Recent Trends in Biomedical and Pharmaceutical Industry Due to Engineered Nanomaterials

Chapter 27

Recent Trends in Biomedical and Pharmaceutical Industry Due to Engineered Nanomaterials Ali N. Chakoli and Masud Sadeghzadeh Nuclear Science and Technology Research Institute, Tehran, Iran

27.1 INTRODUCTION Discovery of new harmful technologies and changing lifestyles around the world have increased cancer diseases. Although global developments paved the way for prevention and early diagnosis of many cancers as well as appropriate treatment strategies for cancer patients, there are a wide variety of issues that are still to be solved. Among them, delivering a drug by traditional chemotherapy method includes some side effects inside the patient body. In this way, a drug would be able to circulate in the bloodstream and imposes a bad effect on normal cells by a noncontrolled treatment manner. In order to achieve efficient targeted delivery, the designed system must avoid the host’s defense mechanisms and circulate to its intended site of action. Today, application of nanoparticles to deliver drugs to cancer cells, especially for the development of novel approaches for cancer detection and treatment, is well known as the most publicized use of nanotechnology in drug delivery under development. There are many reports in the literature in which ethylene glycol molecules are attached to nanoparticles and deliver therapeutic drugs to cancer tumors. In this way, the white blood cells are not able to recognize the nanoparticles, as foreign materials, due to the existence of the ethylene glycol molecules which allow them to circulate in the bloodstream long enough to attach to cancer tumors. Generally, nanomaterials divide into two basic types of nanoparticles: nanocrystalline materials and nanostructured materials. Nanocrystal drugs are readily manufactured and can substitute for the less well performing bulk materials. However, nanostructured materials can

categorize into two subclasses: polymer-based and nonpolymer-based nanocompounds. Although it is just the tip of the drug delivery iceberg, nanotechnology can be utilized as drug delivery systems to be more efficient and potentially less unpleasant for the patient. While some techniques are only imagined, new developments are at various stages of testing, or actually being currently used. If one’s application of a drug consists of an occasional aspirin, there is no need for serious work on drug delivery. But for a diabetic patient, who has to inject insulin several times a day, or a cancer patient experiencing debilitating side effects from the treatment, the benefits of improved drug delivery could change their life. Drug delivery systems are known as useful methods which are utilized to ensure that drugs get into the body and reach the tissue or organ (target) of interest. On the other hand, drug delivery systems are so-called engineered technologies for the targeted delivery and/or controlled release of therapeutic and diagnostic agents. Drugs have long been used to improve health and extend lives. The practice of drug delivery has changed dramatically in the past few decades and even greater changes are anticipated in the near future. However like other new drug treatments, there are also a few challenges for most drug delivery systems that include solubility, in vivo stability, intestinal absorption, poor bioavailability, sustained and targeted delivery to site of action, side effects, therapeutic effectiveness, and plasma fluctuations of drugs, all of which should be considered [1]. In this chapter we present the state-of-the-art and new findings on the applications of nanomaterials and nanotechnology in the biomedical and pharmaceutical industries.

Handbook of Nanomaterials for Industrial Applications. DOI: https://doi.org/10.1016/B978-0-12-813351-4.00028-6 © 2018 Elsevier Inc. All rights reserved.

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27.2 DRUG DELIVERY NANOSYSTEMS Nowadays, several advantages are well known for controlled drug delivery systems compared to the traditional forms of drug. Hence, when a drug is transported to the target organ, the place of action, its undesirable side effects as well as its influence on vital tissues can be minimized. Consequently, the target site receives lower doses of the drug due to high accumulation of therapeutic compounds in it. This new form of treatment is especially important where a discrepancy between the dose and the concentration of a drug influences its therapeutic results or toxic effects. Moreover, cell-specific targeting can be accomplished by attaching drugs to specially designed carriers. Several nanostructures, such as dendrimers, liposomes, silicon or carbon materials, polymers, and magnetic nanoparticles (MNPs), have been tested as carriers in drug delivery systems [2]. Undoubtedly, our lives will be tremendously affected over the next decade by the development of nanotechnology in very different fields, including pharmacy and medicine. Indeed, physical properties of materials which were used in pharmaceuticals change by reducing their size down to the nanoscale and are leading to the development of a new innovative formulation principle in a more confident way that is known as drug delivery system. On the other hand, nanotechnology is opening up new avenues for drug delivery vehicles [3]. Accordingly, it is possible to engineer nanoparticles so that they are able to attach to diseased cells and allow direct treatment of those cells, resulting in reducing the damage to healthy cells in the body. In other words, it provides a powerful tool in order to measure and to understand biosystems [4]. More specifically, nanomedicine, as a new modality of medicine, can be formed by the use of nanotechnology which thereby refers to treatment and curing of diseases at a molecular scale. However, the development and fabrication of nanostructures at submicronscale and nanoscale, which are mainly polymeric and have multiple advantages, goes toward the advent of new drug delivery systems that are considered to be an approach designed to overcome the abovementioned challenges. Generally, it is well understood that nanostructures have the ability to protect drugs encapsulated within them from hydrolytic and enzymatic degradation in the gastrointestinal tract, and target the delivery of a wide range of drugs to various areas of the body for sustained release. Thus they are able to deliver drugs, proteins, and genes through the peroral route of administration [5 7]. They also can deliver highly water insoluble drugs and can bypass the liver, preventing the first-pass metabolism of the incorporated drug [8,9]. With this mechanism of

