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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
Applications of Nanoparticles in Drug Delivery and Therapeutics is an authoritative review on nanoparticle-based drug delivery systems. This comprehensive volume focuses on the transformative role of nanoparticles in enhancing drug delivery systems and advancing therapeutic applications. By bridging the gap between laboratory research and clinical practice, this book offers a thorough exploration of how nanotechnology is revolutionizing the pharmaceutical industry.
The book is structured into well-organized chapters, each dedicated to a specific aspect of nanoparticle-based drug delivery and therapy. Initial chapters provide a foundational understanding of nanoparticle synthesis, characterization, and functionalization. Subsequent sections cover various types of nanoparticles, including liposomes, dendrimers, and polymeric nanoparticles, highlighting their unique properties and applications. The latter chapters delve into case studies and clinical trials, showcasing real-world applications and the therapeutic potential of nanoparticle technologies in treating diseases like cancer, cardiovascular disorders, and neurodegenerative diseases.
Key features of this book include detailed discussions on the design and optimization of nanoparticles for targeted drug delivery, insights into the regulatory and safety aspects of nanomedicine, and comprehensive reviews of current and emerging therapeutic applications. The book also offers practical guidance on the challenges and future directions in the field, making it an invaluable reference for researchers and practitioners alike.
Chapters 1 and 2 are based on the introduction of nanomaterials used as drug delivery systems, their manufacturing approaches and applications. Chapters 3 and 4 emphasize on the use of nanoparticles in medical diagnostics and in intervention devices. Chapters 5 and 6 illustrate the use of lipids-based nanoparticles in medical imaging and drug delivery. Chapter 7 specifically discusses amino acid functionalized inorganic nanoparticles in diagnostics. Chapter 8 is focused on the special class of nanoparticles “hybrid nanocomposites”. Chapters 9 and 10 covers the applications of silica and fullerene nanomaterials in anticancer drug delivery.
The book is intended as a resource for pharmaceutical scientists, biomedical researchers, and healthcare professionals keen on the latest advancements in drug delivery systems. It also serves as essential reading for graduate students and academics in pharmacology and medical courses that require learning about modern drug delivery systems.
Readership
Students, pharmaceutical scientists and healthcare professionals.
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Seitenzahl: 450
Veröffentlichungsjahr: 2024
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PREFACE I
In recent years, the world of medical science has witnessed a remarkable transformation with the integration of nanotechnology into drug delivery and therapeutic applications. This book, titled "Applications of Nanoparticles in Drug Delivery and Therapeutics" stands as a testament to the groundbreaking strides made in this field.
Nanoparticles, as the building blocks of nanotechnology, have revolutionized the way we approach medical diagnostics, drug delivery, and disease treatment. The chapters within this volume delve into an array of captivating topics, each shedding light on the dynamic and diverse landscape of nanotherapeutics.
From novel synthesis methods of nanomaterials for cutting-edge nanodevices in medical diagnostics to exploring the synergistic relationship between nanotechnology and nutraceuticals, the chapters provide an insightful journey into the ever-evolving realm of nanomedicine. The concept of enzyme-responsive nanoparticles opens new doors for targeted drug delivery, enhancing therapeutic precision while minimizing side effects.
Cancer treatment, one of the most challenging fronts in modern medicine, benefits immensely from nanotherapeutics. The book’s exploration of the application of nanoparticles in cancer treatment underscores the potential to revolutionize how we combat this formidable disease. Similarly, the chapters addressing HIV and Alzheimer’s disease reflect the wide-reaching implications of nanotechnology, even in areas once considered insurmountable.
Beyond the confines of traditional medicine, the application of nanotherapeutics in skin therapy showcases the aesthetic dimensions of this technology, amplifying its impact on enhancing the well-being and confidence of individuals. Moreover, the discussions on the economical and environmental aspects of nanomaterials highlight the responsible and sustainable journey of these innovations from laboratory marvels to real-world industry solutions.
"Applications of Nanoparticles in Drug Delivery and Therapeutics " stands as a testament to human ingenuity and collaborative effort, a guiding light illuminating the path toward a healthier future As the book delves into the patent landscape of nanotechnology in healthcare, it becomes evident that the rapid progress in this field is not only transformative but also holds potential for significant intellectual property development.
This compilation serves as a vital resource for researchers, practitioners, and enthusiasts alike, offering a glimpse into the remarkable strides made in harnessing the power of nanoparticles for the betterment of human health and well-being.
PREFACE II
In the rapidly evolving landscape of modern medicine, the convergence of nanotechnology and pharmaceutical sciences has given rise to a revolutionary paradigm in drug delivery and therapeutic interventions. The utilization of nanoparticles, with their unique physicochemical properties and versatile applications, has opened up new avenues for addressing complex healthcare challenges. This book, "Applications of Nanoparticles in Drug Delivery and Therapeutics", endeavors to provide a comprehensive exploration of the diverse and dynamic field of nanotherapeutics.
The chapters presented within this volume offer an in-depth analysis of how nanoparticles are being harnessed to revolutionize various aspects of healthcare, ranging from antibacterial and antiviral interventions to targeted cancer treatments. Each chapter delves into a specific application of nanotechnology, highlighting the innovative strategies, methodologies, and breakthroughs that are propelling the field forward.
