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Nanocarriers for Drug Delivery: Nanoscience and Nanotechnology in Drug Delivery
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694 pages12 hours
Summary
Nano-carriers for Drug Delivery: Nanoscience and Nanotechnology in Drug Delivery presents recent discoveries in research on the pharmaceutical applications of the various types of nanosystem-based drug delivery systems. As many nanosystems have reached the market over the past decade, this book proves their benefits to patients. It explores these new carriers and the advances in drug delivery they have facilitated. Reflecting the interdisciplinary nature of the subject matter, the book includes experts from different fields, and with various backgrounds and expertise. It will appeal to researchers and students from different disciplines, such as materials science, technology and various biomedical fields.
Coverage includes industrial applications that bridge the gap between lab-based research and practical industrial use. The resulting work is a reference and practical source of guidance for researchers, students and scientists working in the fields of nanotechnology, materials science and technology and biomedical science.
Enables readers from different fields to access recent research and protocols across traditional boundaries Focuses on protocols and techniques, as well as the knowledge base of the field, thus enabling those in R&D to learn about, and successfully deploy, cutting-edge techniques Includes sections on nanocarrier systemsPublisher: Elsevier ScienceReleased: Oct 5, 2018ISBN: 9780128140345Format: book
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Nanocarriers for Drug Delivery
Nanocarriers for Drug Delivery
Nanoscience and Nanotechnology in Drug Delivery
Editors
Shyam S. Mohapatra
Shivendu Ranjan
Nandita Dasgupta
Raghvendra Kumar Mishra
Sabu Thomas
Table of Contents
Cover image
Title page
Copyright
List of Contributors
Foreword
Chapter 1. Efficient Nanocarriers for Drug-Delivery Systems: Types and Fabrication
1. Introduction
2. An Overview of the Role of Nanoparticles in Drug Delivery
3. Types of Nanocarriers: Fabrication Approaches and Applications in Drug Delivery
4. Conclusion
Chapter 2. Nanohybrid Filler-Based Drug-Delivery System
1. Introduction
2. Hybrid Nanomaterials
3. Concluding Remarks and Future Perspectives
Chapter 3. Hydrogel Nanocomposite Systems: Physico-Chemical Characterization and Application for Drug-Delivery Systems
1. Introduction
2. Hydrogels: Physicochemical Properties and General Applications
3. Hydrogel Synthesis
4. Hydrogel Nanocomposites
5. Physicochemical Characterization of Hydrogel Nanocomposites
6. Application of Hydrogel Nanocomposites as Drug-Delivery Systems
7. Concluding Remarks
List of Abbreviations of the Polymers
Chapter 4. Nanopharmaceuticals as Drug-Delivery Systems: For, Against, and Current Applications
1. Introduction
2. History of Nanotechnology and Nano Definitions
3. Nanomedicines and Biological Environment
4. Characterization of Nanomaterials
5. Nanoparticle Types, Applications, Advantages, and Potential
6. Manufacturing Prospects for Nano Drugs, Nanoadditives, and Nanocarriers
7. Regulatory Perspective on the Development of Nanomedicines
8. Scale-Up of Nanomedicines: Preparative Methods and Their Challenges
9. Nanotechnology Clinical Applications
10. Nanotechnology in the Treatment of Neurodegenerative Disorders
11. Problems With Current Nanotechnology Concepts
12. Conclusions
Chapter 5. Nucleic Acid-Based Nanocarriers
1. Introduction
2. Watson–Crick DNA Structure and DNA Nanotechnology
3. DNA Nanotechnology as Drug Delivery
4. Uses of DNA Nanotechnology in Various Diseases
5. Discussion
6. Conclusion
Chapter 6. Protein Nanocarriers for Targeted Drug Delivery for Cancer Therapy
1. Introduction
2. Types of Proteins
3. Preparation Methods of Protein Nanocarriers
4. Preparation Methods for Hybrid Protein Nanocarriers
5. Drug Loading Mechanism of Protein and Hybrid Nanocarriers
6. Protein and Hybrid Protein Nanocarriers in Targeted Drug Delivery
7. Future Prospects
8. Conclusions
Chapter 7. TiO2-Based Nanocarriers for Drug Delivery
1. Introduction
2. Computational Density Functional Theory Method: The Kohn–Sham Approach
3. The Kohn–Sham Equations
4. Computational Methods and Models of Nanoparticles
5. Models of Nanoparticles
6. Curcumin Interaction with TiO2 Anatase Nanoparticles
7. Curcumin Adsorption on the N-Doped Nanoparticles (Position 1)
8. Density of States and Molecular Orbitals
9. Curcumin Adsorption on the N-Doped Nanoparticle (Position 2)
10. Curcumin Adsorption on the Cu/N-Codoped Nanoparticles (Position 3)
11. The Charge Exchange Between Adsorbed Curcumin and TiO2 Nanoparticles
12. The Interaction of Immucillin-A With TiO2 Nanoparticles
13. Adsorption of Immucillin-A on the N-Doped and Cu/N-Codoped TiO2 Nanoparticles
Chapter 8. Lipid-Based Nanoparticles for Drug-Delivery Systems
1. Introduction
2. Liposomes
3. Self-Micro-/nanoemulsifying Drug-Delivery Systems
4. Lipid Nanoparticles
5. Lipid-Based Nanoparticle Characterization Techniques
6. Lipid-Based Nanoparticle Routes of Administration
7. Lipid-Based Nanoparticle Applications in Drug Delivery
8. Conclusion and Future Perspectives
Chapter 9. Mesoporous Silica-Based Nano Drug-Delivery System Synthesis, Characterization, and Applications
1. Mesoporous Silica in General
2. Synthesis and Characterization
3. Factors for Fabrication of Fine-Tuned Mesoporous Silica Nanoparticles
4. Biocompatibility
5. Toxicity
6. Functionalization Strategies
7. Applications
8. Patents
9. Future Prospects
Chapter 10. Hydrogel Nanocomposite Systems: Characterization and Application in Drug-Delivery Systems
1. Introduction
2. Hydrogel Nanocomposite Systems
3. Nanocomposite Hydrogel Properties
4. Hydrogel Nanocomposite Applications in Drug Delivery
5. Conclusions and Future Perspectives
Chapter 11. Mesoporous Silica as Carrier for Drug-Delivery Systems
1. Introduction
2. Synthesis of Mesoporous Silica Nanoparticle Carriers
3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems
4. Perspectives and Outlook for Mesoporous Silica–Based Antibiotic-Delivery Systems
Chapter 12. Cell-Line-Based Studies of Nanotechnology Drug-Delivery Systems: A Brief Review
1. Introduction
2. Nanotechnology-Based Drug-Delivery System
3. Cell Sources and Cell Types
4. Cell-Culture-Based Assays
5. Limitation and Challenges
6. Conclusion and Perspectives
Chapter 13. Nanoscale Drug-Delivery Systems: In Vitro and In Vivo Characterization
1. Introduction
2. In Vitro Characterization of Nanoparticles
3. In Vivo Characterization Assays and Imaging
4. In Vivo Classification
5. Classification Based on Administration Route
6. In Vivo Characterization Based on Structural Properties
7. In Vivo Characterization Based on Functionalization
8. Summary
Chapter 14. Self-Nanoemulsifying Drug-Delivery System and Solidified Self-Nanoemulsifying Drug-Delivery System
1. Introduction
2. Self-Nanoemulsifying Drug-Delivery Systems
3. Solidified Self-Nanoemulsifying Drug-Delivery System
4. Characterization of SNEDDSs and S-SNEDDSs
5. Drug-Release Studies
6. Stability of SNEDDSs and S-SNEDDSs
7. Mechanism of SNEDDS Formation
8. Application of SNEDDSs and S-SNEDDSs
9. Conclusions and Outlooks
Chapter 15. Carbon and Carbon Nanotube Drug Delivery and Its Characterization, Properties, and Applications
1. Introduction
2. Goals of Using Drug Delivery
3. Types of Drug Delivery
4. Functions of Drug Delivery
5. Properties of Drug Delivery
