Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part I) E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
The development of a vector for the delivery of therapeutic drugs in a controlled and targeted fashion is still a major challenge in the treatment of many diseases. The conventional application of drugs may lead to many limitations including poor distribution, limited effectiveness, lack of selectivity and dose dependent toxicity. An efficient drug delivery system can address these problems. Recent nanotechnology advancements in the biomedical field have the potential to meet these challenges in developing drug delivery systems. Nanomaterials are changing the biomedical platform in terms of disease diagnosis, treatment and prevention. Nanomaterials aided drug delivery provides an advantage by enhancing aqueous solubility that leads to improved bioavailability, increased resistance time in the body, decreased side effects by targeting drugs to the specific location, reduced dose dependent toxicity and protection of drugs from early release.
In this two-part book, the contributors have compiled reports of recent studies illustrating the promising nanomaterials that can work as drug carriers which can navigate conventional physiological barriers. A detailed account of several types of nanomaterials including polymeric nanoparticles, liposomes, dendrimers, micelles, carbon nanomaterials, magnetic nanoparticles, solid lipid-based nanoparticles, silica nanomaterials and hydrogels for drug delivery is provided in separate chapters. The contributors also present a discussion on clinical aspects of ongoing research with insights towards future prospects of specific nanotechnologies.
Part I covers the following topics:
· Polymeric nanoparticles
· Characterization of nanostructured systems for bioactive compound delivery
· Liposomes
· Dendrimers
· Nanomicelles
· Carbon nanotubes
· magnetic nanoparticles
The book set is an informative resource for scholars who seek updates in nanomedicine with reference to nanomaterials used in drug delivery systems.
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Seitenzahl: 564
Veröffentlichungsjahr: 2021
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FOREWORD
Engineered nanomaterials (ENMs), due to their interesting physicochemical properties such as smaller size, larger surface area, electrical, optical and magnetic properties are being sought in a wide range of applications including technology, cosmetics, food packaging, medical imaging and drug delivery. Carbon nanotubes (CNTs), quantum dots, mesoporous and amorphous nanosilica, nanosilver, nano titanium and zinc oxides are some of the ENMs currently in commerce. Nevertheless, the attractive physicochemical characteristics of the ENMs also create concerns when exposed to, with respect to human and ecosystem health. This book on “nanomaterials” is very timely, and touches upon the different aspects of application of ENMs in drug delivery. The chapters in this book discuss the use of a spectrum of nanomaterials in drug delivery including nano metal oxides, CNTs and lipid nanoparticles, their various nanoforms, synthesis, characterization, efficacy in terms of drug delivery and the need for toxicity testing. Physicochemical characterization is an important aspect in nanotechnology, especially, in the realm of drug delivery. The synthesis of ENMs can introduce batch to batch variation in terms of size, shape, surface characteristics and chemical composition based on source materials and synthetic routes. Moreover, the stability of ENMs can be affected based on storage conditions. This book has thus given an importance to the aspect of physicochemical testing and discusses the different analytical methods to assess morphology, surface functionalities, behavior in solution, stability, etc. This book on “nanomaterials” also identifies the need for toxicity testing of the ENMs in drug delivery. Toxicity testing is a critical component for the selection of safer ENMs for application in drug delivery and to meet regulatory standards. This book has done a fantastic job in familiarizing the reader with the scope and application of the various ENMs and their nanoforms in drug delivery along with some insight into medical imaging and computational aspect of structure-activity relationships. I congratulate the editor Dr. Surendra Nimesh on doing a fantastic job with this book on the application ENMs in drug delivery, which is one of the promising emerging medical technologies.
PREFACE
Chemically synthesized drugs have been one of the major tools to combat several diseases, including bacterial and viral infections. These drug molecules however, face several barriers that include poor cellular uptake and instability in the physiological environment that mask the therapeutic potential. In order to circumvent these issues, there is a need to develop vehicles that could effectively and safely transport the drug molecules to the target sites. Nanotechnology has come up as one of the potent and viable strategies due to which, several candidates have been proposed, such as nanoparticles, liposomes, carbon nanotubes, mesoporous silica nanoparticles, etc. These vectors can be modulated to achieve delivery of even those drugs which are highly unstable making it difficult to reach the desired sites. This book compilation brings together some of the eminent scientists, working in different dimensions of nanotechnology. They have contributed chapters in their domain of knowledge that we believe would be really useful, not only for the young researchers, but also for the experts looking for some exhaustive compilations.