In Chapter 1, "Nanotherapeutics as Antibacterial and Antiviral Agents: Approach Beyond Antibiotics", we venture beyond conventional antibiotics, showcasing how nanoparticles are redefining the fight against microbial threats.
Chapter 2, "Novel Approaches for the Synthesis of Nanomaterials for Nanodevices in Medical Diagnostics", explores the cutting-edge techniques employed in the creation of nanomaterials tailored for diagnostic purposes, underscoring their potential to revolutionize medical diagnostics.
Chapter 3, "Application of Nanotechnology in Nutraceuticals and Functional Foods", uncovers the intersection of nanotechnology and nutrition, revealing how nanoparticles are enhancing the bioavailability and therapeutic potential of nutraceuticals. The concept of enzyme-responsive nanoparticles is the focus of Chapter 4, elucidating their pivotal role in intelligent drug delivery systems that respond to specific biochemical cues.
In Chapter 5, "Application of Nanotherapeutics in Cancer Treatment", the spotlight shifts to oncology, where nanoparticles are emerging as potent tools for precise cancer targeting and therapy.
Chapter 6, "Anti-HIV Nanotherapeutics and their Challenges in the Future", takes on the formidable challenge of combatting HIV, exploring the promises and hurdles associated with nanotechnology-based HIV interventions.
The ongoing battle against Alzheimer's Disease takes center stage in Chapter 7, "Current Perspectives of Nanotherapeutics for the Treatment of Alzheimer’s Disease", revealing how nanoparticles may offer novel avenues for therapeutic intervention.
Chapter 8, "Nanotherapeutics in Skin Therapy", turns attention to dermatology, showcasing the transformative potential of nanoparticles in skincare and dermatological treatments.
The socioeconomic dimensions of nanomaterials find their place in Chapter 9, "Economical and Environmental Aspects of Nanomaterials: Journey of Sustainable and Cost-Effective Nanoparticles from Lab to Industry", where we explore the transition of nanotherapeutics from research laboratories to industrial applications, considering both economic viability and environmental sustainability.
Finally, Chapter 10, "Patent Landscape of Nanotechnology in Healthcare", offers a comprehensive overview of the patent landscape surrounding nanotechnology applications in healthcare, shedding light on the innovations and intellectual property shaping the field.
Collectively, these chapters endeavor to provide a panoramic view of the multifaceted landscape of nanoparticle applications in drug delivery and therapeutics. They celebrate the strides made thus far while also acknowledging the challenges that lie ahead. As we embark on this journey through the realm of nanotherapeutics, we invite readers to explore the potential of these minuscule agents to effect monumental changes in the way we approach and conquer complex medical challenges.
List of Contributors
Nanotherapeutics as Antibacterial and Antiviral Agents: Approach beyond Antibiotics
Raman Singh1,Vidushi Gupta2,Nisha3,Kuldeep Singh1,*Abstract
The field of nanotherapeutics has evolved over the last few decades, and the scientific community has become increasingly interested in exploring and developing versatile biomaterial nanosystems for clinical medicine. Antimicrobials, despite their many advances, have been plagued by an ever-growing problem of antimicrobial resistance. This threat has been labeled the “post-antibiotic era” by the WHO and other organizations. Nanoparticles (NPs)-based therapeutics have recently emerged as new tools for combating deadly bacterial infections. Traditional antimicrobials face challenges, such as antibiotic resistance, which nanoparticle-based strategies can overcome. This chapter discusses various nanotherapeutics and their essential roles in antimicrobial therapy. This book chapter delves into the burgeoning field of nanotherapeutics, focusing on their potential as innovative solutions to combat bacterial and viral infections. With the escalating threat of antimicrobial resistance and the ongoing challenge of emerging viral pathogens, traditional treatment modalities are increasingly inadequate. Nanotechnology offers a promising avenue for the development of novel antibacterial and antiviral agents, presenting unique advantages such as enhanced drug delivery, improved bioavailability, and targeted action. The chapter provides an overview of the mechanisms by which nanotherapeutics exert their antimicrobial effects, including direct disruption of bacterial and viral structures, inhibition of essential cellular processes, and modulation of host immune responses. Various types of nanoparticles, such as liposomes, polymeric nanoparticles, and metallic nanoparticles, are explored for their ability to encapsulate and deliver antimicrobial agents to target sites with precision. Furthermore, the chapter discusses the potential applications of nanotherapeutics in addressing key challenges associated with conventional antibiotics and antiviral drugs, including drug resistance, adverse effects, and limited efficacy. By leveraging the unique physicochemical properties of nanoparticles, researchers aim to develop therapeutic strategies that minimize off-target effects, reduce the likelihood of resistance development, and enhance patient outcomes.
Despite the promising advancements in nanotherapeutics, several hurdles remain on the path to clinical translation, including standardization of manufacturing processes, evaluation of safety profiles, and regulatory approval. The chapter underscores the importance of interdisciplinary collaboration among scientists, clinicians, and regulatory agencies to overcome these challenges and realize the full potential of nanotherapeutics in clinical practice.
