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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
This book provides a compressive overview of nanotechnology in modern drug discovery for students and researchers. The book starts with the fundamentals of nanotechnology followed by nanomaterials in pharmaceutical drug design, drug delivery applications, regulatory aspects, formulation and nanoparticle biotransformation. It provides a step by step guide through the drug development process while conveying information about the benefits of nanomaterials for therapy. The book concludes with perspective on the future of nanotechnology-based drug discovery, summarizing current knowledge on nanotherapeutics and translational medicine.
Key Features
- Explains the fundamentals of nanotechnology in drug discovery
- Includes up-to-date information on modern nanopharmaceutical manufacturing, nanomaterials, and nanoparticle-based drug therapy
- Practice questions for learners and a list of references for advanced readers for each chapter
Readership
Students and researchers in pharmacology and pharmaceutical manufacturing programs.
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Seitenzahl: 421
Veröffentlichungsjahr: 2024
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PREFACE
Drug discovery is a critical step in the treatment and cure of diseases, involving identifying drug targets, lead identification, modification, synthesis, characterisation, validation, optimization, screening, and tests for therapeutic efficacy. Drug research and development have been greatly impacted by nanotechnology, resulting in the development of novel medicines for diseases that were previously incurable. At present, the pharmaceutical industry is attempting to minimize the time needed for medication development in response to the growing demand for fast drug development. Nanotechnology has allowed for the evolution of critical processes in traditional drug discovery, with an emphasis on enhancing lead identification, modifications, synthesis, stability, and target selectivity. There has been a surge in nanomedicine research over the last few decades, which is now being translated into commercialization endeavours throughout the world, leading to the marketing of various nano-drugs.
This book is intended for students and researchers who are just starting out in the modern drug development sector, where nanotechnology has taken up a significant space. The book will progressively expose readers to the topic of nanotechnology-based drug research by first examining the fundamentals of nanoparticles. Then this book will cover the utilization of nanotechnology throughout the drug development process from lab to market, focusing on lead identification and synthesis, drug delivery, nano-drug toxicity, in-vivo fate of NPs, and finally regulations on NPs-based drugs in various countries. The work then finally focuses on the future perspective of nanotechnology in drug discovery. Eventually, the readers will have an overall idea of how nanotechnology has improved the conventional drug development process. The abstract and conclusion given at the beginning and end of each chapter will provide the readers with concise information that is elaborated throughout the chapters.
We anticipate that this book will serve as a reference book, offering an in-depth account of how nanotechnology has revolutionized the drug development process while highlighting the intriguing recent findings in the field.
Fundamentals of Nanotechnology
Laksiri Weerasinghe,Imalka Munaweera,Senuri KumarageAbstract
Nanomaterials, a category of materials with a dimension in the nanometric range (1 nm-100 nm), were first recognized in 1959. They have unique physical, chemical, and mechanical properties, with nanoparticle size affecting properties like melting temperature, ionization potential, colour, electron affinity, electrical conductivity, and magnetism which is different from their bulk material. Nanotechnology improves biomarker development and aids in developing more sensitive treatments in medicine using nanodevices which enhances drug discovery by improving the understanding of biological processes, disease mechanisms, and signalling pathways.
This chapter provides an overview of nanomaterials and examines their distinct properties. The key top-down and bottom-up methods for synthesizing nanomaterials are also explained along with specific examples. The chapter will also include a summary of several nanoparticle characterization methods and the attributes associated with each method. In addition, comprehensive information about advanced devices that have been inspired by nanotechnology to increase the efficiency of the drug development process through a better understanding of the biological mechanisms underlying diseases, signalling pathways, and the precise effects of medications have also been discussed. The chapter will conclude by outlining the advantages and challenges of using nanotechnology in drug development and treatment.
1. Introduction to nanomaterials
Although nanomaterials are not a new phenomenon in nature, interest in engineering at a very tiny scale arose following Richard P Feynman's legendary talk titled “There's plenty of space at the bottom” on 29th December 1959, at the annual meeting of the American Physical Society, when he spoke of manipulating and controlling things on a microscopic scale. Feynman is often considered as the first visionary of nanotechnology due to his clairvoyance. Unfortunately, it took the scientific community more than three decades to turn his vision into reality due to a lack of suitable tools and processes.
The prefix “nano” is derived from the Greek word for “dwarf.” Nanomaterials represent a category of special materials that have at least one dimension in the nanometric range (1 nm-100 nm). The size comparison of nanomaterials is given in Fig. (1). Nanomaterials are classified into four types as zero-dimensional (0D), one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) nanostructures. All three dimensions are present at the nanoscale in zero-dimensional nanostructures. These nanoparticles resemble point particles and display quantum confinement. 1D nanoparticles have at least one dimension bigger than nanoscales (i.e. 100 nm), with the remaining dimensions occurring within the nano range. Nanofibers, nanotubes, and nanorods are the most frequent types of one-dimensional nanoparticles. The most popular examples of 2D nanomaterials are nanofilms, nanolayers, and nanocoatings, which are plate-like structures having two dimensions larger than the nanoscale. Although the constituents of 3D nanomaterials are smaller than 100 nm, none of their dimensions are less than the nanoscale. Nanomaterials with three dimensions are formed when the nanoscale particles are combined. These substances are typically nonporous and have a wide range of uses. The most common types of three-dimensional nanomaterials include nanocomposites, bundles of nanofibers, and multi-nanolayer structures [1, 2].