6. Applications of Drug Delivery
7. Case Study of Carbon Nanotube Drug Delivery
8. Sources of Carbon
Chapter 16. Carbon Nanotubes: Synthesis, Characterization, and Applications in Drug-Delivery Systems
1. Introduction
2. Carbon Nanotubes: Synthesis and Nomenclature
3. Functionalization
4. Biomedical Applications
5. Conclusion and Outlook
Chapter 17. Polymer-Based Nanomaterials for Drug-Delivery Carriers
1. Introduction
2. Types of Polymer-Based Nanomaterials
3. Methods of Preparation
4. Characteristics of Polymeric Nano Materials
5. Applications
6. Characterizations of Polymeric Nanomaterials
7. Ongoing Research
8. Environment and Health Safety
9. Challenges and Limitations
10. Conclusion
Chapter 18. Polymeric Nanomaterials: Methods of Preparation and Characterization
1. Introduction
2. Types of Polymers
3. Polymer-Based Therapeutics for Drug Delivery
4. Biomedical Applications
5. Challenges and Concluding Remarks
Index
Copyright
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List of Contributors
Amirali Abbasi, Azarbaijan Shahid Madani University, Tabriz, Iran
Aiah A. Almokdad, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates
Sandra Amado
School of Health Sciences at the Polytechnic Institute of Leiria, Leiria, Portugal
Center for Rapid & Sustainable Product Development, Polytechnic Institute of Leiria, Leiria, Portugal
Fatma B. Arslan, Hacettepe University, Ankara, Turkey
Zein Barakat, University of South Florida Morsani College of Medicine, Tampa, FL, United States
Daniela Berger, University Politehnica
of Bucharest, Bucharest, Romania
Talitha C. dos Santos, Universidade Federal de Santa Catarina, Florianópolis, Brazil
Anna Calarco, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Sema Çalış, Hacettepe University, Ankara, Turkey
Thiago Caon, Universidade Federal de Santa Catarina, Florianópolis, Brazil
Yılmaz Çapan, Hacettepe University, Ankara, Turkey
Asit Kumar Chakraborty, Vidyasagar University, Midnapore, India
Hitendra S. Chand, Florida International University, Miami, FL, United States
Raffaele Conte, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Mihaela Deaconu, University Politehnica
of Bucharest, Bucharest, Romania
Manar S. Debe, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates
Adriana De Luise, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Francesca Di Cristo, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Anna Di Salle, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Hakan Eroğlu, Hacettepe University, Ankara, Turkey
Débora F. Argenta, Universidade Federal de Santa Catarina, Florianópolis, Brazil
Evelyn Garcia, Florida International University, Miami, FL, United States
Mónica C. García
Universidad Nacional de Córdoba, Córdoba, Argentina
Unidad de Investigación y Desarrollo en Tecnología Farmacéutica – UNITEFA (CONICET-UNC), Córdoba, Argentina
Sougata Ghosh, RK University, Rajkot, Gujarat, India
Claude Girardet, Université de Bourgogne Franche-Comté, NIT, EA 4662, Besançon Cedex, France
Geetha B. Heggannavar, Karnatak University, Dharwad, India
Guillaume Herlem, Université de Bourgogne Franche-Comté, NIT, EA 4662, Besançon Cedex, France
Yingying Huang, Nanyang Technological University, Singapore
Chun Hui Zhou
Zhejiang University of Technology, Hangzhou, China
Qing Yang Institute for Industrial Minerals (QYIM), An Hui, China
Rahul D. Jayant, Florida International University, Miami, FL, United States
Mahadevappa Y. Kariduraganavar, Karnatak University, Dharwad, India
Ajeet Kaushik, Florida International University, Miami, FL, United States
Raj Kumar
Bar-Ilan University, Ramat Gan, Israel
School of Basic Sciences and Advanced Material Research Center, Indian Institute of Technology Mandi, Mandi, India
Li Li, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
Pei Qi Lim, Nanyang Technological University, Singapore
Angela M. Campos, Universidade Federal de Santa Catarina, Florianópolis, Brazil
Stephanie Martinez, Florida International University, Miami, FL, United States
Cristian Matei, University Politehnica
of Bucharest, Bucharest, Romania
Olivier Micheau, Université de Bourgogne Franche-Comté, LNC UMR1231, Dijon, France
Raghvendra Kumar Mishra
Mahatma Gandhi University, Kottayam, India
Indian Institute of Space Science and Technology, Thiruvananthapuram, India
Geoffrey R. Mitchell
Center for Rapid & Sustainable Product Development, Polytechnic Institute of Leiria, Leiria, Portugal
Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Raul-Augustin Mitran, Ilie Murgulescu
Institute of Physical Chemistry, Bucharest, Romania
Shyam Mohapatra, University of South Florida, Tampa, FL, United States
Subhra Mohapatra
University of South Florida Morsani College of Medicine, Tampa, FL, United States
James A Haley Veterans Affairs Hospital, Tampa, FL, United States
Shyam S. Mohapatra
University of South Florida Morsani College of Medicine, Tampa, FL, United States
James A Haley Veterans Affairs Hospital, Tampa, FL, United States
Miguel Moreno Raja, Nanyang Technological University, Singapore
Madhavan Nair, Florida International University, Miami, FL, United States
Kıvılcım Öztürk Atar, Hacettepe University, Ankara, Turkey
Gianfranco Peluso, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Orsolina Petillo, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Fabien Picaud, Université de Bourgogne Franche-Comté, NIT, EA 4662, Besançon Cedex, France
Zhi Ping Xu, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
Francesco Riccitiello, University of Naples Federico II
, Naples, Italy
Sumia I.M. shaluf, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates
Ravikumar Shinde, Rajarshi Shahu Mahavidyalaya, Latur, India
Anthony Singer, University of South Florida Morsani College of Medicine, Tampa, FL, United States
Nuchnapa Tangboriboon, Kasetsart University, Bangkok, Thailand
Sabu Thomas, Mahatma Gandhi University, Kottayam, India
Santosh K. Tiwari, Indian Institute of Technology (ISM), Dhanbad, India
Paula M. Uberman
Universidad Nacional de Córdoba, Córdoba, Argentina
Instituto de Investigaciones en Fisicoquímica de Córdoba – INFIQC (CONICET-UNC), Córdoba, Argentina
Anna Valentino, Institute of Agro-Environmental and Forest Biology (IBAF), Italian National Research Council (CNR), Naples, Italy
Subbu Venkatraman, Nanyang Technological University, Singapore
Yee Shan Wong, Nanyang Technological University, Singapore
Gordon M. Xiong, Nanyang Technological University, Singapore
Hemant K.S. Yadav, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates
Yiming Zhang, Nanyang Technological University, Singapore
Foreword
It has been a pleasure to go over the contents of the three volumes of Nanocarriers for Drug Delivery, Characterization and Biology of Nanomaterials for Drug Delivery, and Applications of Targeted Nano Drugs and Delivery Systems, which together form a much valued compendium of knowledge for those interested in advanced microscale and nanoscale drug delivery systems.
These three volumes of nanomedicine literature would be an excellent compilation to incorporate into any educational program as recommended textbooks or other forms and will allow students to get a more in-depth and broader exposure to the course material. Having these comprehensive resources would greatly advance students' knowledge regarding the vast applications and variety of the types of nanoparticles that are relevant to the field of pharmaceutical nanotechnology. Also, having this resource may help some students narrow down their desired topic of research for their respective projects.