1. INTRODUCTION
Nanomedicine utilizes engineered nanomaterials and nanostructures for highly targeted medical intervention at the molecular scale. It includes the design, development, regulation, and application of nanotherapeutics, drugs, and devices based on nanoparticles typically under 100nm in size. Nanotherapeutics provide opportunities to enhance the safety, efficacy, and delivery of conventional therapies. Nanoparticles themselves can serve as therapeutic agents through properties such as the generation of reactive oxygen species. Photodynamic therapy uses light-activated nanoparticle photosensitizers for targeted cancer cell destruction [1].
Nanotherapeutics offer novel opportunities to improve the safety and efficacy of conventional treatments. Nanoparticles themselves can be used as therapeutic agents. Metal nanoparticles have prompted research on nanotherapeutic prospects through covalent bonding with biological molecules such as peptides, proteins, and antibodies. Amphiphilic polymer nanoaggregates also have selective antimicrobial effects and can enable on-demand antibiotic delivery or reinvigorate outdated antibiotics. Polymeric nanoparticles can deliver intracellular antibiotics to sites that are otherwise inaccessible, such as macrophages. For antiviral applications, the nanomaterial design is tailored based
on the delivery route. Vascular permeability or ligand functionalization determines their targeting mechanism. Nanomaterials have the potential to boost existing antiretrovirals by preventing nonspecific interactions and reducing toxicity.
2. FORMULATION OF NANOTHERAPEUTICS
Nanotherapeutic formulations offer promising opportunities to combat bacterial infections using novel delivery mechanisms. Nanotherapeutic formulations utilize various nanomaterials, including liposomes, polymers, proteins, drug nano- crystals, and inorganic nanoparticles. These nanomaterials facilitate innovative drug delivery systems with enhanced safety, efficacy, and stability compared to conventional formulations.
For treating bacterial infections, nanotherapeutics can simultaneously target pathogen invasion and host immune response pathways. This dual targeting approach creates opportunities to develop new treatments that can overcome antimicrobial resistance. The versatility of nanoparticle-based delivery systems offers tremendous potential for transforming the treatment of bacterial infections if clinical translation challenges can be overcome through further research [2-5].
3. CLASSIFICATION OF NANOTHERAPEUTICS
Nanotherapeutics can be classified according to their constituents (Fig. 1). The classification highlights the diverse types of nanotherapeutics on the basis of their composition, therapeutic applications, and mechanisms of action. The field of nanotherapeutics continues to evolve, with ongoing research and development aimed at improving drug delivery, enhancing therapeutic efficacy, and addressing challenges related to safety and regulatory guidelines.
Fig. (1)) Classification of nanotherapeutics.3.1. Protein-Based Nanotherapeutics
Many industries and the food industry have long relied on protein-based nanoparticles. Jeong and colleagues reported near-infrared (NIR) light-responsive vanadium-doped adhesive proteinic nanoparticles (NP) as multimodal cancer nanotherapeutics with enhanced therapeutic efficacy and high specificity [6].
Numerous emerging nanotechnology-based interventions, such as antiviral nanoparticles and nanoparticle-based DNA and mRNA vaccines, have become crucial in the fight against fatal severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) by facilitating early detection and enabling target-orientated multidrug therapeutics [7].
Recently, Voci et al. reviewed the physicochemical properties and preparation methods of nanoparticles composed of vegetable proteins, as well as the pharmacological characteristics of these potential nanomedicines for pharmaceutical application [8].
Protein nanotherapeutics take advantage of the structure and function of naturally occurring proteins to produce biocompatible, multifunctional nanostructures that have enormous potential as treatments for a wide range of diseases.
3.2. Lipid-Based Nanotherapeutics
3.2.1. Liposomes
In 1965, Alec D. Bangham discovered liposomes, which were the first class of therapeutic NPs approved for the treatment of cancer [9]. Due to their biocompatibility, biodegradability, nontoxicity, and non-immunogenicity, they make up a significant portion of nanotherapeutics in clinical trials [10]. Liposomes are spherical vesicles based on phospholipids and cholesterol that form at least one lipid bilayer around an aqueous core in water and can encapsulate hydrophilic and hydrophobic substances through Van der Waals forces. The size, number of lamellae, surface charge, bilayer rigidity, surface modification, and preparation method influence the properties of liposomes. The size of the lipid vesicles ranges from 0.025 to 2.5 m. They can be categorized according to the number of layers [11]. Liposome drug delivery systems are nanosized spheres made up of one or more lipid bilayer membranes that surround an aqueous core [12]. Liposomes are being developed as unique and promising technologies to assist in the delivery of antimicrobials to sites of microbial infection [13-17]. As a drug delivery vehicle, liposomes offer several advantages, which are as follows [18, 19]:
Because of their amphiphilic structure, liposomes can transport hydrophilic and hydrophobic drugs.Liposome-based nanotherapeutics have improved therapeutic efficacy and decreased nonspecific toxicity due to their increased accumulation at lesion sites and improved pharmacokinetics.Liposomes improve drug stability and circulation half-life by shielding the encapsulated drug from the external environment.Functionalization of the surface of liposomes allows the development of controlled-release drug delivery systems.These nanocarriers have a natural propensity to accumulate in the liver, which enables them to serve as an effective drug delivery system for conditions that affect the liver, such as chronic hepatitis C virus infection [20]. Research on liposomes has focused primarily on their potential use as carriers for anti-HIV drugs, HIV vaccine delivery, and siRNA. These carriers suffer from a number of drawbacks, some of which include poor stability both in vitro and in vivo, a low rate of integration in lipid bilayers or an aqueous core, and a high cost [21]. The antimicrobials contained within them can be rapidly released into cell membranes or within bacteria, which is one of the reasons why several of them have been granted clinical approval. Doxorubicin was the first liposomal nanotherapeutic to receive approval from the FDA.