Fig. (1)) Length scale showing size of nanomaterials. Reproduced with permission from [6] © 2015, Neha Pradhan et al. published by Hindawi Publishing Corporation, distributed under the terms of the Creative Commons Attribution 3.0 International. https://creativecommons.org/licenses/by/3.0/.Beyond mere miniaturisation, nanotechnology has other applications. Materials at the nanoscale have distinctly different physical, chemical, and mechanical properties from bulk materials. When grain size is reduced to nanoscale dimensions, considerable changes are made to the properties, and the resulting qualities typically outperform those of conventional materials. The fact that nanoparticles are used in so many different applications is not surprising. The potential applications of nanomaterials are being discovered in ever-greater quantities.
Nature is undoubtedly the most important source of inspiration for nanoscientists and nanotechnologists. Many nanoparticles and nano-based systems have been refined by nature over millions of years through the process of evolution. Practically all fields of science and technology, including nanoscience and nanotechnology, can benefit from simple observation of the natural occurrences occurring around us. The cell membranes, as well as various other functioning organelles and enzymes, which are responsible for all metabolic activity in the body, are all nanometric in size. It is unsurprising that nanoparticles are employed in so many different applications [3-5].
Quantum phenomena, increased surface area, and self-assembly are mostly credited for the special features of nanomaterials. At the nanoscale, quantum effects may appear to govern how matter behaves, influencing how materials behave electrically, optically, and magnetically. This is because, at the nanoscale, matter no longer complies with Newtonian physics but rather with quantum mechanics, which is explicated by quantum confinement, size effect, and density of states. The bulk properties of a material are set by the average of all the quantum forces acting on all the atoms simultaneously. Yet, as structures get progressively smaller, eventually there comes a moment where averaging is no longer effective. Moreover, compared to bulk materials generated from the same mass, nanoparticles have a considerably greater surface area. When the fraction of surface atoms becomes greater, reactivity of the material is enhanced due to an increased number of active sites. In certain circumstances, inert materials in their bulk form turn out to be reactive when manufactured at the nanoscale level. All nanomaterials, regardless of their shape, including nanoparticles, nanowires, nanotubes, and nanocoatings, are affected by the increasing surface area. Finally, self-assembly is a process that relies on the arrangement of individual components to create structured or ordered patterns.
It reflects the information contained in each individual molecule, including shape, charge, polarizability, and other characteristics that affect their attracting or repelling interactions, particularly at the nanoscale. Whilst it can also exploit kinetically labile covalent connections, molecular self-assembly often benefits from supramolecular interactions such as ionic, van der Waals, hydrogen, hydrophobic, and coordination bonds. Ordered nanostructures develop as a result of ordered nanoparticles' inherent mobility as they equilibrate between aggregated and non-aggregated states, giving rise to a number of intriguing properties like error correction, self-healing, and great sensitivity to environmental cues [7].
When a particle size falls below the nanoscale in at least one dimension, properties that are not generally size dependent, such as melting temperature, ionisation potential, colour, and electron affinity, electrical conductivity, or magnetism, start to change with size. In this case, the properties of matter may be tailored to their desired values by varying the size of nanoparticles and the thickness of thin layers or wires. The ability to alter and change dimensions at the nanoscale has significantly improved by making it feasible to achieve the interesting features of nanostructures.
1.1. Changes in Thermal Properties
In bulk metals, electrons are the principal thermal energy carriers, and their distribution could be manipulated by nano structuring. The narrower energy bands generated by quantum confinement as a result of changed electron distribution can alter the temperature-related properties including melting point, phase transitions, thermal conductivity, and heat capacity [8].
1.2. Changes in Optical Properties
Nanomaterials have unique optical characteristics like colour, luminescence, and non-linear optical properties that are governed by “plasmons” and quantum size confinement. Certain inorganic NPs have intriguing optical characteristics based on their surface functionalization and particle size [9]. Their emission wavelengths may be controlled from the UV through the visible to the near-infrared parts of the spectrum by altering the size and composition of the nanomaterials. The emission wavelength of colloidal CdSe-CdS core-shell nanoparticles, for instance, may be changed to emit light at different wavelengths in the visible spectrum by varying their size from 2 to 6 nm in diameter, with the smaller particles generating blue light and the larger particles red light [10].
1.3. Changes in Electronic Properties
The shifts in electronic characteristics that take place as the system length scale shrinks are mostly attributable to the rising influence of the electrons' wave-like quality owing to quantum mechanical effects and the dearth of scattering centres [11]. The discrete aspect of the energy levels re-emerges when the system size approaches the de Broglie wavelength of the electrons, yet a completely discrete energy spectrum is only seen in systems that are restricted in all three dimensions. Because of their wave-like nature, electrons may tunnel quantum mechanically between two closely neighbouring nanostructures, and if a voltage is supplied between two nanostructures that have coinciding discrete energy levels, resonant tunnelling occurs, boosting the tunnelling current. Quantum dots display conductivity that is reliant on the presence of other charge carriers and, subsequently, the charge state of the dot due to their extreme confinement. Single-electron conduction processes produced by these Coulomb blockade effects only need a small amount of energy to turn on a switch, transistor, or memory device [12].
