophoresis to improve skin absorption of drugs (cre...
Figure 10.9 Mechanism of fractional ablative laser technology to improve skin ...
Figure 10.10 Mechanism of jet injection to improve skin absorption of drugs (c...
Figure 10.11 Schematic structure of different types of liposomes (created with...
Figure 10.12 Comparative permeation of liposomes, ethosomes, transfersomes, tr...
Figure 10.13 Schematic structure of SLN, NLC, and nanoemulsion (created with B...
Figure 10.14 Schematic structures of nanocapsules, nanospheres and polymeric m...
Figure 10.15 Different types of microneedles (created with BioRender.com).
Figure 10.16 (a) Different types of transdermal patches; (b) examples of trans...
Figure 10.17 Techniques to assess topical bioavailability of drugs (date obtai...
Figure 10.18 Schematic illustration of tape stripping technique (see the text ...
Figure 10.19 Schematic illustration of skin microdialysis technique (created w...
Figure 10.20 Schematic illustration of dermal open-flow microperfusion (dOFM) ...
Figure 10.21 Vasoconstriction technique (created with BioRender.com).
Figure 10.22 The stepwise process of percutaneous drug absorption (data obtain...
Figure 10.23 The flux across the skin from a transdermal formulation. The equa...
Figure 10.24 A typical plot obtained from skin absorption studies (lag-time is...
Chapter 11
Figure 11.1 Anatomy of the eye (created with BioRender.com).
Figure 11.2 Classification of ocular drug delivery barriers.
Figure 11.3 The main anatomical barriers to ocular drug delivery (created with...
Figure 11.4 Challenges and opportunities of ocular drug delivery.
Figure 11.5 Ocular pharmacokinetics.
Chapter 12
Figure 12.1 (a) Anatomy of vagina; (b) different layers of the vagina (created...
Figure 12.2 Classification of vaginal drug delivery systems.
Guide
Cover Page
Table of Contents
Series Page
Title Page
Copyright Page
Preface
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Scrivener Publishing100 Cummings Center, Suite 541JBeverly, MA 01915-6106
Publishers at ScrivenerMartin Scrivener ([email protected])Phillip Carmical ([email protected])
Novel Drug Delivery Systems
Fundamentals and Applications
Edited by
Mehrdad Hamidi
Pharmaceutical Nanotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
and
Mahsa Sayed Tabatabaei
HIDA Pharmaceutical Technologies Development Center, HIDA Pharmaceuticals, Tehran, Iran
This edition first published 2025 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2025 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-119-85228-5
Cover image: Adobe FireflyCover design by Russell Richardson
Preface
The ever-changing nature of diseases and the emergence of a series of new health complications, whether or not they are classified as diseases, have caused a big paradigm shift in drug therapy. Furthermore, vast changes in human lifestyle and economic situations have forced the pharmaceutical world to explore the development of novel, efficient and affordable drug products. Alternatively, the emergence of promising novel technologies that should improve the therapeutic performance of drugs are also a driving force in the development of new pharmaceuticals with enhanced pharmacokinetic/pharmacodynamics characteristics.
Novel Drug Delivery Systems (NDDSs) are defined as a series of attempts, approaches, scenarios, methods, and systems (e.g., drug carriers) that can deliver active drug molecules intentionally to a desired location with a desired time regimen, i.e., via spatially- and/or temporally-controlled release. In comparison to the discovery and development of new active molecules, new drug delivery systems—categorized in the pharma industry/regulatory as new dosage forms—are a remarkably inexpensive and timesaving process. There is no doubt that in the coming years, NDDSs will become increasingly prominent in different therapy categories, making the field more and more attractive worldwide.
This book presents the most recent updates in the field of NDDSs to a variety of audiences including university professors, students, researchers, policymakers, managers, industrial pharmacists, and even drug prescribers. It provides a cooperative space for more serious consideration of this relatively new class of pharmaceuticals and explores how these systems offer the safer, more efficacious, and more feasible management of emerging diseases.
The first section of the book is devoted to the general principles underlying the NDDSs, including the scientific and therapeutic basis of these systems, as well as epidemiologic and economic trends behind the development of NDDSs. It then discusses the market-oriented aspects of NDDSs including the major trends, events, and projections of NDDSs in the global market. In chapters 3 to 12, a taxonomy based on the route of entry of NDDSs is presented, which is more attractive and practical for the clinic, pharmaceutical industry, and pharmaceutical market. Finally, the book concludes with a forward-looking report that outlines the probable future directions of NDDSs.
The real futuristic scenarios for the development of NDDSs will depend on different determinants both from the market and technology sides. Nonetheless, the future of NDDSs is very promising and attractive to pharmaceutical companies that will drive the expansion of the current boundaries of the territory of NDDSs.
We hope that you find the resource informational, engaging, and enlightening. Our deepest thanks go out to Martin Scrivener and Scrivener Publishing for their assistance and the publication of this book.