Whereas Nanocarriers for Drug Delivery would best fit the introductory knowledge of diverse nanomaterials used in drug delivery, Characterization and Biology of Nanomaterials for Drug Delivery and Applications of Targeted Nano Drugs and Delivery Systems would best fit the advanced levels of drug delivery courses. Also, these latter two volumes would be very helpful and allow students to diverge to more individualized paths, depending upon the desired specialization. Also, the sections based on risk and toxicity are critically important to the knowledge that can be applicable to each class of nanomaterial.
Overall, I strongly believe that all three volumes would be advantageous to students, faculty, and researchers as a real treatise in nanotechnology throughout the entirety of any educational program related to nanoscale drug delivery, and also in other future scientific endeavors.
Mandip Sachdeva, PhD, Professor and Section Leader, Pharmaceutics, Editor in Chief, CRC Critical Reviews in Therapeutic Drug Carrier Systems, AAPS Fellow, 2007, Fulbright Fellow, 2014, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA
Chapter 1
Efficient Nanocarriers for Drug-Delivery Systems
Types and Fabrication
Raghvendra Kumar Mishra¹,², Santosh K. Tiwari³, Shyam Mohapatra⁴, and Sabu Thomas¹ ¹Mahatma Gandhi University, Kottayam, India ²Indian Institute of Space Science and Technology, Thiruvananthapuram, India ³Indian Institute of Technology (ISM), Dhanbad, India ⁴University of South Florida, Tampa, FL, United States
Abstract
Drug delivery relates to techniques, originations, technology, and solutions for delivering drug compounds inside the body as required to safely and securely fulfill their preferred medical concern. A variety of materials are under examination for drug delivery and, stated more explicitly, for tumor treatment, as well as for similar disease problems. Nowadays, pharmaceutical sciences are utilizing nanoparticles to enhance efficiency and reduce toxicity together with the adverse effects of medicines. In this chapter, we have thoroughly highlighted consistent release, extensive mechanisms, chronic activity, regulated release, and timed-release dosage. Herein, we have also presented an overview of some of the currently used nanomaterials' statuses and prospects for drug delivery. In addition to the potential beneficial use of nanomaterials, attention is drawn to the question of how we should proceed with the safety evaluation of nanoparticle formulations for the betterment of drug delivery. Although, for pharmaceutical use, the current requirements seem to be adequate to detect the adverse effects of nanoparticle formulations, it can be expected that all aspects of nanoparticle toxicology may need to be reviewed further in the near future.
Keywords
Application; Characterization; Drug delivery; Fabrication; Nanocarrier; Nanoparticles
1. Introduction
Advanced nanomaterial therapeutic systems hold particular advantages over conventional therapeutic systems. Most commonly, accelerated removal of drugs by scavenger cells can be constrained by modulating the size of nanoparticles (NPs). The capability to capsulize and transport inadequately water-soluble drugs offers affirmative potency for pharmaceutical applications. The reliability of controlled drug release allows modifying the pharmacokinetics of drugs and diminishing their toxic and side consequences. Ultimately, enhanced biodistribution and boosted intracellular penetration enhance the efficiency of drugs [1,2].
The aforementioned assets of NPs satisfy the conditions to enhance chemotherapy for cancer, in which it is important to keep the desired drug levels in tumor tissue and to weaken the drug concern for healthy tissues. NPs of optimal size can move through the capillary vascular walls and assist in passive tumor targeting because of the consequences of strengthened permeability and retention on the tumor vasculature. The elevated permeability of the tumor neovasculature improves the extravasation of NPs due to extensive gaps between vascular endothelial cells and obstinate angiogenesis inside specific tumors. Moreover, impaired tumor lymphatic drainage behaves synergistically toward the accumulation of NPs in the tumor environment. However, precise receptors overexpressed on the membrane of tumor cells can be victimized to produce requisite targeting ligands that adhere to the NPs. In this respect, it has been noticed that specific ligands such as vitamins, lectin, carbohydrates, antibodies, and fragments of some antibodies can mediate endocytosis, thereby extending the selectivity of drug delivery [3–5].
Normally, the biodistribution of NPs is profoundly reliant on their geometrical properties, size, shape, and also surface properties. In this regard, a significant number of NPs have actually been produced and executed, for instance, nanovesicles, nanomicelles, nanoliposomes, and nanogels, together with nanodendrimers. These NPs can be described in terms of their constituting components, like polymeric NPs, mesoporous NPs, magnetic NPs, gold NPs, and so forth. Among the wide range of materials that are utilized for developing the polymeric NPs, organic and natural polymers manifest certain positive aspects in their versatility of style and design, modification, synthesis, and active functionalization. Specifically, NP-dependent amphiphilic polymers show a noteworthy involvement in the delivery of poorly water-soluble tablets, along with other medicines. The polymer is usually applied for biocompatible purposes, for example, copolymers of polycaprolactone, poly(glycolic acid), polyethylene glycol, poly(lactic acid), polysaccharides, polypeptides, etc. In addition, polysaccharides are thoroughly employed as the elementary unit for the synthesis of drug-delivery vehicles. Nowadays, many lipids and also artificial polymers are unquestionably employed as drug-delivery vehicles [6–8]. Plenty of nanocarriers for tumor therapy mostly driven by nanomaterials have evolved and additionally shown remarkable results in preclinical tests in recent decades. Amphiphilic NPs, specifically in carbohydrate- as well as their derivatives-based NPs, are taken into account and manufactured using several chemical and physical techniques [9–11].
An amphiphilic configuration for drug delivery has hydrophilic parts and hydrophobic moieties. The hydrophilic sections are responsible for hydration as well as swelling, although the hydrophobic portions are likely to decrease the water contact because their contact with water is dynamically unfavorable. Owing to the substantial hydrophilicity of polysaccharides, grafting hydrophobic segments to polysaccharides is vital for making many kinds of amphiphilic systems. Based on the physical and chemical characteristics of polysaccharides and modified polysaccharides, there are two broad techniques for developing an amphiphilic system (Fig. 1.1): first, covalent conjugation, and second, covalent intermolecular interactions [12–14]. Polysaccharides, in addition to their derivatives containing carboxylic, acid hydroxyl, and amino-functional categories, may respond with an array of hydrophobic moieties via the ester, amide, urea, and hydrazone bonds to create amphiphilic molecules. Likewise, hydrophobic moieties comprise all hydrophobic molecules, for example, fatty acids and bile acids, as well as cholesterol; hydrophobic macromolecules, for instance, polyester and polyanhydride; and hydrophobic drugs, including paclitaxel. The covalent chemical bonds between polysaccharides and hydrophobic moieties are generally labile for effective drug release, for example, pH sensitive or enzyme cleavable and reductive, and so on, under most cancer cellular situations. The considerable amphiphilic polymers are likely to self-assemble into NPs in aqueous surroundings through hydrophobic interactions [15,16]. The noncovalent interactions may well include electrostatic interactions, host–guest memory, metal–ligand, π–π stacking, charge transfer interactions, hydrogen bonding, and so forth. In comparison to covalent interactions, these kinds of interactions are fairly weak, and in noncovalent interactions, the resultant amphiphilic systems are usually referred to as supramolecular amphiphiles, or superamphiphiles. These supramolecular amphiphiles are promising as stimulus-responsive nanocarriers because of their unique properties. As to the carbohydrate-dependent amphiphilic arrangements for drug delivery, the most common noncovalent interactions manipulated to assemble supramolecular amphiphilic systems are electrostatic interactions, host–guest recognition, π–π stacking, or mixtures of them all. Polyelectrolytes (macromolecules with charges) are produced through ionic crosslinkers by means of electrostatic attraction between molecules with cationic as well as anionic groups. Certain polyelectrolytic complexes may additionally self-assemble into distinct NPs. Nevertheless, the consequential NPs are labile in the exterior surroundings by reason of the much less stable ionic crosslinkers and less strong ionic interactions as compressed networks. Usually, the development and stability of the complexes are influenced by not only the inner aspects of polyelectrolytes, for example, charge density, chain overall flexibility, molecular weight, and distribution of charge, but also possibly the outer aspects, which include ionic strength, temperature, and pH value together with mixing techniques. Polysaccharides are a vital component for developing polyelectrolytes. As an illustration, absolutely positively charged polysaccharides, including chitosan, and negatively charged polysaccharides, like hyaluronan and heparin, may create complexes with inversely charged polyelectrolytes. The fairly neutral polysaccharide may also be converted into charged polyelectrolytes via a variety of chemical adjustments. Common chemical transformations are the addition of an amino group to polysaccharides for positively charged polyelectrolytes and the establishment of a carboxylic group or sulfate group to polysaccharides concerning negatively charged polyelectrolytes [17–20].