1.4. Changes in Electrical Properties
Materials are classified into three categories based on their electrical properties: conductors, semiconductors, and insulators. The ability to fill the energy separation between the valence band and the conduction band determines whether a material is a conductor, semiconductor, or an insulator. A metal becomes a semiconductor as its size is reduced because the quantum confinement effect causes the band gap to widen when a particle's size decreases in the nanoscale domain. Some nanoparticles exhibit electrical properties that are absolutely extraordinary and are related to their unique architectures. Carbon nanotubes, for instance, can be either conductors or semiconductors depending on their nanostructure [13, 14].
1.5. Changes in Magnetic Properties
The magnetic behaviour is determined by the structure and temperature of a material, and the regular size of traditionally anticipated domains is about 1 µm. Surface effects, the ratio of surface atoms to total atoms, and quantum effects start to take precedence as the dimension of a magnetic material is reduced. Due to the high surface-to-volume ratio, a large number of atoms have different magnetic couplings with their surroundings, giving rise to diverse magnetic properties [15].
1.6. Changes in Chemical Properties
With the predominance of surface effects at nanoscale the chemical properties also change in nano-materials compared to their bulk counterparts. Significantly the reactivity of the materials are enhanced substantially at nanoscale [16]. Nanomaterials are more energetic and catalytically active than bulk materials, due to the presence of more atoms on their surface than larger structures. The enhanced chemical activity is brought on by the large number of atoms that are exposed on the surface. Because of the high surface reactivity, contaminants may potentially interact more with nanomaterials; the nature of this interaction depends on the surface structure and the type of chemical bonding [17].
2. Synthesis and characterization methods of nanomaterials
The “bottom-up” and “top-down” techniques are the most common ways to categorize the synthesis of nanostructures. Individual atoms and molecules are brought together or self-assembled to create nanostructured materials in the bottom-up method. Liquids and gases are used as the starting material in this process. With the top-down method, a microcrystalline substance is broken up into a nanocrystalline substance. This category includes all solid state routes. If the process parameters are well controlled, bottom-up approaches may often produce very small nanostructures of individual nanoparticles, nanoshells, etc., with narrow size distributions. The top-down approaches can result in bulk nanostructured materials. While top-down techniques can be scaled up easily, many bottom-up systems are finding it difficult to scale up. Consequently, depending on the needs of a specific application, it is clear that both of these techniques complement one another [18].
2.1. Bottom-up Synthesis Methods
The two main types of bottom-up techniques for the synthesis of nanomaterials are known as solid-phase and liquid-phase techniques. Chemical vapour deposition (CVD), thermal decomposition and physical vapour deposition (PVD) approaches are available for solid phase methods. Nevertheless, most bottom-up techniques for nanomaterial production, such as liquid/liquid procedures (chemical reduction, biological reduction, solvothermal, spray drying, and spray pyrolysis) and sedimentation methods (sol-gel, alkaline precipitation, co-precipitation, and hydrolysis), are performed in the liquid phase [19].
2.1.1. Chemical Vapour Deposition
In CVD processes, a precursor gas is heated to form thin coatings on heated surfaces inside a reaction chamber, where at the end volatile by-products and unreacted precursor gases are subsequently removed by gas flow. Plasmas, ions, hot filaments, lasers, photons, and combustion reactions are used in modern CVD procedures to speed up deposition and reduce reaction temperature [19]. CVD is one of the standard methods for producing CNTs by chemical breakdown of a gaseous hydrocarbon on a substrate using a metal catalyst. This breakdown of the gaseous hydrocarbon at the surface of catalyst particles will cause the availability of carbon at the edges of the nanoparticles where nanotubes can develop [20]. CNT has demonstrated effectiveness and safety in the treatment of a number of illnesses, including cancer and brain tumours, using phototherapy, gene therapy, antiviral, antifungal, and antibacterial therapies, as well as other biomedical applications based on nanotechnology. Furthermore Titanium Nitride NPs which shows potential photothermal therapeutic ability for cancer treatment has also been synthesized frequently using CVD method [21].
2.1.2. Physical Vapour Deposition
A thin layer is deposited using the PVD technology, which builds the coating on the substrate atom by atom. PVD involves the vaporisation or atomization of substance from a solid source, also known as the target. Deposited thin films usually range in thickness from a few atomic layers to many microns. This procedure changes the surface's properties as well as the region between the substrate and the deposited substance. On the other hand, the properties of the films can also be influenced by the qualities of the substrate. Atomic deposits can be produced in a variety of conditions, including vacuum, gaseous, plasma, and electrolytic. A further benefit of the vacuum in the deposition chamber is that it will reduce gaseous contamination when the material is being deposited [22]. Graphitic NPs which are extensively used in medical applications have been synthesized using PVD methods like arc discharge, irradiation, vaporisation, and sputtering techniques [23].