Mehrdad Hamidi and Mahsa Sayed Tabatabaei
October 2024
1Introduction to Novel Drug Delivery Systems
Mehrdad Hamidi1,2*, Mahsa Sayed Tabatabaei2, Mohammad Moslehi3 and Maedeh Barati3
1Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, Iran
2HIDA Pharmaceutical Technologies Development Center, HIDA Pharmaceuticals, Tehran, Iran
3Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract
Conventional drug delivery systems are referred to as classical drug delivery approaches, mainly aimed at immediate drug release for rapid absorption, without making a deliberate attempt to solve the challenges ahead (e.g., repeated dosing, fluctuations, and systemic side effects) or create an added value (e.g., controlling the release rate). Such restrictions opened the arena for Novel Drug Delivery Systems (NDDSs), with major competitive advantages, to be raised. NDDSs is a broad term to describe all the formulations, dosage forms, devices, techniques, technologies, and approaches that are used intentionally to exert temporal and/or spatial control over drug delivery in the host body. It has been decades since the emergence of the NDDS concept and since then, numerous types of NDDSs have been introduced and developed. In this chapter, after a brief review of their historical background, an attempt has been made to present a comprehensive classification of what is known today as NDDSs (mainly including nanocarriers, microcarriers, cell-based carriers, and drug delivery devices). Then, following a Why-How-What Framework, the “Why” of developing NDDSs will first be discussed, looking at the positive impact they can have on each phase of pharmacokinetic phases (LADME: Liberation, Absorption, Distribution, Metabolism, and Excretion). Then, “How” to overcome the biological barriers facing NDDSs to achieve an optimal drug release at the right time in the right place, and the formulation considerations that should be taken into account to achieve this goal will be explained. Finally, “What” therapeutics can be potentially delivered by NDDSs, to combat the diseases, will be addressed.
Keywords: Novel drug delivery systems, controlled release, nanocarriers, pharmacokinetics, drug delivery barriers
1.1 Historical Background
Conventional drug delivery encompasses classical approaches of drug administration that immediately release the drug and increase its plasma concentration, but are incapable of maintaining it in the therapeutic window, therefore, during an exponential decrease, the drug level rapidly enters the sub-therapeutic region [1]. Accordingly, conventional drug delivery faces two major challenges. First, in many cases, such a timeframe is not long enough to create the desired therapeutic effects; so, repeated dosing is inevitable. Second, they generally exhibit fluctuations; that is, they either step beyond the toxic level or fall below the therapeutic limit [2]. Moreover, conventional drug delivery suffers from a lack of target specificity, premature metabolism/excretion, and inadequate bioavailability [1]. These limitations have led to an upsurge of research in the last decades on novel drug delivery systems (generally referred to as NDDSs) to improve the therapeutic efficacy and safety of drugs.
The emergence of NDDSs dates back to the mid-1960s when the idea of “an implanted, zero-order, reservoir drug delivery device” was sparked by Folkman and Long [3]. From then until the late 1970s, the basics of controlled drug delivery namely drug release mechanisms were established. This led to the development of the first generation of NDDSs including once/twice-a-day oral delivery systems and once-a-day/week transdermal patches [4].
In the second generation of NDDSs (from around the 1980s to the 2010s), concepts such as zero-order drug release, smart polymers, and peptide/protein delivery using biodegradable depots attracted more and more attention [4]. Consequently, different zero-order–controlled drug delivery devices (such as ophthalmic inserts, transdermal patches, and osmotic pumps), swelling/gelling hydrogel systems, and polymer matrices for gradual delivery were developed. This period during which macroscopic drug delivery systems were developed is known as the “macro era”. In parallel with these advancements, thanks to the development of biodegradable polymers, macroscopic zero-order systems evolved into microscopic sustained-release ones (the so-called “micro era”) [5].
In the mid to late 1970s, polymer-drug conjugates arose based on three fundamental concepts of PEGylation, active targeting, and passive targeting. Later, the liposomes and polymeric micelles (previously introduced in the 1960s and 1970s, respectively [6]), were PEGylated, thus taking an important step in the field of nanoscale carriers. In the last decade of the second generation, the expansion of nanosystems ushered in a modern age in drug delivery, which was the “nano era” of targeted drug delivery systems [5]. The nanoscopic era brings to life the concept coined by Ehrlich a century ago, called “Magic Bullet” (selective targeting of a pathogen without harming the host organism) [7].
Starting around the 2010s and still ongoing, the third generation of NDDSs covers a wide range of recent developments, including modulated, long-term (6–12 months), self-regulated, and targeted drug delivery systems [5, 7]. Also, today, significant attention has been drawn to biologically precise and controlled delivery systems with more biological and less material-oriented properties—the so-called personalized medicine [8]. The drive to achieve better NDDSs and commercialize them has continued unabated to this day and will continue to do so.
1.2 Definition, Terminology, and Taxonomy
The general term “novel drug delivery systems” is regularly referred to as the approaches, methods, formulations, dosage forms, devices, techniques, and technologies that are, collectively, known as the systems intended to exert some kind of time and/or spatial control on the drug delivery throughout the host body.