Figure 1.1 Nanoparticles and their characteristics as agents for efficient drug delivery. HTCC , N -[(2-hydroxy-3-trimethylammonium)propyl]chitosan.
Adopted from Franco MKKD, de Araújo DR, de Paula E, Cavalcanti L, Yokaichiya F, X-ray scattering techniques applied in the development of drug delivery systems. In: X-ray scattering. InTech; 2017. https://doi.org/10.5772/65326.
2. An Overview of the Role of Nanoparticles in Drug Delivery
The host–guest hypothesis is used in host–guest chemistry for molecular identification, with the interaction performed depending on noncovalent as well as ionic bonding. This kind of host–guest analysis is a commonly used approach to produce supramolecular amphiphilic delivery devices. Among the popular host compounds, those such as cyclodextrins, cucurbiturils, calixarenes, and porphyrins are the most often used molecule categories in pharmaceutics as well as drug delivery. The cyclodextrins facilitate the introduction of complexes with hydrophobic molecules into their hydrophobic hollow void (cavity). There are basically two common types of these kinds of complexes: linear polymers, which may penetrate the cavities of cyclodextrins to create polypseudorotaxanes, and cyclodextrin cavities, which host hydrophobic head sections of site visitor molecules by means of hydrophobic interactions to develop host–guest complexes [22,23]. The amphiphilicity of the entire complex might be modified by the adjustment of host cyclodextrins as well as guest molecules. The functionalization and modification help to include the hydrophobic moieties with cyclodextrins or guest molecules or even the mixture of both. π–π stacking refers to attractive, noncovalent connections between aromatic systems. These types of interactions are incredibly essential for catalysis and molecular identification as well as protein–ligand associations. Currently, intermolecular π–π stacking is receiving much more consideration and continues to be used for drug-delivery strategies. This sort of pharmaceutical delivery device is generally manufactured from aromatic system drugs including an aromatic (π-rich) as well as the anticancer drug doxorubicin, for example, graphene, carbon nanotubes, fullerene, and carbon black NPs [20,24]. Despite this, without proper surface alteration, carbon NPs cannot diffuse into water, which restricts their use in a wide variety of application forms. Many polysaccharides are being developed that are biocompatible and appropriate for conjugation with aromatic moieties, which is helpful for transporting aromatic drugs by making use of intermolecular π–π stacking attraction [25].
Furthermore, nonaromatic drugs are also converted into candidates for π–π stacking drug delivery through combining aromatic moieties as a result of cleavable chemical bonds. Apart from π–π stacking, hydrophobic interactions also provide a synergistic effect for pharmaceutical encapsulation as well as self-assembly to develop nanoassemblies like vesicles or micelles. These amphiphilic NPs are able to take on a great number of shapes depending on the chemical constitution and physical assembly processes, including micelles, vesicles, nanogels, or dendrimers, which are generally presented in Fig. 1.2. The features of certain types of nanomaterials are examined in detail below.
1. NPs made of amphiphilic polymers having both water-loving polar and fat-loving structural units within the individual polymeric system are known as amphiphilic or amphipathic polymers. These types of structural arrangements are the foundation for a variety of investigations in nanoscience and are generally derived from flash solvent or nonsolvent nanoprecipitation strategies; both of these strategies make it possible to control the dimensions. The surface of NPs is often modified by the inclusion of particular functional groups, which leads to various functions and the most effective deposition of the drug at the desired site [27].
2. Micelle polymers are framed through systematized self-assembly in an aqueous solution containing amphiphilic macromolecules, which results in extensive amphiphilic multiblock copolymers composed of hydrophilic as well as hydrophobic units and provides a core–shell nanostructure. The hydrophobic units connect with one another and are then assembled to create an interior core enclosed by an external corona comprising hydrophilic sections. Micelle dimensions tend to be established by changing the ratio as well as the form of hydrophobic and hydrophilic moieties. Freight molecules tend to be covalently conjugated to the polymers or physically encapsulated into the interior of micelles [28].
Figure 1.2 An overview of nanostructured materials for nanomedicine.
Adopted with permission from Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharmacological reports 2012;64(5):1020–37. https://doi.org/10.1016/S1734-1140(12)70901-5.
3. Organic, modified natural, or artificial polymers are generally used to make vesicles. Vesicles are developed by means of the aggregation of such type of molecules, and basically comprise an encapsulating surface that looks like a biological cell membrane, which has an interior volume of solvent. As a result of the unique architectural structure, both hydrophilic and hydrophobic medicines are equally enclosed in the vesicles [29].
4. Numerous nanogels that have turned out to be useful for drug-delivery applications are produced by using polymeric particles approximating a 3D molecular system formed through covalent interactions or in some instances self-assembly. These kinds of nanogels display an extremely porous polymer network, and drug molecules can be inserted into the interior porous volume of the gel structure. Sasaki and coworkers nicely explain a very easy and efficient method for the processing of a nanogel. The schematic diagram of a unique nanogel is presented in Fig. 1.3. The swelling characteristic of nanogels can be regulated for the governed release of a cargo drug under the appropriate environmental circumstances.
5. Dendrimers are produced from the successively regulated addition of elementary units to an initiator molecule that has a consistent treelike construction. Medicines are held in the branched entities through noncovalent bonding. For the same purposes, the engineered nanomaterials may act differently. Such nanomaterials may be of a biological nature, like lipids, phospholipids, lactic acid, dextran, or chitosan. The interactions of these materials with cells, for some of the biological components like phospholipids, will be quite different compared with the nonbiological components [31].
Figure 1.3 Schematic diagram of a nanogel for the drug delivery.
Adopted from Sasaki Y, Yamane S, Kurosu K, Sawada S-I, Akiyoshi K. Templated formation of hydroxyapatite nanoparticles from self-assembled nanogels containing tricarboxylate groups. Polymers 2012;4:1056–64. https://doi.org/10.3390/polym4021056.
2.1. Carriers and Vehicles for Drug Delivery
Advancement in nanotechnology have a substantial impact on various industrial sectors, particularly pharmacotherapy, together with materials technology and biotechnology. Within this arena distinct forms of NPs in the role of nanocarrier (e.g., liposomes, polymers, micelles, and consequently carbon-based nanomaterials) are steadily being applied in pharmaceutical applications, for example, the delivery of macromolecules as therapeutic agents (drugs and genes). The functions of (1) vehicles for drug delivery and (2) chemical stimuli exploited for triggering the smart NP–controlled release of drugs are well illustrated in Fig. 1.4.