2.1.3. Thermal Decomposition
This is a type of chemical decomposition process that is mediated by heat and results in the generation of nanoparticles with high crystallinity and limited size distribution. Organometallic compounds are decomposed in this process at high refluxing temperatures in solvents with high boiling points and with the assistance of stabilizing surfactants. Thermal decomposition is commonly utilized in the creation of metal oxide nanoparticles such as ZnO [24], Fe3O4 [25], CuO [26], Co3O4 [27], metal nanoparticles such as Fe [28], Ni [29] and Co [30], and alloys such as CoPt3 [31] and FePt [32]. The size, shape, and polydispersity of the resulting nanoparticles may be controlled by adjusting the ratios of the precursors, solvents, and surfactants [33, 34].
2.1.4. Chemical Reduction
This is one of the most adaptable procedures. In the majority of situations, with the Brust-Schiffrin two-phase process, in which chemical reduction occurs at the oil-water interface. As the precursor in the chemical reduction technique, an aqueous solution containing metal ions is employed. The ions are reduced to their metallic form by adding sodium borohydrate [35], sodium citrate [36, 37], sodium ascorbate [38] or hydrazine hydrate [39] in a volatile organic solvent such as toluene [40] or chloroform [41] to the reaction mixture. Nanoparticles aggregate and form clusters as a result of this process. Therefore, it is necessary to utilise capping agents to stop colloidal nanoparticle aggregation. Otherwise, it can be impossible to control the sizes of the final nanoparticle [42]. The most commonly used stabilizing agents include amines and thiols such as dodecylamine [43], dodecanethiol [44], alkanethiolates [45], surfactants [46], polymers [47], carboxylic acids [48] and organic compounds [49]. For instance gold nanoparticles (AuNPs) which is widely applied as biosensors, anticancer agents and in drug delivery are synthesized frequently by chemical reduction in major two steps. A reduction agent will provide electrons to reduce the gold ions, Au3+ and Au+ to Au0 which is the electric state for nanoparticles. Then a stabilizing agent will stabilize nanoparticles against aggregation [50].
2.1.5. Photo-reduction
One of the downsides of the chemical reduction process is the use of large amounts of reducing and stabilising chemicals, which must be eliminated from the finished product in the last step. A feasible solution to this issue is photo-reduction, which includes exposing the reaction mixture to a light source and photoreducing agents without the use of stabilising or capping compounds [51]. The photoreduction process has the advantage of largely eliminating undesirable by-products, and it may be used in both the solid and liquid phases [19]. AgNPs synthesized by the photoreduction of Leaves and Fruit Extracts of Plinia cauliflora and Punica granatum has shown high antimicrobial activity against Gram-negative and Gram-positive bacteria and yeast as well.
2.1.6. Biological Synthesis
The concepts of green chemistry are the foundation of the biological synthesis method, which is also known as “green synthesis.” The primary solvent in the reaction mixture is water, however methanol and ethanol may also be employed. This approach has the benefit of using the reducing agent as a capping agent. The two main categories of reducing and capping agents employed in the green synthesis process are microorganisms and plant extracts [19]. For instance palladium NPs synthesized using the extract from brown alga, Padina boryana as a bio-capping and bio-reduction agent, has exhibited strong antibacterial/antibiofilm activities against Staphylococcus aureus, Escherichia fergusonii, Acinetobacter pittii, Pseudomonas aeruginosa, Aeromonas enteropelogenes, and Proteus mirabilis [52].
2.1.7. Solvothermal
The solvothermal approach has the potential to produce novel materials by using a variety of organic solvents as a reaction medium. The molecular weight, dipole moment, polarity, density, boiling point, melting point, heat of evaporation, and dielectric constant are just a few of the qualities that are impacted by the solvent of choice. Benzyl alcohol, propanol, butanol, heptanol, ethyl alcohol, and others are examples of the solvents used in the solvothermal process [53]. Leucine coated cobalt ferrite (CoFe2O4) nanoparticles loaded with DOX has been synthesized using solvothermal method with ethylene glycol and it has shown high cell viability towards the HeLa cells [54].
2.1.8. Sol-gel
This is a method for producing metal oxide nanoparticles and oxide composites. When the reaction media involves water, the term aqueous sol-gel is used and the procedure is known as the non-aqueous sol-gel method when organic solvents are involved. The non-aqueous sol-gel approach produces superior metal-oxides in terms of surface characteristics, nanoparticle size, morphological features, and chemical composition. The qualities of the final product are significantly influenced by the solvent and precursor metal salt used in the sol-gel process. The procedure is frequently carried out in three steps: hydrolysis (which creates the hydroxides of the precursors), condensation (which condenses the hydroxides into a 3D gel), and drying (leading to a xerogel or aerogel depending on the drying method) [55]. Teicoplanin drug loaded chitosan nanoparticles crosslinked with tripolyphosphate ion have been syntheized by Kahdestani et al., and accessed for its ability of sustained drug delivery [56]. It is observed that 28.2% of teicoplanin was released in the frst 10 h and the release is continued gradually to receive 37.4% in 100 h.