Based on the mode of control exerted on the drug release, the technology/approach used, and the route of drug entry to the host body, a series of terms have been used interchangeably to describe the different NDDSs. Although there is no distinct separation between the application of the popular terms used to indicate the different types of NDDSs, some of them are used more frequently for per-oral NDDSs, including sustained-release, extended-release, controlled-release, modified-release, delayed-release, and retard. On the other side, a variety of terms, such as long-acting, prolonged-release, and long-action, have been used in recent years for injectable NDDSs. The important fact behind the application of a variety of attributes to assign to the NDDSs upon being launched to the pharma market is using the opportunity of having a new “surprising” name or, otherwise, attaching a new product to an existing successful product platform already in the market.
Different aspects of NNDSs have been used in an attempt to classify these products, the most popular of which is the route of administration. In Figure 1.1, a summary of different classification systems found in the literature for NDDSs is shown as an infographic. Figure 1.2 illustrates different types of NDDSs.
1.3 Novel Drug Delivery Systems: Why, How, and What to Deliver?
NDDSs undertake an intermediary role between the drug and the patient to not only mitigate the side effects of the pharmaceutical agents but also elicit efficacy, safety, and patient compliance to treatment [9, 10]. NDDSs can be considered from three perspectives. First, “why delivery?” the answer to which, in a word, is to improve the pharmacokinetic and pharmacodynamic profiles of drugs. Second, “how to deliver?” that is, how to overcome biological barriers and, then, attain a desirable drug release at the right timeframe in the right place via optimizing the design of drug carriers; and third, “what to deliver?” which includes the therapeutics that are intended to reach the site of action within the host body to combat the disease state(s) [9]. In the following, an attempt will be made to briefly address these issues.
1.3.1 Why Delivery?
An ideal drug delivery system can not only protect the drug from physical and chemical destabilizing agents but also deliver it to the right place within the right period [9]. The major parameters determining the appropriate dose and administration route of a drug to achieve the desired therapeutic response are a sequence of processes collectively known as the “LADMER” system [11]. It is a six-letter acronym that stands for liberation, absorption, distribution, metabolism, excretion, and response (see Figure 1.3). Obviously, the outcome of a drug undergoing the LADMER system depends on a complex interrelationship network between the drug, drug product, and the host body [12]. Following, it is discussed how NDDSs affect each LADMER process.
1.3.1.1 Liberation
Liberation is the process by which the drug is released from its administered form. Except for intravascular and peroral true solutions, liberation is considered the first step for all drug products with any administration route. Liberation potentially affects the onset of action, absorption rate, and bioavailability and is controlled by the features of the designed delivery system [12]. Conventional drug products follow an immediate-release profile, which generally leads to a quite rapid drug absorption and subsequent rapid onset and termination of the associated pharmacodynamic effects as well as concentration fluctuations. On the contrary, NDDSs aim to deliberately take control of the release to achieve a better therapeutic outcome and/or patient compliance with minimized fluctuations (Figure 1.4). These systems are generally known as the modified-release (or synonymously, controlled-release, sustained-release, extended-release, prolonged-release, and long-acting) products that endeavor to alter the timing of drug release [13]. It is also possible to improve the solubility and dissolution rate of the drug using solubility enhancement methods (e.g., solid dispersions [14], nanocrystals [15], etc.).
Figure 1.1 A summary of different classification systems for NDDSs.
Figure 1.2 Some types of NDDSs.
Figure 1.3 The steps of drug disposition in the body known by the acronym “LADMER” (Created with BioRender.com).
1.3.1.2 Absorption
To attain an adequate blood concentration and eventually the intended pharmacodynamic effect(s), a drug should be absorbed at an optimal rate via the desired site within the host body [11]. NDDSs can improve the drug absorption using two approaches [9, 16]:
Improvement of bioavailability by changing the solubility, dissolution rate, permeability, or residence time of a drug molecule by adopting different physical or chemical methods. For instance, the down-sizing of a drug crystal (e.g., through micronization and nanomization) enhances the solubility. Nanomization, in particular, can also improve the dissolution rate of drugs
[17]
. There are numerous physical
[18]
and chemical
[19]
approaches (like using microneedles and efflux inhibition, respectively) to enhance the permeability of drugs through different physiological barriers. Mucoadhesive formulations can prolong the residence time and thereby, provide sufficient opportunity for drug absorption
[20]
. Prodrugs can enhance the bioavailability of drugs by improvement of passive and or transport-mediated absorption [
21
,
22
]. Also, they may circumvent efflux transporters
[23]
.
Suggesting a new administration route to bypass the absorption barriers. For instance, some types of NDDSs improve the bioavailability of drugs by providing the possibility of nose-to-brain delivery as a potential alternative approach to accessing the brain without the hindrance of the blood-brain barrier (BBB) [
24
,
25
]. Lymphatic targeted drug delivery is another example of the ability of NDDSs to change the route of drug administration and to improve drug absorption, thereby the effectiveness of treatment
[26]
.