3.2.2. Solid-Lipid Nanoparticles
Colloidal carriers, known as solid-lipid nanoparticles (SLNs), are made up of lipids that are able to maintain their solid state at the temperature of the body. Some examples of these lipids include acetyl palmitate and salts of myristic acid. When compared to synthetic polymer NPs, SLNs have a lower toxicity level, are more stable, and are more readily available. In addition, the state of the lipids is determined by the conditions of the medium, such as temperature and pH, which makes it possible to control the release of the lipids and improve their effectiveness. Lipid nanoparticles present a unique opportunity for the development of new therapeutics as a result of their size-dependent properties [22, 23].
Compared to liposomes, SLNs have better stability and are easier to scale up to the manufacturing scale. They can deliver drugs to active phagocytic cells in the liver in vivo and in vitro. Antitubercular medications, including isoniazid, rifampicin, and pyrazinamide-loaded SLN systems, reduce dose frequency and improve patient compliance [24] Excellent biocompatibility, improved stability of pharmaceuticals and high and enhanced drug content are some of the advantages of solid-lipid nanoparticles [25].
3.3. Inorganic Nanoparticles
Inorganic nanoparticles are made up of different metallic oxides that vary in size, shape, solubility, and stability. They are typically synthesized by reducing metallic salts like silver, gold, or titanium using reducing agents. The reducing agent links the nanoparticle surface to the drug or biomolecule of interest, so appropriate selection is critical for drug loading and delivery. The choice of reducing agent affects the loading capacity, drug release kinetics, particle aggregation, and antimicrobial efficacy. Compared to organic nanoparticles,inorganic metallic nanoparticles usually have smaller sizes and higher drug-loading capacities. Careful optimization of the composition of inorganic nanoparticles, the reducing agent, and surface chemistry is needed to develop effective antimicrobial drug delivery systems with high stability [26].
Inorganic nanoparticles often have broad-spectrum antibacterial activity against both gram-positive and gram-negative bacteria. Their small size and high surface area to volume ratio allow interaction with bacteria and penetration into cell membranes. Antibacterial mechanisms involve the generation of reactive oxygen species, the release of metal ions, the compromise of membrane integrity, and the interruption of respiratory activity [27-29].
3.3.1. Gold Nanoparticles (AUNP)
The electromagnetic and physical properties of AuNPs make them suitable for a wide range of applications, including drug delivery vectors, diagnostic imaging, and exogenous absorbers for tumor thermal ablation [30]. Colloidal AuNPs have various advantages, including a bioconjugation surface for molecular probes, significant light scattering properties, and the ability to modify their plasmon resonance spectrum as they aggregate. They have wide applications in drug delivery, cancer detection, and biological imaging [31]. AuNPs exhibit an antiviral action by binding to peroxidase-mimic enzymes and aid in viral detection. Cancer cells can be killed by these NPs because they are less toxic than AgNPs. Loeb et al. revealed that bacteriophages can be inactivated when exposed to gold nanorods and that the pathogen and NP must be close to each other for nanoparticle adsorption on the surface to be effective [32]. However, direct contact is not always required, as virus inactivation is achieved by the generation of plasmon-enhanced shock waves, which alter the viral membrane and reduce viral binding [33].
3.3.2. Silver Nanoparticles (AGNP)
Silver nanoparticles (AgNPs) have garnered significant interest as broad-spectrum antimicrobial agents because of their potent antibacterial activities. AgNPs exert antibacterial effects through various mechanisms, making it difficult for bacteria to develop resistance. They can bind to and disrupt bacterial cell membranes, increasing permeability. AgNPs have also shown antiviral effects against influenza viruses [34]. Additionally, surface-enhanced Raman spectroscopy using antibody-functionalized AgNPs have been used to detect methicillin-resistant Staphylococcus aureus (MRSA). Recently, an innovative SERS technique using positively charged AgNPs has been reported for the rapid identification of MRSA [35, 36]. Overall, AgNPs are promising for various antimicrobial applications ranging from bacterial inhibition to viral inactivation and pathogen detection. The ongoing research aims to expand the biomedical utility and improve the efficacy of AgNP antimicrobial platforms.
3.3.3. Quantum Dots (QDS)
Quantum dots (QDs) are semiconductor nanocrystals that exhibit unique optical and electronic properties due to quantum confinement effects. As fluorescent nanoprobes, QDs have been explored for detecting and imaging bacteria. Strategies are being investigated to enhance sensitivity. QDs can deliver various therapeutic cargoes such as peptides, drugs, and nucleic acids intracellularly, enabling diverse applications [37, 38].