2.1.9. Co-precipitation
One of the earliest wet chemical processes to produce nanomaterials is co-precipitation. In this approach, more than one compound is precipitated simultaneously from a salt precursor. Hydroxides, carbonates, chlorides, sulphates, and oxalates are the most regularly employed precipitants [19]. Co-precipitation is an efficient, rapid, and simple technique that may be readily scaled up for commercial use. It is an effective way to make nanomaterials without using hazardous organic solvents or high temperatures and pressures. Other benefits of this approach is its simplicity in controlling particle size and composition. However, this approach has certain drawbacks, including issues with batch-to-batch repeatability, time consumption, and contamination of the samples with trace contaminants that will precipitate simultaneously [57]. Magnetite nanoparticles used in therapeutic applications can be synthesized using this method. For instance, magnetite (Fe3O4) has been synthesized by co-precipitating FeCl2.4H2O and FeCl3.6H2O in distilled water that was previously purged by nitrogen. The synthesized Fe3O4 were directly coated with organic (Oleic Acid), inorganic (SiO2) and polymeric (PEG) coatings and cell viability has been assessed with MTT assay for Hepatoma G2 cells [58].
2.2. Top-down Synthesis Methods
2.2.1. Mechanical Ball Milling
In comparison to alternative top-down approaches, mechanical ball milling is typically advantageous to produce various types of nanoparticles. This synthesis method is particularly useful when the synthesis procedure begins on a micrometre scale. A suitable milling medium and powder made up of a mixture of materials are often added to the mill with the goal of blending and particle-size reduction of the constituents. Charge ratio, milling time, drum rotation speed, brittleness of basic materials, size and size distribution, and ball building material are the key elements influencing the size of nanoparticles created from the milling process [59]. Additionally, milling temperature has a substantial impact on diffusivity. Higher temperatures are predicted to produce atomically mobile phases such as intermetallics, whereas lower temperatures mostly produce amorphous structures [60]. Peptides are prospective medicine candidates due to their efficiency, selectivity, and biodegradability. Mechanochemical peptide synthesis necessitates a modest amount of low-impact solvent (such as EtOAc or tBuOAc) and is a generally eco-friendly workup with better safety. Pure N-(4-methoxyphenyl)-benzamide which can be used for the synthesis of the drug candidates of Benzimidazole derivatives has been synthesized by ball milling a crude mixture of benzoic acid, p-anisidine, anhydrous nitromethane, 4-dimethylaminopyridine (DMAP) and N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide·HCl for 10-30 minutes [61]. Furthermore, within 180 minutes of milling with a single 12 mm diameter stainless steel ball at 30 Hz frequency, five homo- and hetero-dipeptides were produced starting with N-Boc-protected glycine or alanine and benzyl esters of glycine or alanine in the form of tosylate salts. Procainamide which is an antiarrhythmic drug has been synthesized successfully using K2CO3-assisted ball milling of p-nitrobenzoyl chloride with N,N-diethylenediamine for amide coupling followed by catalytic transfer hydrogenation under liquid assisted grinding [62].
2.2.2. Nanolithography
The study of producing nanometric-scale particles from bulk materials is referred to as nanolithography. The size of the synthesized nanoparticles obtained by this process ranges from 1 to 100 nm. To produce nanomaterials, a variety of nanolithography techniques have been utilized, including electron beam, optical process, nanoimprint, and high energy proton beams. In general, lithography is the process of producing nanoparticles of a certain form and size from light-sensitive bulk materials by selectively removing a portion of the bulk materials. The capacity to create single-size nanoparticle clusters in any desired form and size is the main advantage of this technique [63-65]. Rod-shaped docetaxel-loaded Poly(D,L-lactide-co-glycolide) nanoparticles has been synthesized using imprint lithography based technique referred to as Particle Replication in Nonwetting Templates which was then tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represented the taxane resistant, basal-like subtype of triple-negative breast cancer [66]. The nanosystem of the drug has shown improved tumour growth inhibition and significantly increased median survival time.
2.2.3. Laser Ablation
One of the primary techniques for creating nanoparticles from different precursor liquids is laser ablation. When the metallic solution is combined with the liquid medium and subjected to a laser beam, the metallic solution condenses to form nanoparticles with sizes ranging from 1-100 nm. This procedure does not produce any toxic by-products, is cost-effective, and does not involve any hazardous chemicals or stabilizing agents. This is considered as a green synthesis method since both water and organic liquids can be used to form stable nanoparticles [67-71]. Al-Kinani et al., synthesized a new formula of curcumin loaded, chitosan, gold and folic acid -coated Fe magnetic nanoparticles Fe@Au-CS-CU-FA nanoparticle by pulsed laser ablation in liquid by forming a water-in-oil microemulsion [72]. The NPs has shown sustained releasing behaviour, good stability and resulted in decrease of T-47D cell viability and induced 85% apoptosis.