Figure 1.4 Plasma drug concentration-time curves of systems with different release profiles. (MEC: minimum effective concentration, MTC: minimum toxic concentration).
1.3.1.3 Distribution
Drug distribution refers to the reversible movement of drugs from the bloodstream to the tissues [27]. This process is affected by the characteristics of the drug molecule/delivery system as well as the host body [28]. NDDSs can potentially modify the distribution pattern of drugs via two major strategies:
Structural modifications of the drug molecule. For instance, prodrugs may demonstrate a significantly different distribution pattern than the parent drug due to their different physicochemical properties
[29]
.
Adjustment of some drug/carrier properties, other than the molecular structure of the drug, based on a strategy intended for passive or active drug targeting. Passive targeting relies on some basic physical properties of the carrier, mainly the size, which favors the drug distribution to a particular location within the host body. Enhanced permeation and retention (EPR) is a typical example of this strategy which is based on the passing of a narrow-sized carrier population through the ‘leaky vessels’ of the defected (cancer and inflamed) tissues, thereby drug molecules accumulate in target tissue to a higher extent than they do in healthy tissues [
30
,
31
]. EPR is applicable both for macromolecular therapeutics and small molecule drugs via encapsulation within the nanocarriers. Active targeting, on the other hand, is based on the differentiation between healthy and affected tissues by the drug carrier via some kind of “intelligence,” thus leading to selective accumulation in the target site(s). Active targeting is generally realized by the surface decoration of nanocarriers with special ligands to bind to the receptors on the target tissue
[30]
. Also, it is possible to conjugate tumor-specific ligands to cytotoxic drugs to provide prodrugs with high selectivity
[32]
.
1.3.1.4 Metabolism
NDDSs can change the pattern of drug metabolism and clearance in various ways, including changing drug transport pathways in the body, decreasing the rate of drug-metabolizing enzyme reactions, bypassing efflux transporters, and delaying drug release (hence, reducing the drug presentation rate to the hepatic or other kinds of enzymes) [9]. By the simplest definition, metabolism or biotransformation is the enzymatic modification(s) of different chemicals in vivo[33]. Biotransformation often leads to inactivation or detoxification. However, it may sometimes provide active metabolites, like what happens with prodrugs [34]. The logic of prodrug design is to take advantage of an intentional metabolism, which may occur in various organs/tissues depending on the design model [35]. If the prodrug has optimal metabolic stability, it is treated by the body as a new chemical until it enters the metabolism phase.
Encapsulation within the nanocarriers also influences the drug metabolism pathway. Immediately after entering the blood circulation, nanocarriers are sequestered by the mononuclear phagocytic system (MPS)—a part of the immune system that consists of phagocytic cells, in particular resident macrophages in the liver, spleen, and lymph nodes [36, 37]. Macrophages engulf nanoparticles with adsorbed opsonins (serum proteins) on their surface [38]. Ideally, the nanocarriers should be physicochemically stable in order to avoid the rapid disintegration upon contact with blood components, or premature release of their payload. Also, they must be able to escape the reticuloendothelial system (generally known as RES), i.e., the natural defense system of the host body against the foreign particulate “newcomers” [39]. How nanocarriers interact with the MPS provides a major indicator of their blood circulation half-lives and their clearance rate. Inadequate circulation half-life usually leads to reduced uptake and efficiency of the therapeutics [38].
MPS rapidly recognizes too hydrophobic and charged particles. So, the surface of nanocarriers is preferred to be hydrophilic with a neutral/slight anionic charge. To achieve this, water-soluble polymers (e.g., PEGs) have been widely studied to be conjugated on the surface of nanocarriers [30]. Cloaking of nanocarriers with cell membranes (biomimetic coating) is an alternative approach that not only enhances the longevity of carriers in the bloodstream but can also improve their targetability [40, 41]. Another recently noticed strategy to improve blood circulation is red blood cell (RBC)-hitchhiking, where nanocarriers are adsorbed (non-covalently) on the red blood cells (RBCs) surfaces; then, the associate is injected to reach the downstream organs [42–44]. Alternatively, plasma proteins can undertake the role of carriers. Recently, albumin-based prodrugs or albumin-bound nanocarriers have been developed to prolong the circulation half-lives in a way to improve the antitumor activity of anticancer drugs [45, 46]. In this regard, albumin could serve as a long-circulating carrier to enhance their accumulation through the EPR effect [47]. Engineering the mechanical and morphological characteristics of the nanocarriers is a straightforward strategy to keep them in circulation for an adequately long time [48].
Instead of regulating the drug-body interactions, it is also possible to control drug clearance using sustained-release systems. For instance, in the case of susceptible drugs that rapidly undergo metabolism or clearance, implantable depot systems provide an excellent platform to continuously release the drug for a long time [9].