Chapter 1: It provides a brief exposure to nanotechnology and the imbibition of the drug delivery concept, with relevance to nanotechnology. Some of the pros and cons associated with the implication of nanotechnology have been outlined in this chapter.
Chapter 2: It provides an exhaustive account of the tools and techniques employed for the characterization of nanostructures. This chapter is an overview of the most employed techniques, including dynamic light scattering and laser diffraction for the determination of size distribution, zeta potential and its relationship with the stability and the surface charge of the particles, microscopies (optical microscopy, SEM, TEM, AFM) utilized in morphological analyses, spectroscopies in the infrared or ultraviolet-visible regions, and X-rays diffraction, which help to elucidate the crystalline state, polymorphism and drug-nanosystem interaction and the thermal analyses, which can provide information about the physical state, crystallinity, and stability.
Chapter 3: It deals with liposomes which are spherically shaped micro-vesicles composed of a bilayer of natural or synthetic non-toxic phospholipids, which spontaneously form closed structures when they are hydrated. This chapter accounts for the materials involved in the preparation of liposomes, i.e., techniques for preparation, characterization studies and application of liposomes for drug delivery.
Chapter 4: This chapter discusses dendrimers, which are highly branched synthetic polymeric macromolecules with a distinct three-dimensional spherical shape and nanometric size (1 - 100nm). This chapter reports the role of dendrimers in drug delivery systems for various agents in biology and medical science. Additionally, it covers the important aspectsof the dendrimers in the diagnoses of different types of cancer diagnosis and other therapies.
Chapter 5: It discusses nanomicelles which are colloidal dispersions containing a hydrophobic core and a hydrophilic shell that self-assemble into the nanosize range of 10 -100 nm. Pharmaceutically, nanomicelles serve as outstanding carriers as they can avert or moderate drug degradation by dropping adverse side-effects, thereby augmenting drug permeation through biological barriers with very minimum or no irritation at all, which ultimately enhance bioavailability. In this chapter, a critical history of nanomicelles is provided from its fundamental theory to preclinical and clinical achievements.
Chapter 6: It outlines details about carbon nanotubes (CNTs) which are defined as concentrically rolled graphene sheets but with many chiralities and helicities. Various synthetic approaches like arc discharge method, laser ablation methods, chemical vapour deposition, and pyrolysis are employed to produce CNTs. The present chapter explains the discovery of CNTs, their types, synthetic methods, various reactions possible with the usage of CNTs, applications of CNTs, safety profile, and the challenges involved.
Chapter 7: It describes the application of magnetic nanoparticles in drug delivery. Numerous magnetic nanoparticle-based formulations are already available in the market and even many more are under different stages of development. This chapter describes the progress done in this area due to the well-established synthesis procedures of size and shape-controlled magnetic nanoparticles, as well as their well-recognized surface functionalization approaches.
List of Contributors
Polymeric Nanoparticles as a Promising Drug Delivery Vehicle
Nidhi Gupta1,Ramesh Chandra2,Surendra Nimesh3,*Abstract
With every era, medical science faces challenges to provide the best health care and efficient drug therapy for the treatment of existing diseases. Current regimes of chemical drugs, though beneficial in a certain sector, have several disadvantages; cytotoxicity and adverse health effects are of primary concern. To accomplish efficient as well as the safe mode of transport for drugs and bioactive molecules, nanotechnology has provided an answer in terms of nanomedicines. Polymeric nanoparticles that can easily be modified to suit the needs not only act as a vehicle to efficiently deliver the drug to the target site but also enhance the bioavailability of the drug. Polymer-drug conjugation delivers the drug specifically to the targeted tumors. The conjugation facilitates increased retention time and enhanced cellular permeability that enables better suppression of the tumors. This chapter gives an insight into the properties of nanoparticles, highlighting the associated advantages and limitations of polymeric nanoparticles as a vehicle of drug delivery to cells.