2.2.4. Electrospinning
This is a common top-down technique that uses electrostatic forces to propel a conductive fluid to produce fibrous structures ranging from few nanometres to tens of micrometres. In this process a high voltage is supplied to the spinneret to charge the polymer solution, forming a potential gradient between the polymer droplet and the ground collector. When the voltage is high enough, the polymer jet will reach the ground collector, forming ultrafine fibers. These fibers will be deposited on a grounded collector plate to produce a nanofibrous membrane. The capability to control the surface morphology and chemical functionality of the produced fiber membranes have allowed the use of electrospun nanofibers in variety of disciplines [73, 74] Depending on the field of application electrospun fibers can be engineered to be core-shell [75], hollow [76], anisotropic [77], or biphasic structures [78].
Farkas et al., have developed a doxycycline (DOX) loaded polylactic acid-hydroxyapatite electrospun membrane as a drug delivery vehicle [79]. The Doxy-loaded PLA-HAP nanofiber system prepared by physical adsorption was found to be the most acceptable membrane to provide a prolonged release of DOX, in simulated body fluid and phosphate buffer solution rather than an immediate release of DOX. A Resveratrol-loaded polylactic acid (PLA) electrospun membrane has been employed as a pH-responsive drug delivery vessel which exhibited antibacterial and antibiofilm properties against Pseudomonas aeruginosa PAO1, and Streptococcus mutans [80]. The data acquired indicated that in acidic conditions, the RSV release rate from the PLA-membrane was significantly higher than in neutral pH. Furthermore, there has been a notable increase in RSV release during a pH shift from neutral to slightly acidic. Thus when the pH of the surrounding environment is neutral, PLA-RSV membranes can function as drug reservoirs. When the pH drops, as happens when an oral bacterial infection is present, the membranes begin to release bioactive compounds.
2.3. Characterisation of Nanomaterials
Throughout the last three decades, a variety of analytical tools for the characterization of nanomaterials have been developed. They have assisted in structural characterisation and understand the behaviour of nanomaterials and nanostructures. Different methods have been used to describe various physical and chemical aspects of nanomaterials, including size, shape, crystal structure, elemental content, and other nano-structural features. Therefore, it is possible to evaluate a single physical attribute of nanoparticles using more than one approach. In other words, the outcomes of various characterization approaches may be related to or complementary. Therefore, choosing the optimum method for nanomaterial characterization is undoubtedly crucial. Herein, we have summarized the different methods for nanomaterial characterization and the characteristic property analysed. (Table 1)
3. Nanodevices
Drug discovery requires a thorough grasp of biological processes, from the molecular to the physiological, as well as a comprehension of disease in terms of protein synthesis, gene expression, and specific cellular and tissue responses. Technological advancements have been sparked by nanotechnology to increase the efficiency of the drug development process. Additionally, nanotechnology has given scientists a number of techniques to better understand the biological mechanisms underlying disease, signaling pathways, and the precise effects of medications [86].
Analysis of signalling pathways by using nanobiotechnology techniques might provide new insights into disease management processes. Identification of more efficient biomarkers and understanding the mechanism of action in drugs tremendously help in drug discovery. Harnessing the strategies of nanotechnology for diagnostic purposes is successfully obtained in medicine. New dimensions of diagnostic tools have been explored with the aid of this cutting-edge technique. More sensitive diagnostic kits, with the capability of probing the bodily problems at cellular pores and receptor level than existing ones were developed. Additionally, the degree of hazardous and harmful effects has been significantly decreased as a result of the use of miniature diagnostic materials. Below, we've covered a number of nano-enabled diagnostic tools used in the medical field.
3.1. Atomic Force Microscopy
Atomic force microscopy (AFM) is a versatile nanoscale technology that enables high-resolution imaging of biological macromolecules in their natural environment with a high signal-to-noise ratio. Additionally, AFM offers a delicate method for working with biomolecular machinery and aids in comprehending the molecular interactions and functionality of cell structures. The advancement of the AFM is the application of nanomechanical cantilevers, where a cantilever with a sharp tip at one end is used to image surfaces on molecular and atomic size [87]. As a result of the research and development done thus far, it has been discovered that high-rate AFM has entered the realm of time at the nanoscale and millisecond resolution in chemical processes, such as the visualization of the real-time motion of myosin on an actin filament [88]. AFM allows for the application and measurement of stresses in the piconewton to micronewton on spatially defined areas with dimensions ranging from a few nanometers to several tens of micrometers. AFM can measure mechanical properties such as force, pressure, adhesion, elasticity, tension, viscosity, and energy dissipation [89].