1.3.1.5 Excretion
Drug excretion refers to several pathways that collectively remove the drug and/or its metabolite(s) from the body [49]. The time it takes for a drug to be excreted should be carefully considered; not so short that there is no opportunity for efficacy, and not so long that it jeopardizes safety [39, 50]. There are various routes of drug excretion including urine (kidneys), feces (liver), saliva, sweat, respiration, breast milk, and so on [49]. In the case of nanocarriers, the liver and spleen undertake a more prominent role. The route of administration has a key role in determining which organs contribute the most to accumulation and elimination [51]. Nanocarrierdependent factors are also of crucial importance. Zhang et al.[52] have proposed a flowchart demonstrating what excretory path a nanoparticle takes based on its properties. Accordingly, how nanoparticles are disposed of depends on three main factors including (i) size, (ii) degradability, and (iii) their interaction with the liver [51].
Prodrugs may be eliminated by renal or biliary excretion mechanisms. Briefly, the bioavailable fraction of the prodrug is metabolized and activated as the parent drug. The formation of metabolite(s) other than the drug is also possible, which will subsequently be excreted. The drug may be further metabolized to a daughter metabolite or directly excreted in the urine. Depending on the circumstances, a prodrug may show a longer or shorter elimination half-life than its parent molecule [53]. Generally speaking, drug delivery systems can be engineered to be excreted in an expected pattern. Figure 1.5 represents some novel systems/strategies employed to improve the performance of the drug in each of the pharmacokinetic phases.
Figure 1.5 By affecting which phase of LADME, NDDSs improve pharmacokinetics? (Created with BioRender.com).
1.3.2 How to Deliver?
1.3.2.1 Drug Delivery Barriers
Being constantly exposed to various types of xenobiotics from different origins and via different routes (e.g., skin contact, ingestion, inhalation, etc.), the body is equipped with highly efficient barriers at the cell, tissue, organ, and system levels [54]. As an external substance, the drug is no exception to this rule. Therefore, drugs have to travel a long and winding road, as shown in Figure 1.6. Which barriers and to what extent they play a role varies depending on the route of drug administration, characteristics of the drug molecule/delivery system, and the disease state.
1.3.2.2 Overcoming Strategies
Three main scenarios assumed for NDDSs to overcome the drug delivery barriers, are discussed below.
Disruption of Barriers
In both epithelium and endothelium, tight junctions form a tremendous barrier to paracellular drug absorption [55]. Tight junction modulation (using chelating agents, cationic polymers, toxins, etc.) is an attempt to address this issue [56]. However, despite their efficiency, the commercialization of tight junction modulators is hampered by safety concerns [55]. In the case of oral drug delivery, one of the major factors that lead to inadequate absorption is drug efflux. Therefore, suppressing the drug efflux pumps (using different excipients and inhibitors) or reducing their function (silencing transporters, for instance) is of great interest to improve the oral bioavailability of the drug [57]. Another example of impairing barrier performance is temporal disruption of the stratum corneum to improve percutaneous drug delivery. In this regard, different chemical (e.g., surfactants, solvents, lipids [58]) and physical (e.g., iontophoresis, sonophoresis [59]) enhancers have been studied with more or less success.
Figure 1.6 Drug delivery barriers [9, 34, 52, 75].
Bypassing Barriers
Delayed drug release that is commonly realized through enteric-coating is the best-known example of this category that bypasses the harsh stomach environment thanks to the presence of the gastro-resistant pH-activated polymeric layer [60]. Microneedles are other drug delivery systems whose rationale is to circumvent the successive physiological barriers [61]. Drugs administered via special routes (e.g., sublingual [62], lymphatic [63], and nose-to-brain [64] drug delivery) naturally escape first-pass metabolism. To conquer the mucus barrier, mucus-penetrating carriers have recently emerged that could freely diffuse across the mucus (e.g., in the gastrointestinal tract [65], vagina [66], eye [67], lung [68]) due to their small enough size and muco-inert surface [67]. Above all, a variety of nanotechnology-based drug delivery systems [54] and prodrug strategies [69, 70] have been extensively developed over recent decades to conquer the physiological barriers.
Seizing the Opportunity of Barriers
Mucoadhesives are promising drug delivery systems that adhere to the mucus layer for an extended time aided by interfacial forces [71]. They not only protect their cargo (particularly, biomolecules) against degradation but also improve drug bioavailability by allowing localized and unidirectional diffusion for a prolonged time [72, 73]. Stimuli-responsive systems which release their cargo in response to special triggers (pH, enzymes, microflora, etc.) are a prime example of using physiological/pathophysiological conditions for the benefit of therapy [74]. As another example, hepatic first pass, although a threat to the bioavailability of many drugs, could be an opportunity for liver-targeted prodrugs [75] and nanoparticles [76].
1.3.2.3 Designing Criteria of NDDSs
Thanks to the advances in different scientific fields such as material sciences (e.g., biomaterials), manufacturing techniques (e.g., 3D printing), and computational tools (e.g., artificial intelligence) along with learning from nature (e.g., bio-inspired design), it has been possible for pharmaceutical researchers to precisely design and manipulate the characteristics of drug delivery systems. The first step to achieving such systems is the logical selection of a drug molecule and its appropriate delivery system. Here, we briefly deal with the drug- and delivery system-related considerations that should be considered.