Photoexcited QDs can demonstrate broad-spectrum antimicrobial activity, even against multidrug-resistant strains of bacteria such as MRSA, carbapenem-resistant E. coli, and Klebsiella and Salmonella-producing ESBL. This is attributed to the ability of photoexcited QDs to produce reactive oxygen species that damage bacterial cells. The combination of fluorescent labeling and antimicrobial functionality makes QDs versatile for microbial detection and treatment. This includes strains of Staphylococcus aureus that are resistant to methicillin, Escherichia coli that are resistant to carbapenem, Klebsiella pneumoniae and Salmonella typhimurium that produce extended-spectrum lactamases [39].
Quantum dots possess unique properties such as small size, high surface area, and tunable optics that make them well-suited for antimicrobial applications. When illuminated, quantum dots can generate reactive oxygen species that damage bacteria through oxidative stress. Their small size facilitates close interaction with bacteria, allowing direct disruption of cell membranes and leakage of contents. Quantum dots may also inhibit bacterial growth by interfering with proteins and enzymes involved in metabolism and replication. In general, the combination of the production of reactive oxygen species, the breakdown of the membrane, and the inhibition of growth pathways contribute to the antimicrobial efficacy of light-activated quantum dots against drug-resistant bacteria. Tuning the properties of quantum dots can further optimize their antimicrobial performance and broaden their clinical utility [40-44].
3.4. Polymer-Based Nanotherapeutics
Polymer-based nanoparticles are emerging as promising carriers for therapeutic and diagnostic agents. Polymer NPs have hydrophilic and hydrophobic components that are held together by a polymeric matrix that can be made from either synthetic or natural polymers. They are biodegradable, biocompatible, and excellent carriers for controlled and sustained drug delivery. Polymeric nanoparticles can keep unstable parts of drugs from breaking down, which can prevent dangerous side effects. Polymer-based nanotherapeutics can be used to treat burns [45]. Polymeric nanomaterials allow unprecedented control over drug delivery and therapy, but translation from bedside to bench remains a key challenge for polymer-based nanotherapeutics.
3.4.1. Polymeric Micelles
These micelles are formed by block amphiphilic copolymer micelles ranging from 20 to 80 nm. The use of polymeric micelles in anticancer therapy has received the greatest attention [46].
They can enable passive and active targeted drug delivery, gene delivery, and diagnostic imaging. However, polymeric micelles also have limitations, such as low drug loading and poor incorporation stability, leading to premature release [47]. A study showed that polymeric micelles increased the antimicrobial and anticancer properties of the drug salinomycin. The micellar formulation improved salinomycin solubility, toxicity profile, and efficacy against bacterial pathogens and cancer cell lines. Polymeric micelles exhibit lower toxicity compared to other organic nanoparticles [48].
Further research aims to overcome challenges such as poor drug loading and develop polymeric micelles as more effective nanocarriers for antimicrobial, anticancer, and other drug delivery applications.
3.4.2. Dendrimers
Dendrimers are hyperbranched nanoscale polymers with tunable structures that have emerged as promising antimicrobial platforms. Organic dendrimers are characterized by a multifunctional core, interior layers, and a multivalent surface that can contain multiple chemical moieties [49]. Cationic dendrimers can exhibit antibacterial effects by disrupting bacterial cell membranes. They have shown efficacy against both gram-positive and gram-negative bacteria [50-52]. Dendrimers can be functionalized with groups such as PEG to improve biocompatibility and loaded with antibiotics for sustained antimicrobial release [50, 53]. They can be combined with antimicrobial peptides, cell-penetrating peptides, and antiviral peptides to target bacteria, viruses, and biofilms.(54)
Dendrimers have also demonstrated antiviral effects by interacting and interfering with viral particles, entry, and replication. Polylysine-based dendrimers have been investigated as antiviral agents, demonstrating clinical success in combating viral infections [54, 55].
VivaGel, a polylysine dendrimer gel, is the most well-known dendrimer antiviral agent and the first dendrimer microbicide approved. The antiviral and antibacterial properties of the dendrimer gel VivaGel illustrate the potential of engineered dendrimer nanosystems to prevent the transmission of sexually acquired infections. VivaGel contains the dendrimer SPL7013, which has naphthalene disulfonate surface groups that bind to viruses [56]. It has shown antiviral efficacy against HIV and HSV by preventing viral attachment to host cells [57-60]. VivaGel also exhibits antibacterial properties against bacterial vaginosis [61]. VivaGel highlights the promise of dendrimer nanotechnology in infectious disease interventions, both antiviral and antibacterial.
Dendrimers offer a versatile platform for the development of antimicrobial agents. Their unique structure, tunable properties, and ability to interact with microbial pathogens make them promising candidates for combating bacterial and viral infections. More research is needed to optimize their design, improve their efficacy, and evaluate their safety for clinical applications.
3.4.3. Nanofibers
Nanofibers are fibers with diameters typically less than 1000 nm that exhibit unique properties stemming from their high surface area to volume ratios. They can be manufactured from various materials using techniques such as electrospinning and optimized to achieve the desired mechanical, electrical, optical and surface characteristics [62-64].