The significance of AFM lies in several key factors. First off, because of its extraordinarily high resolution, molecular- and even atomic-scale structures may be directly imaged in three dimensions. Second, sample preparation for AFM is simple, there is minimal harm to the original structure, and the sample's original structure may be precisely and objectively assessed. Thirdly, because samples can be examined in close to physiological settings, real-time AFM recordings of the dynamic activities of molecules, organelles, and other structures in living cells are possible [90]. Furthermore, intermolecular forces, charge, pH, and other physicochemical properties of sample materials may all be measured using AFM. Additionally, specific molecules or forces of interaction, such as ligand-receptor interactions, can be located using the functionalized probe. AFM thus has a significant chance of being used in biomedicine and clinical medicine, especially in the diagnosis and treatment of cancer [91]. AFM also makes it possible to investigate the mechanisms of anticancer medications at the cellular and molecular levels, enabling the assessment of their effectiveness and providing new opportunities for the prevention of tumour cell proliferation [92-94]. For instance, alterations in cell and tissue mechanics are among the traits of cancer, however, it is unclear how the stiffening of the tissue affects the growth of tumours. Mammary tumour cells and surrounding tissues have been measured for stiffness in situ using AFM to better understand this process, and it was discovered that tumour tissues are stiffer than isolated tumour cells [95-97].These studies show how AFM may be used to study mechanical characteristics associated with illness in settings that retain the physiological milieu. Alzheimer's disease is identified by intracellular neurofibrillary lesions and β-Amyloid (Aβ) plaques in the brain. Song et al. [98] investigated the interactions between vanillin and Aβ polypeptide using AFM in conjunction with fluorescence spectroscopy. Their findings showed that vanillin depolymerized Aβ1-42 aggregates in a dose-dependent manner, and the authors hypothesized that vanillin would be a promising pharmacological therapy for Alzheimer's disease.
3.2. Nanoarrays/nanochips
Micro- and nanoarrays are increasingly used as analytical instruments and platforms for evaluating chemical libraries, analyzing reactions at nanoliter scales, and attaining densities of thousands of spots/cm2, surpassing the scale and density restrictions of well plates. These nanoarrays are miniature versions of microarrays, dispersed in micron or sub-micron spatial ranges [99].
Nanoarrays are static, regulated systems that have a high level of sensitivity and selectivity by nature [100]. Given these properties, nanoarrays have been employed for biomolecular analysis which are difficult to study in vitro due to their dynamic structure and have been used for the detection of pathogens in trace amounts [101, 102]. Nanoarrays are employed in bio-affinity testing for proteins, nucleic acids, and receptor-ligand pairs because they can quantify interactions between individual molecules with resolutions as low as one nanometre [86]. Nanoarray technology is expanding rapidly and has the potential for advancing pharmaceutical research and development.
Nanoarrays can store 104–105 more characteristics than traditional microarrays. Consequently, several targets may be promptly and simultaneously screened in a single experiment. Additionally, just a few target molecules may be identified for a given analyte concentration, and only extremely small amounts of sample and reagent are needed resulting in much lower detection limits than microarrays. Furthermore, just 1/10000 of the surface area needed by traditional microarray devices is needed for nanoarrays, and around 1500 nanoarray devices may be fitted into the same space as one microarray device. Last but not least, since biorecognition is intrinsically a nanoscopic phenomenon rather than a microscopic or macroscopic event, nanoarrays can be utilized to shed light on crucial problems surrounding biomolecular recognition [103].
The Nano Chip System has achieved 100% accuracy in the detection of nanoparticles by electrically enhancing the hybridization of complementary DNA strands. The Nano Chip System combines contemporary microelectronics and molecular biology into a platform technology with widespread commercial applications in the domains of genomic diagnostics. This method facilitates the investigation of DNA sequences or the pairing of separated DNA strands by using complementary DNA strands from the known collection that act as probes. DNA microarray experiments, which use the power of a digital device to separate DNA probes to particular websites at the array depending on charge and size, are currently conducted using DNA chips. Using these probes to analyze test sample (blood) data, DNA sequences may then be found [104].
3.3. Nanofluidics
Research tools for the explication of essential phenomena in nanoscale confined fluids have been made available by nanofluidics [105]. It is a particularly ideal platform for high-throughput biological Screening of single cell sample analysis because the volume of the nanospace is between aL (= (100 nm)3) and fL (= (1000 nm)3), which is 104 to 103 times smaller than the volume of a single cell [106].
Small molecules and particles including NPs, DNA fragments, and proteins have been effectively separated using nanofluidic devices [107, 108]. For cell biology, disease pathology, drug development, and medical therapies, living single-cell analysis is essential for identifying genes in cells, proteomics, and the temporal and spatial variety of physiology and pathology. Understanding the causes of life-threatening serious diseases is extremely important. For obtaining the average information about cells, the traditional single cell analysis concentrates on a large number of cells or cell lysis. As a result, it is unable to assess the actual, real-time data on variations between individual cells, which restricts the growth of several industries, including the biomedical sector. Small sample volumes, fast response times, easy operation, and effective processing, which have been widely employed in complicated procedures such single cell capture, separation, and detection, distinguish nanofluidics-based biochemical analysis from conventional approaches [106].
In a recent study, a nanofluidic device that has great sensitivity, resolution, and speed was established to continually assess the purity and bioactivity of biologics. A continuous size-based examination of biologics was carried out using periodic and angled nanofilter arrays as molecular sieve structures. The supernatant of the cell culture can be directly used to continually assess several important safety and effectiveness measures, including binding, folding, and aggregation [109]. Additionally, they are enhancing the created nanofluidic device's capacity to track additional crucial quality characteristics during bio-manufacturing, such as binding affinity and glycosylation of monoclonal antibodies. To accomplish “real-time” and “multi-modal” quality analytics, the monitoring system will be further optimized [110]. Future bio-manufacturing processes are expected to be safer and more effective and broad applications in systems biology, personalized medicine, pathogen detection, drug development, and clinical research are expected with nanofluidic technology [111].