INTRODUCTION
The desire to develop efficient drug delivery vectors with required therapeutic need lead to envision of several possible strategies, including the usage of modified or natural polymeric nanoparticles. The bio-availability and distribution of the drug depend upon its physicochemical properties and molecular structure. Due to the uneven distribution of drugs and its accumulation at non-specific sites, the desired efficacy of the drug is reduced at the diseased site that might cause
toxic and undesirable effects. Henceforth, researchers are always seeking the challenging task of looking for new strategies, to develop delivery systems that may possess maximum therapeutic potential with minimal toxicity. To design and develop better targeting strategies to deliver drugs with more efficiency and specifically, it is essential not only to understand the characteristics of the target but also the mechanism of action of the drugs involved for targeting.
Particle-based drug carriers have been modified to provide better accessibility and efficiency of the drug at the site of action with its increased availability. For desirable therapeutic response, the size of the matrix has to be controlled along with the entrapped drug molecule. According to the size of the particles, the following categorization is done:
For particles in size range 50-200 µm: macroparticles1-50 µm particles are termed microparticlesParticles with size 1-1000 nm are categorized as nanoparticlesNanoparticles and microparticles have found their utilization in several genes and drug delivery based researches. The size of microparticles restricts their entry into capillaries and, therefore, are unavailable at tissue sinusoids, though they were found being in circulation. However, these particles get accumulated in the adjacent tissues adjoining the capillaries and were observed to discharge encapsulated drug molecules gradually at the target site. The modified microparticles act as depot system that can be delivered via subcutaneous, intraperitoneal, intra-arterial or intravenous administering routes, resulting in a gradual release of the drug and protection from in vivo degradation. Engineered polymer with controlled size and swelling and breaking properties can help in the efficient release of drug at the target site. Taking into consideration all these key factors, starch, albumin, polylactic acid, and ethyl cellulose have been deployed to prepare biodegradable microparticles that would be used for chemoembolisation.
The limitation of microparticles was rapid clearance by RES (reticuloendothelial system) defense mechanism. To overcome this rapid removal of the particles from circulation and to have prolonged circulation of particles, a decrease in particle size was sought. The reduction in particle size renders nanoparticles a better carrier vehicle not only for polynucleotides but also for enzymes and proteins, irrespective of the route of administration. Reduced size nanoparticles have increased surface area and henceforth, enhanced adsorption of drug or biological molecules. Nanoparticles not only release the encapsulated or adsorbed drug or a bioactive molecule at the target site but also act as carriers for these molecules. The size of the particles in the nano range can render them to pass easily through capillaries and made them more available for systematic application with significant impact. Particles, either metallic or polymeric, that fall in size range of 1-100 nm are termed nanoparticles. For the first time in science, polymeric nanoparticles were prepared and characterized by Birrenbach and coworkers in 1976 [1]. This study had triggered extensive onset towards research involving designing and developing novel nanoparticles based carrier systems. Thus, these nanoparticles can be employed for the targeted delivery of drugs and biomolecules. On reaching the target site, the entrapped drug or biomolecule in the polymeric nanoparticles can be released from the complex through either one or a combination of the following mechanisms:
Hydration of the nanoparticles matrix led to swelling and henceforth, bursting of the particles, or slow-release by diffusion.The modified polymeric nanoparticles can be targeted for enzymatic degradation at the specific site that resulted in the release of the drug.Drug molecules entrapped in swollen nanoparticles could be released by chemical cleavage.One of the most remarkable repercussions of nanotechnology is nanomedicine; the latter term is an umbrella term that conjugates various types of particles in nanoscale size with medical potentials such as liposomes, quantum dots, polymeric micelles, polymer-drug conjugates, dendrimers, inorganic nano particles, biodegradable nanoparticles, and other materials. In nanomedicine, the most potential candidate is nanoparticles that possess wider significant applications in the fields of target-specific drug and gene delivery. The small-sized nanoparticles are capable of better penetration in the tissue and henceforth, having targeted activity at the specific site of action [2]. Polymeric nanoparticles are explored extensively as an efficient delivery vector for drugs, more promising for anticancer drugs. These nanocarriers are modified for the release of drugs at a specific site, for example, the particles can be targeted or release drug based on stimuli response [3].