Applications of nanofibers leverage their extremely high porosity, tunable pore sizes, flexibility in surface functionalization, and ability to control drug release kinetics. They have been extensively explored in fields including filtration, energy storage, tissue engineering, drug delivery, and other biomedical areas [65, 66].
For antibacterial drug delivery, nanofibers allow for high drug-loading capacities and sustained release through basic incorporation methods or advanced structured designs. Smart nanofibers with stimuli-responsive properties also enable triggered drug release [67, 68]. Nanofibers loaded with silver nanoparticles have shown enhanced antimicrobial efficacy against both gram-positive and gram-negative bacteria. The nanoparticles are continuously released from the nanofibers [69].
Cationic polymer nanofibers with embedded silver nanoparticles exhibit excellent antibacterial performance that exceeds silver-loaded PMMA nanofibers [70].
For wound healing, nanofibers provide a scaffold for cell growth and act as a physical barrier to infection when used as wound dressings [71]. Honey/chitosan nanofiber mats with natural extracts such as Allium sativum and Cleome droserifolia display antimicrobial and wound-healing properties [72]. Electrospun nanofibers have been explored as drug delivery systems for wound healing, providing sustained release of therapeutic agents [73, 74]. Polycaprolactone nanofibers loaded with Terminalia arjuna extract show antibacterial effects against gram-positive and gram-negative bacteria [73].
Further research is warranted on optimizing nanofiber fabrication, composition, and structure to maximize their antimicrobial potency for applications such as wound dressings.
In addition, nanofibers can co-deliver antibacterial agents along with wound-healing factors to improve therapeutic outcomes. Their versatility enables the concurrent delivery of multiple therapeutic agents. However, further R&D is required to optimize nanofiber systems for biomedical applications and scale up manufacturing.. A comprehensive investigation of clinical translation and commercialization will help unlock the full potential of nanofiber technology.
3.5. Drug Nanocrystals
Drug nanocrystals are crystalline drug particles in the nanometre-size range (typically 100-1000 nm). They are essentially drug nanoparticles with a crystalline character, as opposed to amorphous (Fig. 2) [75]. The term nanocrystal specifically refers to the solid, crystalline state of drug nanoparticles. Nanocrystal formation can result from top-down breakdown of microcrystals or from bottom-up approaches. The method of production affects whether the nanoparticle product is crystalline or amorphous. Amorphous drug nanoparticles are sometimes referred to as “amorphous nanocrystals”, though this can be misleading. Unlike other polymeric nanoparticles, drug nanocrystals are composed entirely of the active drug without any carrier materials [76]. Nanosizing confers advantages like increased solubility and bioavailability to poorly soluble crystalline drugs.
When drug nanocrystals are dispersed in liquid media like water, aqueous solutions, polyethylene glycol, or oils, they form “nanosuspensions”. Surfactants or polymeric stabilizers are required to stabilize dispersed nanocrystal particles and prevent aggregation. The resulting nanosuspensions have improved solubility and bioavailability compared to those of larger drug particles while avoiding issues with truly dissolved drugs. Nanosuspensions allow the delivery of poorly soluble drugs in a stabilized nanoparticulate form suitable for various administration routes, including intravenous, oral, pulmonary, and topical [77-79].
Drug resistance mechanisms in bacteria can be circumvented by drug nanocrystals, which, as a result of their antimicrobial potential, can also inhibit the formation of biofilms or other crucial processes. The use of drug nanocrystals is one application of nanotechnology that has been shown to be effective. This application is intended to improve the solubility and bioavailability of drugs that have a low degree of solubility. Despite this, the pharmaceutical industry continues to face challenges in the areas of stability, manufacturing, toxicity, and delivery.
Fig. (2)) Properties of drug nanocrystals.4. Advantages and Disadvantages of Different Types of Nanoparticles
No single nanoparticle is ideal. The advantages and disadvantages of nanoparticles as nanotherapeutics can vary depending on the specific nanoparticle type, formulation, and application. Researchers combine the advantages of different nanoparticles and use surface modifications to minimize the disadvantages. The ideal nanoparticle system depends on the specific application and drug being delivered. A balanced evaluation of therapeutic efficacy, safety profile, and manufacturability is required for clinical translation. Table 1 provides a summary of the various types of nanoparticles that can be used as nanotherapeutics, together with the benefits and drawbacks associated with each.
When used as nanotherapeutics, nanoparticles provide a number of benefits, including improved cellular interaction, targeted drug delivery, and reduced systemic toxicity. However, the type of nanoparticle that is used should be selected after careful consideration, with consideration given to aspects such as particle size and stability as well as the amount of drug that can be loaded and the specificity of the target. To address these challenges and optimize the design and performance of nanotherapeutics for a variety of diseases and conditions, more research and development are required.
5. Nanotherapeutics in Antimicrobial Therapy
Bacterial infections remain a major global health burden, complicated by the increase in antibiotic resistance and biofilm-associated infections in the medical, industrial and environmental sectors [80-87]. This underscores the need for new antibacterial approaches. Nanoparticle-based materials have attracted interest as promising antimicrobial agents. Their development through nanotechnology has significant potential to advance biomedical research and therapy. Effective nanoparticle systems with broad-spectrum bactericidal activity could provide alternative means to combat persistent and emerging bacterial threats.