Additionally, drug delivery systems that are remotely controlled have included nanofluidics as actuators. For example, using electrostatic gating, Di Trani et al. have created a SiC-coated nanofluidic membrane that can reliably regulate the distribution of quantum dots and methotrexate, a first-line treatment for rheumatoid arthritis [112]. Hence, it has been proposed as a remedy for the inadequacy of sophisticated systems for the controlled and customized delivery of therapeutic interventions, which hinders the best possible management of conditions like diabetes, hypertension, and rheumatoid arthritis.
3.4. Nano Biosensors
Diagnostics are now provided in a personalized manner by considering the needs of disease management and the patient's disease profile. On this note, the advancements in point-of-care (POC) sensing unit fabrication, device integration, interfacing, packaging, and sensing performance have been enabled by nanotechnology. Modern biosensing technology is being actively marketed as the next generation of non-invasive illness detection techniques [113]. A biosensor is a biological component that detects and signals the activity, presence, or concentration of a specific biological molecule in solution through biochemical changes. The biological signal is changed into a measurable signal using a transducer. The selectivity and sensitivity of biosensors are essential traits. Nanoparticles are crucial in medical diagnostics because they are physiologically and chemically sensitive and may identify certain cells or body regions. Utilizing markers and distinctive biomolecules, nanobiosensors may distinguish between various cell types and recognize cancer cells. This makes it possible to monitor how different body parts are growing, and developing on delivering drugs. Even from outside the body, nanobiosensors are capable of detecting large-scale variations and signals linked to identical molecules within the body. By locating the fluoresced nanodot that was previously injected, a doctor might detect malignancies within the body by using the fluorescence characteristics of quantum dots of specific metals. Due to its capacity to detect specific DNA, genetic abnormalities might be identified specifically and sooner [114, 115]. Using metastasis-initiating cells (MIC), Ganesh et al. created a self-functionalized nanosensor for the early detection and forecasting of cancer metastasis. The nanosensor was generated by interacting a laser pulse with a carbon substrate in an oxygen-rich environment. By examining intracellular biological functions and tumour microenvironment features, it can identify MIC.
3.5. Nanobiopsy
Nano biopsy is a less invasive technique used in nanosurgery to examine live cells. It can serve as a platform for evaluating the prevalence of mitochondrial mutations in cancer research and clinical cancer care. Therefore, a nano biopsy might serve as the basis for a dynamic subcellular genetic study [116]. And it will help the researchers to track disease progression.
The system is based on scanning ion conductance microscopy, which has lately received attention for its capacity to capture high-resolution images of live cells in both space and time [117, 118]. The specimen is extracted using a glass nanopipette that is between 50 and 100 nm in size. The nanopipette is permitted to descend to a depth of around 1 nm to penetrate the cell membrane to enter the cell. The fluid can then enter the pipette once a voltage is introduced across the tip. The cell and cell membrane are both intact after the pipette has been removed from the cell. The electrolyte solution is then poured into the nanopipette, and the size of the ion current is evaluated at its tip. The size of the ion current diminishes when the nanopipette gets closer to a cell membrane [117, 119, 120].
Recently, nanopipettes have been used to localize delivery molecules to various subcellular locations, monitor the electrophysiology at tiny synaptic buttons, and trap molecules in lipid bilayers. Briefly, a liquid-liquid interface forms at the nanopipette aperture when an organic solution is placed within and submerged in an aqueous solution. The force created by applying a voltage across this contact can cause the aqueous solution to flow into and out of the nanopipette. [117, 121-123] The few copies of mitochondrial DNA that may be aspirated from a live cell using nanopipettes may serve as the foundation for less invasive and more precise disease progression monitoring. Nanobiopsy could pave the way for the creation of new therapeutic classes that will lessen a variety of illnesses, including Parkinson's and Alzheimer's disease. The nanopipette may be utilized as a platform for cancer research and therapeutic care, clarifying the function of heterogeneity in primary tumour tissues and systematically identifying important factors in disease development and possible metastatic states [124, 125]. The most difficult malignancies to identify in a person are frequently brain tumours. Biopsies allow for to diagnose if a tumour is benign or malignant in other tissues. However because the brain is such a unique organ, it is best to avoid removing brain tissue. However, the less intrusive nature of nanobiopsy provides an option [126]. By integrating the nanopipette platform with downstream sequencing technology, gene expression in individual cells can be fully examined and the influence of pharmacological processes on mutation-selection can be more thoroughly addressed [127].
4. Advantages of Employing Nanomaterials and Nanodevices in Drug Discovery
This rapidly developing field enables multidisciplinary researchers to create multifunctional nanoparticles that can target, identify, and treat a range of diseases. The development of improved diagnostic methods, therapeutic formulations, and drug delivery systems is one of the main objectives of nanotechnology in the field of drug research and development. The scientific community is increasingly focusing on the unique chemical and physical properties of nanoscale materials in search of potential applications to improve human health.