The preferred drug-delivery system is supposed to be both site specific and timed-release regulated. The regulated release of drugs is often triggered by a range of external or sometimes internal stimuli, such as heat, solvent polarity, the action of biomolecules, or ionic strength, and the impacts of electromagnetic fields or light, as exemplified in Fig. 1.4. In addition to these types of stimuli, the temperature range is able to act as an internal or external stimulus. In the same way, redox, pH, and enzyme activity are well established as internal stimuli and also, alternatively, light and magnetic fields are recognized as external stimuli. Long-lasting, effective nanocarriers that can respond to variations in their surrounding environmental variables are of great importance for pharmaceutical as well as gene-delivery applications. The key word smart
has been applied to NPs that can respond in a foreseeable and specific manner to external/internal stimuli. Such types of carriers allow controlled release of the filled drugs, leading to a total depression of their adverse reactions while enhancing their therapeutic proficiency. Technologically smart NPs could possibly be responsive to various combinations of distinctive stimuli to give an additional boost to their specificity, for highly targeted as well as consequently regulated drug delivery. The development of unique nanomaterials from the thriving area of nanoscience has made improvements in the investigations in nearly all areas of technology and engineering. Smart nanostructures are being examined throughout the globe, and consequently, their individual and interesting characteristics provide expectations for the design of more effective drug-delivery vehicles. NPs are able to play a vital part as drug-delivery systems because of their dimensions; their physical, chemical, and electrical characteristics are undoubtedly tunable and they can be conveniently functionalized and applied at nontoxic levels for specific or passive drug delivery [32–34].
Smart NPs are expected to be effective agents for specifically targeted delivery of drugs, especially water-insoluble chemical compounds, which enables them to be useful in the vast field of dual-function cancer diagnosis and therapy systems. They are able to evade the reticuloendothelial system and may possess the ability to cross the blood–brain barrier in addition to the blood–testicle barrier. Their functionalization is a comparatively uncomplicated procedure, and suitable functionalization may also allow imaging coupled with real-time tracking of drug delivery to tumors. Even though the protein corona–induced screening of NPs has a major role in the mitigation of their cytotoxicity, protein attachments can likewise lessen the performance of targeted NPs by covering up or simply shielding the active targeting ligands. Numerous organic and inorganic NPs seem to have been employed in drug-delivery systems. As an example, graphene was identified recently and has had a significant influence on almost all areas of applied science, varying from nanoelectronics, gas sensors, or even biosensors to composites and, notably, to nanomedicine. In the field of stimulus-triggered drug-delivery systems, intensive research has been focused on graphene because it is comparatively biocompatible and can be functionalized quite easily. As a consequence of its theoretically calculated remarkable specific surface area of 2630 m²/g, just one layer of graphene oxide nanosheets could be packed with medicines to much more than twice its weight. The higher electrical and thermal conductivity of graphene nanosheets, their higher absorbance of near-infrared radiation, and their nontoxicity at minimal concentrations are highly unusual, and many scientific efforts are being directed toward making this nanomaterial into a stimulus-responsive type [35–38].
Figure 1.4 Various physical and chemical stimuli exploited for triggering smart nanoparticles in controlled release of drugs. GSH (glutathione); T (temperature).
Adopted from Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics 2016;6:1306–23. https://doi.org/10.7150/thno.14858.
2.2. Need for Nanocarriers for Drug Delivery: an Outline
The trends in the development of NPs for sensible drug-delivery systems are briefly reviewed in this portion of the chapter. An extensive point of view is provided for classifying their responsiveness to various stimuli, whether physical (light irradiation, magnetic force, electricity, temperature, mechanical agitation, or ultrasound), chemical (redox or pH), or biological factors (particular biomolecules as well as enzymes). We additionally take a look at the related nanotoxicity of these kinds of nanocarriers and their future in biological systems, along with the cell detection consequences of the protein corona. In addition, short background details of each class and their respective functional mechanisms are covered.
2.3. Thermoresponsive Nanoparticles
Heat and temperature are the most prevalent parameters adopted to trigger the release of medicines in a stimulus-responsive drug-delivery strategy that is spatiotemporally regulated. The hyperthermic character of most infected pathological areas and also tumors may possibly represent an interior stimulus. Appropriate exterior temperature adjustments can likewise be used to switch on thermoresponsive NPs, offering an appealing choice for a stimulus-responsive drug-delivery system, and NPs can swiftly respond to temperature alterations. Another significant potential of these kinds of drug delivery is implantation in the infected tissue and cells. The effective drug-delivery system must retain its load in improper situations and locations and discharge the medicine, with regulated kinetics, inside the target cells and tissues, for example, tumors [39,40]. Probably the most well established materials that have been employed in drug-delivery systems are temperature-sensitive polymers, which can change their configuration from a shrunken structure to an engorged structure in response to an alteration of temperature. Considering that there is certainly a modification of solubility with temperature, the perceptible characteristics of these particular polymers extend to the release of the encapsulated medicine. These are generally described by an upper critical solution temperature (UCST) and a lower critical solution temperature (LCST). By adjusting the temperature around the UCST or LCST, a phase transformation contributing to swelling or shrinking happens. Nanovalve devices are already being utilized in efforts to regulate medicine release along with the opening of gates that deal with the mesopores of mesoporous silica NPs, which enables them to become more sensitive to light and pH as well as temperature. Thermoresponsive polymers are used like an on–off switch
[41,42]. Just to illustrate, the authors made the very first use of a flexible nylon membrane, connecting N-isopropylacrylamide (NIPAAm) to the surface of the membrane. They demonstrated that at temperatures above 35°C shrinkage as well as collapse of NIPAAm took place, the nanovalve closed off, and as a consequence drug release was diminished. On the other hand, at a temperature below the LCST (35°C), the valve opened up, and afterward amplified medicine release was found, due to the swelling of the polymer [43]. Lue et al. employed another approach concerning the utilization of NIPAAm as well as acrylic acid (AAc) copolymers as brush hydrogels,
which were grafted onto the surface of a porous polycarbonate, and also revealed that at temperatures above the LCST, the NIPAAm-co-AAc brush experienced shrinkage leading to amplified release of the drug from the pores. However, by lowering the temperature below the LCST, the medicine delivery path was clogged as a result of swelling of the brushes [44,45]. Fig. 1.5 depicts the phase transition of the hydrogel.
Smart nanobombs are an additional category of temperature-sensitive drug-delivery systems, which manifest a reversible phase transformation in which they swell from the nanoscale to the microscale if the temperature reduces. This decrease in temperature is related to cold shock
or even cryotherapy.
To illustrate, Lee et al. produced a superexpandable pluronic/polyethylenimine (PEI) nanogel with 150-nm diameter at 37°C, which was used by infected cells. After cell uptake, the temperature was reduced to 20°C, whereby the nanogel had a phase transformation with magnificent swelling, its actual size increasing by 800-fold to 1.4 μm. This dimension of growth created a huge interior hydrostatic pressure within the cells and a physical force that caused the breakdown of the intracellular endosome compartments and blew up
the tumor cells, producing necrotic cell termination. Active stimulus-responsive nanocarriers with the highest possible level of sensitivity to negligible variations of body temperature, for example in the matter of tumors, are anticipated. Advancements concerning thermosensitive drug-delivery systems have already branched off for various purposes, such as necessary protein delivery in tissue engineering as well as for bone-tissue regeneration, codelivery of drugs and genes, triggered therapeutic angiogenesis in unnecessary vascular disease, development of a meaningful smart dermatological formula, ophthalmic drug delivery with upgraded corneal permeation and retention capacity, and mucoadhesive thermogel-based vaginal delivery. Further, utilization seems to have been documented in cutaneous protein delivery, treatment of inflammatory intestinal disease with upgraded colonic retention of drugs, delivery to the uterus for effectual treatment of uterine illness (e.g., bovine reproductive issues), effective minor hyperthermia with higher tumor retention, substantial specificity in the direction of cancer and angiogenic cells, and so on [47–50]. Distinct functions of temperature-responsive polymeric drug-delivery systems are mentioned in Table 1.1.