Polycationic polymeric nanoparticles are extensively worked upon to develop delivery strategies for DNA and siRNA. Polymeric nanoparticles can be categorized, namely, as (i) nanospheres that are spherical shaped particles of nanometer size. These nanoparticles can be modified such that the drug or biomolecule of choice can either be trapped in the spherical nanoparticles or adsorbed on the outer surface or both. (ii) Nanocapsules possess a solid polymeric shell with an inner liquid core. The required molecules can either be adsorbed on the outer surface or entrapped inside the core or both. Other than these two common forms, various other forms of nanoparticles have also been reported, for example, nanorods, nanotubes, cones, spheroids, etc. Several natural polycationic polymers, such as chitosan and synthetic ones, including PEI, have been investigated to deliver nucleic acids either in the form of nano-complexes or particles.
Recently, microfluidics-based strategies are researched to prepare nanoparticles that can be tuned to be tailored and reproduce structure. The process is being conducted in a microchannel, in a very controlled manner; small volume of liquid reagents is rapidly mixed to form nanoparticles. These synthesized polymeric and lipid nanoparticles can be used for their applications in nanomedicine [4].
POLYMERIC NANOPARTICLES FOR DNA/SIRNA DELIVERY
Nucleic acids are being extensively investigated as a potent tool for therapeutic gene expression inhibition. DNA and siRNA have similar physicochemical properties, rendering vectors suitable for DNA delivery to be a useful carrier for siRNA as well. Linear and branched, both types of cationic polymers, are efficiently used as DNA transfecting agents. The mechanism behind this complex formation is that the positively charged polymers form polyplexes via electrostatic interactions with the negatively charged phosphates of DNA [5], resulting in DNA condensation and protection from being degraded by nucleases. A similar mechanism is utilised for the formation of siRNA-polymer polyplexes or nanoparticles mediated siRNA delivery. Some other polymeric vectors such as micelles, nanoplexes, nanocapsules, and nanogels were also employed for siRNA delivery [6]. A few studies in this arena had shown remarkable strategies for the delivery of specific siRNA for the treatment of several human diseases or silencing of endothelial genes without having any off-target impact on hepatocytic genes [7, 8]. The physico-chemical properties of polyplexes such as surface charge, structure, and size depends on the ratio of the positive charges present on cationic polymers (due to the presence of amino group) to the number of negatively charged phosphate groups of siRNA (i.e., N/P ratio).
ADVANTAGES AND LIMITATIONS OF NANOPARTICLES
Owing to their compact size, nanoparticles can easily cross cellular membranes to facilitate gene or drug distribution in the cells. These are remarkably less cleared by reticuloendothelial system clearance due to their smaller size and could penetrate better into tissues and cells. Polymeric nanoparticles have advantages, and can easily be manipulated because of varying molecular weight, linear and branched, and possess better biostability, are safe and less immunogenic. Even proteins that are beneficial for the study of stem cell research, for example, stromal cell-derived factor 1 (SDF-1) and bone morphogenetic protein 2 (BMP-2) that are involved with mobilization and osteogenesis of mesenchymal stem cells, can be successfully delivered using chitosan-agarose-gelatin nanoparticles [9]. The cost of preparation is quite low and these particles have a high delivery range with respect to the size of the transgene to be delivered. For specific targeted delivery of either plasmids or siRNA, several moieties such as RGD peptides or transferrin can be attached to polymeric nanoparticles [10, 11].