5.1. Antibacterial Mechanism of Nanoparticles
The increasing use of nanoparticles (NPs) in medicine has driven interest in understanding their antibacterial mechanisms. Metallic NPs, in particular, have emerged as promising antibacterial agents. For NPs to exert antibacterial effects, they need to interact with bacterial cells, typically through van der Waals or electrostatic forces. This interaction enables NPs to cross the bacterial membrane and access intracellular components.
Metallic NPs exhibit broad-spectrum antibacterial activity through various mechanisms that involve crossing the cell membrane and disrupting vital intracellular processes. Three main mechanisms used by NPs to produce antibacterial effects have been identified:
(a). Induction of oxidative stress by the generation of reactive oxygen species that exceed bacterial antioxidant defenses [88].(b). Release of metal ions that can disrupt the integrity of the bacterial membrane and bind to intracellular proteins/enzymes [89].(c). Non-oxidative mechanisms such as interruption of transmembrane electrochemical gradients, inhibition of energy metabolism, and physical damage to cell membranes [90].Elucidating the predominant antibacterial mechanisms of different NPs guides strategies to enhance their potency and expand their clinical applications as antibacterial agents.
5.1.1. Oxidative Stress
Oxidative stress occurs when cells cannot detoxify reactive oxygen species (ROS) as quickly as they are being produced, leading to their accumulation [88]. ROS generation and clearance in bacterial cells are balanced under normal conditions. However, when the cell produces too much ROS, the redox balance favors oxidation. This imbalanced state causes oxidative stress, which destroys the components of bacterial cells [91].
Different types of nanoparticles can produce various ROS by reducing oxygen molecules through their surface chemistry and properties. The four main forms of ROS are hydrogen peroxide, superoxide radical, singlet oxygen, and hydroxyl radical. CuO-NPs generate all four forms of ROS, while Mg and Ca-NPs produce superoxides.
At low levels, cells can counteract ROS using enzyme and nonenzymatic antioxidant defenses such as catalase, SOD, glutathione, etc. However, at high concentrations, ROS can overwhelm these defenses, damage proteins/DNA, and cause lipid peroxidation, disrupting cell membranes. By generating ROS that exceeds the antioxidant capacity of bacteria, nanoparticles induce oxidative stress, impair metabolism, and ultimately cause cell death [92].
Oxidative stress modifies the permeability of the cell membrane. Intracellular ROS causes membrane integrity loss and attacks proteins and enzymes important for cell shape and maintaining normal physiological functions in bacterial cells. Furthermore, it induces an increase in the expression of oxidative proteins, which leads to cell death and apoptosis.
Understanding the specific ROS production mechanisms of different nanoparticles allows the rational design to maximize their antimicrobial oxidative stress effects. The oxidative stress caused by nanoparticle-mediated ROS is a key factor that contributes to their antibacterial activity against a broad spectrum of pathogens.
5.1.2. Metal-ion Release
Nanoparticles made of metals, such as silver, gold, copper, and zinc oxide, are capable of releasing metal ions when subjected to the processes of oxidation, dissolution, and corrosion [93]. Metal ions released from metal oxide NPs exert antibacterial effects through both membrane disruption and by binding to and deactivating critical intracellular proteins and enzymes in bacterial cells [89]. This multi-target mechanism is what makes metal oxide NPs effective broad-spectrum antimicrobial agents. The following key events occur:
Metal oxide nanoparticles (NP) such as ZnO, CuO, TiO2 can slowly release metal ions through dissolution.These ions interact with and penetrate the bacterial cell membrane.Inside the bacteria cell, the metal ions bind to specific functional groups on proteins and nucleic acids.Binding to -SH, -NH, -COOH, and other groups causes structural changes and deactivation of key enzymes and proteins.This disruption of intracellular biomolecules inhibits normal bacterial physiological processes such as metabolism, transport, cell division, etc.Ultimately, the cumulative effect of metal-ion-biomolecule binding is damage to the cell membrane, protein dysfunction, interrupted biochemical pathways, and inhibition of the microorganism.Higher concentrations of internalized metal ions lead to increased oxidative stress, impaired metabolism, loss of cell viability, and bacterial cell death.During the antibacterial process of metal oxide suspension, the impact of metal ions on the pH inside lipid vesicles is minimal. Thus, other mechanisms such as direct membrane disruption, oxidative stress, and interruption of intracellular processes play a greater role in the antimicrobial activity of metal oxide NPs compared to metal ion dissolution [94].
The development of assays to correlate release with therapeutic effects and safety is an important step for the future. Future directions include the design of nanoparticles that have programmed metal ion release profiles.
5.1.3. Non-oxidative Mechanisms
The interaction of NPs with the cell wall is a non-oxidative process. The bacterial cell has a multi-layered structure. This acts as a protective shield against any unpredictable and adverse environment. Gram-positive and gram-negative bacteria have different adsorption pathways for nanoparticles (NPs) based on their distinct cell membrane structures. Gram-positive bacteria allow direct peptidoglycan access, whereas gram-negative bacteria have an additional outer membrane barrier that must be overcome before peptidoglycan interaction. Understanding these pathways helps to engineer NPs to selectively target bacteria. Furthermore, the nonporous outer membrane of gram-negative bacteria provides an additional barrier that makes them intrinsically more resistant to nanoparticle-induced antibacterial activity compared to gram-positive species [95].