Figure 1.5 Schematic design of drug delivery with respect to temperature; T g (Glass transition temperature).
Adopted from Almeida H, Amaral MH, Lobão P. Temperature and pH stimuli-responsive polymers and their applications in controlled and selfregulated drug delivery. J Appl Pharm Sci 2012;2:1–10. https://doi.org/10.7324/JAPS.2012.2609.
2.4. Magnetic-Responsive Nanoparticles
The power of magnetism is seen as undoubtedly one of the best alternatives for an exterior stimulus because it hardly carries any kind of physical interaction with the entire body, compared with some other stimuli, for example, light irradiation and other types of electrical fields. Specially designed magnetic NPs may be tailored that are magnetically established and regulated; magnetic field-responsive particles are now being analyzed as valuable vehicles for medicine delivery and biomedical targeting. The preliminary work relating to this field was begun in 1960, when Professor M.W. Freeman and his colleagues initially developed the concept of employing magnetic fields in the role of an external trigger to release medicines. Individual domain NPs with inherent superparamagnetic abilities above their controlling temperature (blocking temperature) are dubious applicants for biomedical requirements in comparison with ferromagnetic NPs, in as far as they exhibit absolutely no dipolar attraction within magnetic fields but possess good-quality colloidal stability, with uniform distribution and dispersion within an appropriate polymeric matrix [52,53].
Table 1.1
PLGA–PEG–PLGA, poly(lactic-co-glycolic acid)–polyethylene glycol polymer.
Adopted with permission from No Title, (n.d.). https://doi.org/10.1016/j.apsb.2014.02.005.
The outstanding capability of magnetic NPs to produce heat under the effect of an exterior high-frequency alternating magnetic field (AMF) is known as magnetic hyperthermia. Magnetic NPs, when subjected to a powerful magnetic field, can certainly endure interior stresses and strains as a result of the fluctuating changes generated by magnetic forces. It is usually thought that the heat produced by magnetic NPs in an AMF is due to a couple of mechanisms of inherent rotational motion, possibly a Brownian kind of movement, with an extrinsic motion that predominantly occurs because of the thermal rotation of the magnetic decisive moment of the particles and as a consequence of relaxation via diffusion. This inductive hyperthermia is dependent upon a number of aspects, such as the magnetic saturation along with the hysteresis coefficient; both are equally associated with the dimensions of the NPs. Magnetic fields can be employed for various reasons, including regulated drug release, targeting, imaging, and guidance, in addition to hyperthermal treatment. To illustrate, polymeric NPs may experience thermodynamic phase transformation dependent on their UCST and LCST along with decrease, as stated earlier. This singularity can be generated by magnetic heating, raising the likelihood of drug-release structural disturbance of the NPs, or even by a pumping effect. It is actually valuable, if magnetic NPs are captured inside polymer particles, e.g., hydrogels, with another polymer chain, possibly as a random copolymer or maybe as an interpenetrated network, by adsorption of the chains to the surface of the magnetic NPs. An exterior magnetic field is also able to increase cellular uptake of NPs. Louguet et al. constructed silica-coated magnetic NPs functionalized with thermosensitive block-copolymer brushes with an LCST transformation. The use of an AC magnetic field triggered heat production by the magnetic core and also enhanced the activated release of the medicine on account of conformational alterations happening in the brushes. Magnetic hyperthermia is also governed by changing the field strength. Polymersomes are actually useful for magnetic field–triggered medicine delivery. The assistance and activating capability of magnetic-responsive materials is better than that of temperature or even pH triggers, and in addition they usually are beneficial over a certain distance larger than just a few centimeters. Extracorporeal magnetic instruction can be provided to conquer a number of boundaries of drug-delivery systems, for example, natural physiological obstacles or insufficient specificity for a specific tissue due to the fact that magnetic fields can be spatially targeted. For instance, to get over excessive blood flow in arteries and capillaries after an intravenous injection of nanocarriers, effective magnets can be positioned at the preferred sites [52–56].
2.5. Electrical-Responsive Nanoparticles
Electrically governed drug-delivery based on nanomaterials can be applied for continuous, pulsed, or as-required medicine release by making use of stimulated external electric fields. Electroresponsive medicine release is usually carried out with a variety of media such as electroresponsive nanostructures, electroresponsive compound-loaded materials, or the combination of electroresponsive materials with vehicles responsive to various stimuli, including temperature as well as magnetic field influences. The inclusion of polyelectrolytes containing a wide variety of ionizable species confers response to an electrical stimulus by means of tapering or even expansion of the polymers. To illustrate, Ying et al. created electroresponsive hydrogel NPs for specifically targeted delivery of an antiepileptic medicine. A heightened level of ionization in the structure was accomplished under the effect of an electric field because of the presence of the polyelectrolyte poly(sodium 4-vinylbenzene sulfonate). The swelling ratio and particle size can be adjusted using the exterior electric field. Researchers at Nagoya University (National University of Japan) found another way to generate stimulus-responsive materials in a foreseeable manner. These researchers employed the following procedure to design a unique material: an assortment of carbon nanorings together with iodine was assembled, which was electrically conducting and also irradiated white light once it was subjected to electricity. The modern strategy could assist in producing a group of reliable stimulus-responsive materials that can be used in storage devices, in synthetic muscles, and as pharmaceutical delivery systems (Fig. 1.6A and B) [33,57–59].
Figure 1.6 Novel method for electrical stimulus–responsive materials. (A) Strategy to develop electrical stimulus–responsive materials using a porous solid. (B) Electrical stimulus–induced generation of electric conductivity and white light fluorescence of [ n ]CPP–I (cycloparaphenylene–iodine assembly).
Adopted with permission from Ozaki N, Sakamoto H, Nishihara T, Fujimori T, Hijikata Y, Kimura R, Irle S, Itami K. Electrically activated conductivity and white light emission of a hydrocarbon nanoring–iodine assembly. Angew Chem Int Ed Engl 2017;56:11196–202. https://doi.org/10.1002/anie.201703648.
2.6. Light-Responsive Nanoparticles
Illuminating irradiation is useful to stimulate medicine release. The absorbance of photon energy by materials is dependent upon the respective energy band-gap of the electron in the topmost filled molecular orbital. Light-absorbing materials have an extensive number of realistic applications, such as protecting against UV irradiation in daylight, developing electrical power from solar energy, and behaving like optical contrast agents or fluorescent reporter molecules. Among the number of stimuli used in worthwhile drug-delivery systems, light irradiation sparks considerable interest because of the simplicity of tuning its intensity, the capability to regulate the exposure time as well as the specific location of the tissue, the choice of desirable beam criteria, and the indisputable fact that photoregulated stimulation is considered noninvasive. UV (10–300 nm), visible, or even near-infrared radiation zones (650–900 nm) of the light spectrum are often used to prompt pharmaceutical or gene release from properly developed nanocarriers [61,62]. Even though the considerably higher energy per photon of UV light allows it to ionize as well as cleave covalent bonds with energies in the range of 100 kcal mol−¹, the possible hazards of far-UV to tissues and probable photodestruction of active molecules tend to make these types of wavelengths inappropriate for therapeutic purposes. However, the use of consistent long-wave UV lasers (wavelengths of 200–300 nm) may keep both medicines and tissues intact. UV irradiation is a bit more cytotoxic compared with the alternative regions of the light spectrum, and consequently, its inadequacy to go deeply into the tissue as a result of its absorption by endogenous chromophores (for example, oxy- and deoxyhemoglobin, lipids, and water) is seen as an additional disadvantage. Therefore, wavelengths below 650 nm are viewed to be more appropriate to trigger drug release for skin-based therapy of pathological states, having an effect on the skin layers as well as the mucosa. Supramolecular assemblies formulated to utilize visible light are comparatively unusual. Near-infrared possesses much better transmission throughout tissue because of its actual lesser absorption as well as scattering in tissue due to the fact that hemoglobin, water, and lipids hardly absorb it, leading to considerably less harm to cells and tissues in comparison with visible light. Certain organic chromophores are able to concurrently absorb a pair of photons of low energy [63–66].