Drug-related considerations
Figure 1.7 highlights the most important considerations when selecting a drug molecule to be delivered by controlled-release systems. Also, the inclusion and exclusion criteria for choosing optimal molecules are listed. Accordingly, drug molecules with high molecular weights (e.g., proteins and peptides), inadequate solubility (e.g., BCS classes III and IV), excessive lipophilicity/hydrophilicity, and those unstable in the biological environments (e.g., biologicals) are poorly favorable candidates for controlled-release systems. On the contrary, small molecules, non-ionized drugs, and those whose absorption mechanism is not mediated to carriers are generally considered optimal candidates to be formulated as controlled-release systems [77]. More details are provided in Figure 1.7.
Many drugs in themselves lack the inclusion criteria listed in Figure 1.7. A drug with poor absorption, rapid metabolism, and/or excretion will require a higher dose to attain its therapeutic efficiency; which either leads to side effects and toxicity or is not practical. In these cases, the pharmaceutical attributes of the drug molecule should be modified through chemical modification or formulation (e.g., encapsulation) [78].
Structural modification of a drug molecule to reach a prodrug is considered an efficient tool to improve the physicochemical, pharmacokinetic, and pharmacodynamic properties of the parent drug. This goal is usually achieved by covalent conjugation of hydrophilic moieties (to improve solubility) or lipophilic functionalities (to enhance permeability) to the parent drug. In both cases, absorption and, thereby, bioavailability are positively affected [79]. For BCS classes II and IV, the prodrug increases the bioavailability through the enhancement of water solubility. In the case of BCS class III drugs, the prodrug strategy improves their permeability and may alter their position in BCS class II [80]. Additionally, prodrugs can circumvent efflux transporters [23]. The classical prodrug approach is beneficial for improving permeability through passive diffusion. More recently, however, thanks to the expansion of research on transporters and enzymes, a novel approach called “targeted-prodrug” has emerged that focuses on increasing absorption through transporters [79]. Unlike the BCS I molecules, whose permeation is mainly through passive diffusion, intestinal transporters possess a considerable contribution to the transportation of BCS II-IV drugs [81]. Consequently, targeted-prodrugs are prone to significantly improve the oral bioavailability of drugs via the enhancement of carrier-mediated transportation.
The AUC of a prodrug may differ significantly from that of the drug [29]. This is simply justified given that the volume of distribution (Vd) is strongly dependent on the physicochemical properties of the molecule. For instance, basic drugs often have a Vdof more than 100 L, while this value is approximately 10∼20 L for their acidic metabolites [53]. Additionally, targeted prodrugs may alter the tissue distribution pattern and decrease the toxicity of the drug due to their increased selectivity. Besides, prodrugs can be designed to avoid pre-systemic metabolism (whether in the intestinal membrane or the liver). So, they can pass the metabolic barriers intact until they are hydrolyzed in the blood circulation [82]. Additionally, prodrug is an intelligent approach for protecting drugs against enzymatic degradation [77]. They may also enable a new administration route. Such properties make structural modification a powerful strategy to overcome barriers posed by the body. How prodrugs improve the therapeutic efficiency of drugs is shown in Figure 1.8.
Figure 1.7 Considerations to be observed for designing controlled-release drug delivery systems [75, 97–99] (the inclusion and exclusion criteria of drug molecules are marked with a green tick and an orange cross, respectively).
Formulation-related considerations
As mentioned in previous sections, a common strategy to achieve the desired safety and efficacy using drugs with inappropriate physicochemical and pharmacokinetic properties is to formulate them as a dosage form representing the intended attributes. Considerations related to the formulations used via each route of administration will be discussed in their respective chapters. Here, considering the wide coverage and importance of nanocarriers, considerations relevant to nanotechnology-based delivery systems will be reviewed with special attention to their pharmacokinetics.
During the tortuous journey from the site of administration to the target site, only a small fraction of nanocarriers is fortunate enough to reach their destination. Today, grasping the physiological environment and how it interacts with the carriers, the path has been paved to achieve more efficient nano-based drug delivery systems. As shown in Figure 1.9, the main parameters to be optimized to achieve ideal nanoformulations are their type (material composition), physical/mechanical properties, and surface characteristics. Of those, size, morphology, rigidity, charge, and surface chemistry are among the most important parameters affecting the biofate of nanocarriers. In the following, how these parameters impact each pharmacokinetic process is discussed.
Effect of Composition
Ideally, the nanoparticles should be physicochemically stable so that they do not disintegrate rapidly upon contact with blood components, or release their payload prematurely. Also, they must be able to escape the MPS. Eventually, they should be removed from the body after a while [39]. Nanoparticles whose excretion is carried out within a certain period are favored by the FDA for biomedical applications [83].
Figure 1.8 How prodrugs improve therapeutic efficiency of drugs.
Figure 1.9 Considerations to be observed in design of nanocarriers.