Maleki-Ghaleh et al. (2021) highlighted the antibacterial properties of hydroxyapatite nanoparticles and their interaction with bacterial membranes, causing mechanical damage and entry of nanoparticles into the cytoplasm [96]. Rajakumar and his colleagues investigated how antimicrobial cobalt oxide nanoparticles work and how they interact with the cell wall. They focus on the role of nanoparticle size and surface behavior [97]. Interactions between peptide-modified nanoparticles that can penetrate cells and cells themselves. Streck et al. demonstrated that surface modifications with cell-penetrating peptides lead to increased interactions of nanoparticles with the cell membrane [98].
Interactions between NPs and cell walls involve a variety of different aspects, such as adhesion properties, electrostatic interactions, morphological changes, and surface modifications. An understanding of these interactions is necessary for both the production of useful nanotherapeutics and the formulation of methods for a wide range of applications, including the administration of antimicrobials and the delivery of drugs [90].
5.1.4. Interaction of NP with Bacteria
Different aspects of the cell structure of bacteria allow for their classification as either gram-positive or gram-negative. The peptidoglycan layer of gram-positive bacteria is thick and multi-layered, whereas the peptidoglycan layer of gram-negative bacteria is thin and only has a single layer [99]. In the fight against microorganisms, the significance of nanoparticles' ability to interact with the cell walls of bacteria cannot be overstated. According to Murphy and colleagues, 2005, CTAB, a stabilizing and capping agent, self-assembled an electrically percolating monolayer on Bacillus cereus, resulting in electrostatic interactions between teichoic acid and CTAB coating [100]. Feng et al. reported a significant relation between bacterial viability and AuNP surface adherence to cells. Cationic AuNPs, particularly polyelectrolytes-wrapped gold nanoparticles, were toxic to gram-negative and gram-positive bacteria [101]. Feldheim et al. developed the thiol-gold nanoparticle conjugate, LAL-3346, for E. coli inhibition. In addition to altering membrane permeability, LAL-3346 also shows signs of being taken inside the cell, suggesting that gold nanoparticles may have access to intracellular targets [102].
Nanofibers have often been used in various ways to administer medications. Their application in antibacterial medication administration has recently grown. Compared to other nanotechnological antibacterial medication delivery systems, nanofibers have high loading capacity, high antibacterial agent encapsulation efficiency, and low toxicity [67].
Silver nanoparticles discharge silver ions, which could be a microbe-killing mechanism (Fig. 3). Silver nanoparticles can kill bacteria on their own [103]. Due to their nanoscale size, silver nanoparticles can enter bacterial cell walls and alter the membrane structure. Gram-negative bacteria are more vulnerable to silver nanoparticles [104].
Several different types of nanoparticles, such as those that release nitric oxide (NO NPs), those that contain chitosan (chitosan NPs), and those that contain metals, fight microbes using a variety of different mechanisms. NO's antibacterial activity is mostly mediated by reactive nitrogen oxide intermediates (RNOS), which are formed when NO combines with superoxide. Peroxynitrite, nitrogen dioxide, and dinitrogen trioxide are among the RNOS. At physiological NO concentrations in the host, certain bacteria can already develop enzymes that defend against nitrosative damage in response to NO exposure. NO NPs show broad-spectrum antibacterial action, such as against drug-resistant bacteria [105].
Nanotherapeutics can prevent biofilm infections and help develop new antimicrobials to address antibiotic resistance. Nanotherapeutics like metallic nanoparticles (e.g., AgNPs) show efficacy against a wide variety of resistant and nonresistant bacteria. They have the potential for drug delivery and treatment of infections [106].
Fig. (3)) Antibacterial action of AgNPs.Ag NPs reduce biofilm growth by preventing new bacterial cells from colonizing medical device surfaces (e.g., catheters) or existing biofilm surfaces. There is a technique for applying bioactive silver nanoparticles to plastic catheters. These nontoxic catheters can help patients with indwelling catheters avoid infections because they deliver antibacterial silver to the implantation site in a targeted and consistent manner [107].
Divalent transition metal ions (Ni, Co, and Fe) doped in MgO nanoparticles have antibacterial activity against both gram-negative (E. coli) and gram-positive (S. aureus) bacteria [108]. Ceftazidime and the bifunctional nano-Ag3PO4 have the best synergistic effect on Escherichia coli [109]. Recently, graphene-based nanomaterials have shown antimicrobial activities against different bacteria [110].
Tables (2 and 3) provide a summary of the antimicrobial potential of the nanoparticles.
The preceding discussion has made it abundantly clear that nanoparticles can disrupt bacterial cells and contribute to the bactericidal activity of the particles in a number of different ways. These mechanisms include disruption of membranes, oxidative stress, protein dysfunction, DNA damage, and inhibition of cellular processes. The antibacterial effects of nanoparticles are often attributed to their ability to interact with the components of bacterial cells and result in cell death.