Due to the small size of nanoparticles, usually 10 to 200 nm size ranges, enhanced interaction of nanoparticles with surface biomolecules or within the cell occurs. This size also makes nanoparticles a beneficial delivery vehicle as they can reach inside the tissues, such as tumors with great specificity. This led to improved targeted delivery of genes or drugs to the cancerous cells [12]. But polymeric nanoparticles do have some limitations as well. The polycationic polymers constituting nanoparticles have a charge present on their surface thus; can have strong electrostatic interaction with charged plasma membrane proteins. This leads to instability and, finally, the rupturing of the plasma membrane [13]. In a comparative study between differentially charged polymeric nanoparticles, it was observed polycationic polymers have the highest toxicity, followed by neutral and anionic ones [14]. To overcome the toxicity problem, strategies were developed based on a decrease in surface charge by coating particles with hyaluronic acid or PEG [15, 16]. Of linear and branched PEIs, the former ones are less toxic and henceforth, more suitable for transfection, even at higher N/P ratio [17]. In addition to the above-mentioned limitations, PEI can possess adverse effects as it is a non-biodegradable polymer. Due to this, PEI can be accumulated within the cells and thus, may interfere with important intracellular biochemical processes [18, 19]. The charge of complexes decides the fate of the activation of the complement system. The complement system gets activated if the ratio of positive to negative ions is increased, but its activation is transversely lowered as the PEI/DNA complexes approach neutrality [20, 21]. To reduce the toxicity of complexes, chemical modifications are carried out; in that, small molecular weight PEIs are joined together to generate higher molecular weight PEIs molecules with the help of bi-functional linkages that are degradable. Another polymer that has found its usefulness as an efficient delivery vector for nucleic acids is chitosan. It has applications as a remarkable in vitro and in vivo siRNA delivery vehicle that is capable of ensuring gene knockdown with minimal toxicity [22, 23]. However, one of the major limitations associated with the usage of chitosan is their low transfection efficiency. The physio-chemical requirements for transfection of nanoparticles are not 100% known and henceforth, must be well explicated before their clinical applications. At times, non-specific stimulation does occur for siRNA delivery via nanoparticles. This could be because of the onset of innate immune inflammatory responses that in turn can stimulate type I interferon (IFN) synthesis. RNA duplex interaction with endosomal Toll-like receptors (TLR) leads to INF production that can be started with the delivery of nanoparticle-siRNA in the endosomes [24]. Such problems could be overcome with a few modifications, such as the introduction of 2′-O-methyl nucleotides into siRNA duplex strand interrupts TLR-7 interaction and related non-specific effects [25]. Incorporation of pH-sensitive moieties in the nano matrix can ensure the efficient release of siRNA for gene silencing.
Specific binding of siRNA with target RNA depends on high specificity based on Watson-Crick base pairing that constitutes RNA interference via initiating nucleolytic activity of the RISC complex. But at times, off-target effects have been observed where non-specific RNAi-induced gene silencing occurred with the introduction of a gene-specific siRNA. This could be due to the occurrence of partial Watson-Crick base pairing, leading to cross-reactivity. In fact, in some cases, pairing consisting of only 11-15 contiguous nucleotides is sufficient to induce gene silencing. 10-200 nm size range of nanoparticles is comparable to proteins and similarly, these nanoparticles can readily interact with surface biomolecules or those present in the cells. The small size of nanoparticles, therefore, provides an added advantage of being able to infiltrate tumor tissues with greater specificity and thus improving the delivery of drug/gene in a more targeted manner [12]. To synthesize functionalized nanoparticles, required changes in the addition of various layers and coatings are made [26].
Liposomes are the simplest of nanoparticles that are widely used in clinics for a long time, spherical in structure with lipid bilayers enclosed in an aqueous compartment [27]. In case of liposomes, the fatty layer is supposed to protect and confine the enclosed drug until bound to the outer membrane of the target cells. The solubility of many amphiphilic drugs could be improved by liposomes as the later consist of a hydrophilic core and hydrophobic phospholipid bilayer coat. The advantages of liposomes include not only prolonged circulation time and reduced systemic toxicity but also enhanced uptake into tumors with a constant discharge of their payload [28].