The materials from which nanoparticles are made significantly affect their in vivo retention. In particular, whether nanocarriers are degradable and decomposable or not, determines their elimination pathway. It has been found that nanocarriers constructed from biodegradable materials or those with renal clearable characteristics are more fortunate for clinical translation. Contrarily, non-degradable nanocarriers accumulate in the body, so they are more likely to show toxicity. Most inorganic nanoparticles are neither biodegradable nor easily degraded under bio-relevant conditions. Therefore, their use, especially for the long term, raises concerns about their toxicity. Generally, organic-based nanocarriers are preferable due to being easily clearable from the host body and not creating cytotoxic degradation products. Recently, biodegradable organic-inorganic hybrid nanoparticles have been raised to combine the properties of inorganic moiety and biodegradation characteristics of the organic portion [84].
There are two main mechanisms for nanoparticles to be cleared from the blood and eliminated from the body including (i) renal and (ii) hepatobiliary elimination pathways [52]. A study on quantum dots has shown that efficient urinary excretion is dictated by the pore size cut-off of glomerular filtration in the kidneys which only allows the small nanoparticles with a diameter of < 5.5 nm to be excreted [85]. The molecular weight cutoff for nanoparticles to be excreted via glomerular filtration is conventionally considered to be about 70 kDa [51]. The biofate of larger nanoparticles predominantly depends on their nature and degree of biodegradability. In general, large biodegradable nanoparticles undergo disassembly, breaking down, or metabolism; after which return to general circulation. In these cases, the decision-making cycle about the fate of nanoparticles is repeated; and if the created species are small enough, they can be excreted in the urine [52].
Concerning non-biodegradable nanoparticles, those larger than around 200 nm are efficiently filtered out by Kupffer cells and retained there for a long time (i.e., several months to years) [52, 86]. This is largely due to the slow blood flow rate of about 1000 times in the sinusoids (vascular channels of the liver) which significantly improves the likelihood of nanoparticle interactions with hepatic cells (including Kupffer cells, B cells, and endothelial cells) [87]. If this barrier can be somehow avoided, nanoparticles will again have a different path depending on their size. Particles larger than liver sinusoidal endothelial cell fenestrae having a diameter of about 100 to 200 nm, will not be able to reach the hepatocytes; so, they inevitably re-enter the systemic circulation [52] and RES (e.g., spleen and lymph nodes) is responsible for their elimination [51]. Smaller nanoparticles extravasate through the fenestrae to enter the space of Disse—a location between a sinusoid and a hepatocyte. Thereafter, they are taken up by the hepatocytes; afterward, enter the bile duct and are excreted in the feces [52].
Effect of Size
There is an inverse relationship between the size of nanoparticles and their cellular uptake. In addition, size plays an important role in determining whether nanoparticles are specifically absorbed by the hepatic portal system or the lymphatic pathway; the larger the particle size, the greater the preference for lymph [88]. The average optimal size range of nanoparticles to be absorbed from the gastrointestinal tract is about 20 to 100 nm from enterocytes and 100 to 500 nm from M cells [54]. Larger nanoparticles could be taken up by M cells, but they will be entrapped within the Peyer’s patches [88]. Besides, particle size specifies by which clearance system and how fast the elimination takes place. As a general rule, nanoparticles with a size of 5 to 200 nm are more fortunate to have extended blood circulation (leading to an improved propensity for extravasation). This is because those smaller than 5 nm are quickly excreted by the renal system. On the other hand, resident macrophages of the MPS rapidly clear the blood from particles larger than 200 nm [83]. Consequently, nanoparticles are non-specifically distributed in healthy organs; in particular, they highly accumulate in the liver (fenestrations size range of 50–100 nm) and spleen (with fenestrations of 200–500 nm). Lung capillaries are capable of accumulating micrometric particles with a range of 2 to 5 μm [36]. Except for the listed clearance organs, diffusion through the other healthy blood vessels is only allowed for small molecules. This rule, however, is violated in the inflammatory tissues and tumor vasculature (with fenestrations measuring 380–780 nm), where even particles as large as 200 nm are capable of extravasation and being trapped through the EPR effect—an exceptional opportunity for macromolecules and nanoparticles [31, 36, 83, 89]. As previously mentioned, the EPR effect is a passive targeting mechanism that makes accumulation possible by offering increased vascular permeability (arising from fenestrated leaky vessels) and prolonged retention (due to impaired lymphatic drainage) [31, 90].