2.7. Mechanical-Responsive Nanoparticles
Mechanoresponsive nanostructures are an additional strategy for worthwhile drug delivery on which a small number of reports have been published as of this writing. Usually, this strategy relies upon the assembly as well as disassembly of mechanoresponsive molecules making use of pressure as well as other physical stimuli with the objective of switching the total volume. This strategy promises a biomimetic and simple mechanism for regulated drug delivery in comparison to other external stimulus-based techniques. Just to illustrate, cyclodextrin addition complexes may be influenced by pressure; and destabilization of the inclusional complexity in cyclodextrin–alginate hydrogels via mechanical compression was examined with regard to the patient-regulated release of ondansetron. Faster medicine release took place when the inclusional capability of the β-cyclodextrin was decreased by using stress on an implantable gel; hence there is a growing demand for use of this approach to therapy for serious queasiness due to chemotherapy. Shear stress is a much less frequently mentioned mechanical stimulus that can be used in the design of smart drug-delivery systems [33,59,67]. Shear stress is greater in smaller sections of arteries in comparison with healthy arterial sections. This a significant difference that may be a much better physical/mechanical trigger to prompt medicine release in arterial blood vessels compared with supplementary biological or chemical stimuli. Cardiovascular system disease problems, for example, stenosis and atherosclerosis, may be favorable applications of such endogenous mechanical stimulus responsiveness. Take, for example, a report on organized lenticular liposomes, which were stable under a fixed environment; however, they were not stable in the elevated shear stress of atherosclerosis. The lenticular morphology resulted in a favored break along the equator of the nanostructures, and the amplified release of drugs in the regions of excessive shear stress was found. A second study showed microscale aggregates of NPs, which were separated into their particular nanoscale components under substantial local shear stress, for therapy of thrombosis [68–70].
2.8. Ultrasound-Responsive Nanoparticles
Ultrasound or ultrasonication is regarded as an exterior stimulus, which can produce a mechanical as well as a thermal stimulus. Ultrasound is of terrific dominance in current medical research and development and also has a position in several health care applications, for example, diagnosis at lower frequencies for imaging, and at higher frequencies therapy for the removal of irregular tumors. In the concept of ultrasound-responsive nanocarriers, three primary characteristics are essential: efficient and constant drug encapsulation before dispensing the employed ultrasound waves to the tissue, effective medicine release due to the response to specific ultrasound waves, and the ability to track drug release for imaging together with therapeutic requirements. The biomedical variety of ultrasound waves ranging from 0.1 to 50 MHz has been reported, and the release of medicine from the carriers can at the same time enhance the permeability of biological obstacles via the creation of cavitation bubbles and amplified temperature, leading to enriched drug diffusion. Intonation of an aqueous medium can lead to a unidirectional stream that can interrupt tissue architectural structures. Furthermore, these types of waves generate an oscillating pressure between the layers of biological membranes and produce pores inside, as a result improving the permeability of cell membranes [71,72].
The consequences of ultrasound for transdermal medicine delivery have been extensively mentioned in various studies. The absorption coefficients of ultrasound fluctuate among the distinct parts of the body as well as tissues. Certain tissues, for example, bones, possess considerably higher coefficients in comparison with soft tissues. However, research has shown that the minimum threshold of ultrasound pressure and frequency, along with the collapsed length, may have an impact on this tissue disturbance and may also regulate brain damage if ultrasound is carried out on the head (the consequences of ultrasound are demonstrated in the Fig. 1.7). In a similar manner, as of this writing, scientists are generating a meaningful modern drug-delivery technology that depends on the contrast-enhancing characteristics of microbubbles. This technique is intended to assist ultrasound operators to find tumors depending on their occurrence as well as the tumor-specific network of compact blood vessels. Once a tumor is found, the system shatters the shells of the microbubbles via a concentrated, high-energy ultrasound pulse. As soon as the shells are demolished, the contents of the microbubbles leak into the surroundings, giving the drugs access to a tumor instantly rather than after traveling through the entire bloodstream (Fig. 1.7) [73–75].
Figure 1.7 Schematic diagram showing the effects of ultrasound waves on efficient drug delivery, (A) Drug-loaded microbubbles, (B) the transported substances are released at the site of the tumor [76] .
2.9. pH-Responsive Nanoparticles
It is actually well established that considerable pH gradients can be found throughout the entire body (particularly the gastrointestinal system tract); significant pH variations really exist and these pH rates fluctuate among the lysosomes (4.5–5), endosomes (5.5–6), Golgi apparatus (6.4), and cytosol (7.4). pH differences may be caused by the presence of microbes; there is certainly an acidic milieu in healing wounds and also an alkaline milieu in nonhealing injuries [77,78].
Most significantly there can be lower pH recorded in tumors compared with the respective normal tissues (7.4). This happens as a consequence of the swift proliferation of cancer cells outrunning the blood flow, leading to insufficient provision of oxygen as well as nutrients, and in fact to the consequent production of lactic acid that is generated by glycolysis instead of oxidative phosphorylation in normal cells. This event is termed the Warburg effect. These types of extensively varied pH situations in wide-ranging biological systems have inspired the creation of pH-responsive drug-delivery systems. pH-responsive nanomaterials have shown a number of functions such as pH sensors, theranostic functions, controllable switches, controlled-release surfaces, feasible wettability, and cell-recognition devices. Unique pH-responsive nanocarriers of biphasic colloidal particles and also Janus particles
have already been produced with sophisticated capabilities allowing them to experience morphological changes upon pH alteration, a completely new idea of supreme importance in the design of pH-sensitive drug-delivery systems [40,79,80]. There have been numerous improvements in acute drug-delivery systems influenced by the pH responsiveness of nanosystems during the past few years, which may have led to amazing revolutions in the analysis as well as treatment of a variety of disease problems and also issues including malignancies and infections. They have demonstrated upgraded antitumor effectiveness, a lowering of the side effects of chemotherapy, and delivery of nucleic acids, proteins, peptides, and so forth. pH-responsive drug-delivery systems are able to considerably boost the oral bioavailability of anticancer medicines, generating effective slowing down of tumor expansion, lessening of widespread toxicity, and enhancement of the selectivity for tumor cells, while providing much less cytotoxicity in the direction of normal cells. The pH-sensitive nanomaterials that have been employed in drug-delivery systems are typically categorized into organic, inorganic, and hybrids, and their methods of synthesis, characteristics, and applications have recently been analyzed. The construction of pH-responsive nanocarriers demands an excellent insight into their advantages and use as tools. Peptides are generally seen as effective as well as secure nanocarriers for nonviral delivery of genes to cells, in comparison with bacterial gene delivery systems, even though their structure appears to have been influenced by these bacterial dimensions. Peptide dimensions provide useful advantages, for example, the capability to go through the cell membrane, endosomal fusion (in the minimal pH of the endosome), and nuclear delivery [33,34,67,81].