Dendrimers are branched nanoparticles with an inner core that are made up of different types of polymers such as poly (L-glutamic acid) (PGA), polyamidoamine (PAMAM), poly (ethylene glycol) (PEG), and polyethylenimine (PEI). These polymers have to undergo either convergent or divergent step-growth polymerization [29]. The basic nature of dendrimer is hydrophilicity and henceforth, can be used as a coating agent. The ease of preparation and terminal modifications render dendrimers suitable for targeted delivery or selective imaging of tumors [30, 31]. More than 96% inhibition of growth of tumor cells in animal models was observed with the usage of dendrimers employed to deliver anti-angiogenic angiostatin tissue inhibitor of metalloproteinases gene [32].
Polymer-drug conjugation helps in targeted delivery specifically to tumors with better suppression of the later due to enhanced permeability and retention time. A lot of research had been done to develop polymeric nanoparticles (NPs) that could be biodegraded. These could be prepared from polylactic acid, polyglycolic acid, polylactic-glycolic acid (PLGA), and poly (methyl methacrylate) (PMMA) and served the purposes for both gene and drug delivery. These can be developed as a second generation of carriers to deliver target specific anti-cancer agents and thus form the solid foundation for polymer-bound chemotherapy [33]. The nano-particles have found their use in control as well as treatment of the central nervous system affecting parasitic infections. These particles can cross the blood-brain barrier efficiently and access the infected tissue for drug delivery [34].
One such widely studied, biodegradable, and non-toxic polysaccharide polymer is chitosan, which is biocompatible and protects DNA against DNase ensured degradation [35]. Recent research by Öztürk and coworkers has shown the successful application of poly (lactic-co-glycolic acid) (PLGA) NPs and chitosan (CS)-coated PLGA NPs for oral delivery of clarithromycin against several pathogenic bacteria (D).
Metallic nanoparticles are also pivotal as nontoxic drug carriers for selective delivery, for example, gold NPs. These are modified to be made more beneficial using PEG coatings. In one such study, colloidal gold NPs coated PEG with an incorporated TNF (tumor necrosis factor)-R (PT-cAu-TNF-α) was used to see the effect on tumors. When intravenously administered as thermal therapy in mice models, these NPs showed a significant decline in the growth of tumors [36]. In another study, in MC-38 colon carcinoma, it was observed that colloidal gold NPs bound with thiol derivatized PEG with adsorbed recombinant human TNF on their surface were accumulated specifically in tumors with little or no off-site access to other tissues such as livers, spleens, or other healthy organs [37].
Therefore, it can be concluded that various polymeric nanoparticles can be modified to achieve not only specificity but also enhanced efficiency for the release of drugs or biomolecules at the target site. The increased retention time and reduced clearance by RES provide a lasting effect of the drug moiety at targeted tumors. It can be said at this juncture that in the coming era, polymeric nanoparticles will provide a crucial platform for the delivery of anti-angiogenic and anti-tumorous molecules with enhanced specificity.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.
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Gabriel Silva Borges1,Flávia Lidiane Oliveira da Silva2,Osmar Patrício Almeida2,Taízia Dutra Silva2,Guilherme Carneiro2,*Abstract
Characterization of nanostructured systems is an important aspect to support the choice of the better formulation composition and the best production conditions throughout a development process. Several methods can be used alone or combined for the determination of physical (e.g., mechanical, electrical, electronic, magnetic, thermal and optical), chemical or biological properties of a nanomaterial. This chapter is an overview of the most employed techniques, including dynamic light scattering and laser diffraction for the determination of size distribution; zeta potential and its relationship with stability and the surface charge of the particles; microscopies (optical microscopy, SEM, TEM, AFM) utilized in morphological analyses; spectroscopies in the infrared or ultraviolet-visible regions, and X-rays diffraction, which help to elucidate the crystalline state, polymorphism and drug-nanosystem interaction; and thermal analyses, which can provide information about the physical state, crystallinity, and stability. Further complementary information can be obtained from many other methods, such as nuclear magnetic resonance or Raman spectroscopy, but they are beyond the scope of this chapter. The careful choice of the characterization techniques to be used is certainly a decisive step in the successful and rational development of a nanocarrier formulation.