Effect of Shape
Rod-shaped nanoparticles generally outperform the spherical ones; since they show higher cellular uptake and transcytosis, more efficient internalization, longer retention time in the gastrointestinal tract, better penetration into the interstitial space of villi, and greater lymphatic transport compared with the sphere nanoparticles [54, 91, 92]. This is mainly attributed to the higher chance of rod-shaped particles to contact the cell membrane [93]. Generally, the internalization rate of non-spherical particles with a high aspect ratio is faster than spherical ones [86]. Furthermore, it is worth noting that the aspect ratio of nanoparticles affects their internalization pathway. It has been shown that nanoparticles with high aspect ratios tend to internalize through macropinocytosis into the endothelial and epithelial cells, while sphere-shaped nanoparticles prefer clathrin-mediated endocytosis to enter the endothelial cells [94]. Nanoparticles with different shapes demonstrate special flowability; hence, they may have different circulating half-lives, cell membrane interactions, and MPS uptake. In general, spherical-shaped small nanoparticles migrate at a considerable distance from the capillary walls. Migrating in such a cell-free layer significantly impedes particle-cell contact points, and thereby, the targeting efficiency (whether active or passive accumulation). Accordingly, non-spherical nanoparticles (e.g., discoidal-shaped ones with unique tumbling characteristics) are more exposed to contact cells and to extravasate. Additionally, non-spherical particles typically exhibit longer circulating half-life, partly due to their propensity to align with the blood flow. Concerning macrophage internalization, morphological parameters like aspect ratio and curvature highly affect phagocytosis. Spherical particles with lower normalized curvature are picked up faster by macrophages than the non-spherical ones. Altogether, considerable attention has recently been paid to non-spherical morphologies (e.g., cylindrical, ellipsoidal, discoidal, and worm-like geometries) to achieve improved accumulation within the tumors [36].
Effect of Rigidity
Rigidity has a critical effect on the bioavailability of nanoparticles, and hence, modulating rigidity could help the nanoparticles to effectively conquer the barriers ahead like mucosal and tumor delivery. There is an optimal range for nanoparticle stiffness. Softer nanoparticles show weak mucosal penetration as well as cellular internalization. On the other hand, hard nanoparticles exhibit the appropriate cellular uptake, while they are not able to efficiently penetrate the mucus. Consequently, to overcome the biological multi-barriers of organs and tissues, rigidity modification is promising [95]. The degree of particle stiffness also impacts the biodistribution pattern, half-lives, and efficiency of nanoparticles (by affecting macrophage uptake as well as receptor-mediated cancer cell uptake). Rigid particles larger than the cut-off of splenic interendothelial slits are simply removed while passing through [36, 83, 96]. On the other hand, soft nanoparticles show a low internalization level into the MPS, thus reducing the endocytosis rate and extending blood circulation [96–98]. Consequently, softer particles with higher flexibility are expected to be more favored due to their extended circulation half-life and decreased non-specific accumulation in the spleen [36, 83].
Effect of Surface Properties
Surface charge (which is usually measured by zeta potential; ξ) and hydrophilicity/hydrophobicity are among the most important variables to achieve optimal particle features [99]. Surface properties of nanoparticles impact their overall behavior, both in vitro (e.g., aqueous dispersibility and encapsulation efficiency) and in vivo (e.g., aggregation in the gastrointestinal tract, interactions with biological membranes, biodistribution, biocompatibility, and clearance) [99]. Upon contact with the gut luminal fluids, the charge density of particles may be altered. Depending on the surface charge and interactions that take place between nanoparticles and mucus, the residence time of nanoparticles may be beneficially extended or, disadvantageously, the absorption of nanoparticles is hindered by mucus. Typically, cationic nanoparticles exhibit improved uptake, enhanced internalization, transport (till lamina propria), and considerably increased bioavailability [91]. M cells tend to absorb non-ionic nanoparticles with hydrophobic properties compared with charged hydrophilic ones [88]. The surface charge is of crucial importance in determining circulation lifetime and accumulation of nanoparticles in the target sites. It has been shown that negative and neutral charged particles demonstrate lower adsorption to serum proteins leading to a prolonged circulation half-life. However, highly negative charge particles (ξ < −10 mV) demonstrate a considerable RES uptake. The least RES interaction belongs to around-neutral nanoparticles (-10 mV < ξ < 10 mV) [36, 100]. On the other hand, positively charged particles induce serum protein aggregation and show a high non-specific uptake, preferential internalization within the tumor cells and inflammation sites, and facilitated endosomal release. With all these in mind, an optimal nanoparticle to be accumulated in the tumor is expected to have a neutral or slightly negative surface charge in the blood circulation and a switched positive charge while arriving at the tumor [36].
Effect of Surface Modification and Functionalization
Nanoparticles must be able to protect themselves and the medicine; otherwise, the nanoparticles may form aggregates, drug molecules undergo precipitation, and an early clearance occurs [99]. To avoid this, surface modification of nanoparticles, using PEG or other polymer coatings, is usually carried out which provides hydrophilic surface chemistry. In oral drug delivery, for instance, this can minimize the mucin trapping thereby improving mucosal permeability. Additionally, in the case of lipid-based nanoparticles, the lipolysis is significantly suppressed. These performances could effectively improve the bioavailability of the drug to be delivered orally [91, 101].
Besides, surface modification is an efficient method to improve both passive and active targeting [91]. Concerning passive targeting, for instance, it has been shown that bioadhesive coating not only enhances nanoparticle absorption but also positively affects organ distribution patterns [102].