2.10. Redox-Responsive Nanoparticles
Redox-responsive drug-delivery systems are one of the more beneficial techniques for stimulus-responsive tumors as well as gene treatment. Redox-sensitive degradable nanosystems offer certain positive aspects over many other stimuli, including pH. An excellent response to excessive intracellular amounts of blood glutathione, the release of medicine directly into the nucleus and cytosol, and consistency in extracellular surroundings in which blood glutathione ranges are at minimum are examples of these benefits [40,82,83]. The redox surroundings are influenced by a connected group of redox partners, for example, NADP+/NADPH. The cytoplasm possesses consistent metabolic oxidases, which make an environment for redox signaling that is affected by nitric oxide synthases and NADPH oxidases. Mitochondria in each cell almost all have reducing contents because they are tremendously sensitive to oxidation. The amount of electron transport in mitochondria is greater than in various other cellular spaces. Nuclei are very resilient against oxidation; however, they possess lower redox potentials. The secretory path provides disulfide bonds in proteins that can be exported, through the effects of oxidizing systems and enzymes. The redox possibilities of a cell are typically influenced by the functional state of the cell, most notably the induction of apoptosis, differentiation, adhesion, and proliferation [84–87].
2.11. Various Biomolecular-Responsive Nanoparticles
The presence of particular biomolecules, for example, glucose, adenosine triphosphate, deoxyribonucleic acid, and reactive oxygen species, in precise physiological sites or in pathological situations of living systems has inspired the growth and development of biomolecule-sensitive sophisticated and effective systems. Glucose-responsive regulated release systems have already been the majority of smart drug-delivery systems examined for handling insulin treatment for diabetics to blood glucose ranges. Various mechanisms are being adapted to design these types of smart systems, which generally depend on the transformation of glucose to gluconic acid by glucose oxidase (GOx). By way of the example of human insulin, chitosan and GOx enzyme were utilized in nanocapsules by means of monodispersed microgels that swelled in hyperglycemic situations, resulting in the enzymatic transformation of glucose, protonation of the pH-responsive chitosan matrix, and release of insulin in the form of a self-regulating nanovalve system for therapy of type 1 diabetes [88–90].
2.12. Enzyme-Responsive Nanoparticles
Enzymes perform an important role because of their outstanding biorecognition features and tremendous catalytic characteristics. Their excessive selectivity, as well as their beneficial performance in enzyme-catalyzed responses, is extremely useful in nanomedicine. Because several enzymes are overexpressed in particular tissues, and their concentration can be further increased in an infected state, enzyme-responsive NPs are generally a superb candidate for developing an excellent drug-delivery system. In addition, for medical diagnosis requirements, evaluating or finding an enzyme activity is very useful, for instance, whether its actual dysregulation is a certain characteristic of a particular disease. A drug-delivery system design in this respect would be able to use either a physical or a chemical mode of action. In a chemical manner, if the nanomaterials are regulated by the enzyme, it is easy to design the nanomaterials to release their drug load by degrading the individual structures, which can range from those created from polymers to those with mesoporous silica cores [35,91,92]. Based on the approach employed, transformation or degradation of the nanocarriers by the enzyme may also release the therapeutics further; therefore multimodal nanomedicines with mutually beneficial results may be additionally made to this end. In the physical manner of action, the enzyme-responsive NPs are usually intended to ensure that their macroscale structure is modified by the enzyme while leading to controlled release. In this strategy, the surface of the nanomaterial is altered by adding molecules that are influenced by enzymatic responses causing a general change in their physical properties. In this example, both physical and chemical strategies that enable the system to serve on the basis of necessity are recommended. Dysregulation of enzymatic activity was noticed in various pathological scenarios, which brought about new concepts not only for drug delivery in vivo, but also for the design of novel ultrasensitive sensors for diagnosing disease. Nanomaterials that are employed in enzyme-responsive drug-delivery systems tend to be sensitive to hydrolases or to oxidoreductases [31,67,93].
The enzyme-responsive technique for effective drug delivery is dependent on smart and cost-effective polymers that work as carriers that can release the drug simply upon the catalytic action of the enzyme. The reaction mechanism of enzyme-sensitive materials demands one part that is an enzyme-sensitive moiety, which often is a substrate along with a substrate replicate of the enzyme, in addition to a subsequent component that is accountable for alterations in the interactions inside the nanomaterial that can give rise to macroscopic transformations and drug release. This course of action would not usually call for adjustments in available drugs because they do not have to be chemically connected; however, they may be physically entrapped. In the numerous categories of enzymes, hydrolases are sometimes considered a good choice as effector biomolecules in enzyme-activated drug-delivery systems. In a rational drug-delivery system, the carrier nanomaterial is typically assimilated by the enzyme any time the concentration of both species is sufficient. This strategy is predominantly useful in several treatment procedures, in particular chemotherapy, because it is able to reduce the negative effects of a few hazardous drugs. A few of the enhancements in enzyme-degradable nanocarriers are analyzed by a number of articles mentioned earlier. Proteases and related enzymes have paramount responsibility in many synthetic cellular operations, such as angiogenesis, conception, wound repair, stem cell mobilization, blood coagulation, immune response, necrosis, and apoptosis. Through their actions, the therapeutic results of the drug will be raised and the toxic impacts will be reduced due to lower required doses [35,67,94,95].
3. Types of Nanocarriers: Fabrication Approaches and Applications in Drug Delivery
To deal with difficulties related to conventional medicine delivery caused by minimal drug solubility, overdose, short distribution period, inadequate biodistribution, insufficient selectivity, negative effects, toxin levels, and undesirable pharmacokinetics and pharmacodynamics, significant studies have focused since the beginning of the 21st century in the direction of the growth and development of new, even more effective and useful drug-delivery systems. As per an information search, the majority of medicines are hydrophobic and are not able to dissolve in the bloodstream, which decreases their pharmacological effectiveness and performance. Because of this, their delivery path is especially demanding. Alternatively, a few bioactive agents, for example, proteins, nucleic acids, enzymes, and genes, administered via oral or even intravenous paths, are typically readily degraded by the metabolism and are not able to access the designated targeted sites. Local drug-delivery systems are considered a promising alternative to systemic routes and conventional drug-delivery systems to address many of these limitations, especially by means of local implantation. Local drug-delivery systems at the earlier stages of development were made of biodegradable implants based on poly(methyl methacrylate), poly(glycolic acid) matrices, poly(lactic acid), hyaluronan, chitosan, fibrin, collagen, hydroxyapatite, silk, ceramics, and injectable calcium phosphate cements [35,67,96–98].
These systems have been employed for the delivery of bioactive agents in bone repair work or alternatively tissue regeneration and implantation. Regrettably, many drawbacks are implicit in these systems, for example, the uncontrolled blast release of therapeutics along with the malfunctioning of sustained release over a very extensive period of time or at the preferred dosage. These problems are predominantly caused by the amorphous condition of the biomaterials or their unordered porous architectural structure. Therefore, it is necessary to develop a local drug-delivery system that can successfully deliver drugs with foreseeable release kinetics as well as in sufficient quantities recommended to treat a variety of diseases (cancers, inflammation, and pathogenic infections); most of these are becoming crucial in orthopedics. At the same time, degenerative bone illnesses, for example, osteomyelitis and osteoarthritis, are recognized issues that are spread worldwide, as is the increasing variety of implantation surgeries, which offer serious postsurgical complications (bone marrow inflammation through bacterial contamination, and also blood flow lessening as a result of the compression of blood vessels post–implant surgery). To handle these types of complications, innovative implants for medicine delivery with ordered nanoporous and nanotubular arrangements have been considered, making use of nanotechnology-based tactics [67,96,99,100].
The use of nanotechnology in drugs, known as nanomedicine,
is widely seen as a growing area with extensive opportunity for the growth and development of innovative as well as top-level medicine-delivery systems. The most important illustrations are nanoporous anodic alumina
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