action, considering their specialized uptake mechanisms such as absorptive endocytosis, the oral bioavailability of drugs can be increased and consequently it is possible that they remain in the blood circulation for a longer time. So, it results in releasing the incorporated drug in a sustained and continuous manner leading to less plasma fluctuations, thereby minimizing side-effects caused by drugs [7]. The most significant advantage of nanostructures, which is tightly linked to the size of their constituent particles, is that they are able to penetrate into tissues and are taken up by cells, allowing efficient delivery of drugs to sites of action. Nanostructures were normally found to have 15 250 times higher uptake than that of microparticles in the 1 10-μm range [10]. Recently, hydrogel-based nanoparticles have gained considerable attention as one of the most promising drug delivery systems given their unique potential via integrating the characteristics of a nanoparticle with a hydrogel system (e.g., hydrophilicity and extremely high water content). In this regard, several polymeric hydrogel nanoparticulate systems have been prepared and characterized based on both synthetic and natural polymers. Chitosan and alginate as the most applicable natural polymers have been extensively studied for preparation of natural hydrogel nanoparticles. Among the synthetic group, hydrogel nanoparticles based on poly(vinyl pyrrolidone), poly(vinyl alcohol) (PVA), poly-N-isopropylacrylamide poly(ethylene oxide), and poly(ethyleneimine) have been reported with different characteristics and features with respect to drug delivery. The release mechanism of the loaded agent from hydrogel nanoparticles is complex, regardless of the type of polymer used. Nevertheless, three main vectors including drug diffusion, hydrogel matrix swelling, and chemical reactivity of the drug/matrix might be effective on the mechanism of releasing the drugs. Two major groups of chemically and physically-induced cross-linking methods have been used to form the hydrogel matrix structures [11]. Generally, nanoparticles that are used in drug delivery systems can be divided into two large categories. Accordingly, nanoparticles are designed as multifunctional diagnostic and therapeutic devices. During the last decade a wide variety of carrier types have been developed for pharmaceutical purposes and more specifically for cancer drug delivery and cancer imaging. The best way to create these types of nanoparticles is by a variety of molecules (drug pay-loads) being attached to the surface or encapsulated in the interior of the particle. The development of novel drug delivery systems depends on the advancement of nanotechnology by using a variety of nanomaterials (i.e., polymersomes, liposomes, microspheres, and polymer conjugates) as vehicles to deliver therapeutic agents.

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27.2.1 Liposomes During the almost five decades, the pioneering work of countless liposome researchers has led to the development of important technical advances including longcirculating (PEGylated) liposomes, remote drug loading, extrusion for homogeneous size, liposomes containing nucleic acid polymers, triggered release liposomes, ligand-targeted liposomes, and liposomes containing combinations of drugs. Liposomes were initially introduced by Alec Bangham and were used as a model for cell membranes in biophysical studies [10]. Many years later, investigation on these supermolecules was predominantly begun as they were potentially promising drug carriers. In general, liposomes are vesicles ranging from 30 nm up to several micrometers in which an aqueous volume is entirely surrounded by a phospholipid membrane. They can consist of one (unilamellar) or more (multilamellar) homocentric bilayers of amphipathic lipids (mainly phospholipids). Based on the number of lamellae (lamellarity) and their size, they are characterized as small or large unilamellar vesicles and multilamellar vesicles. In most cases, liposomes are named by the preparation method used for their formation. There are a lot of reviews that summarized available liposome preparation methods. Generally, liposomes can be formed spontaneously when phospholipids are dispersed in water. However, the preparation of drug-encapsulating liposomes with high drug encapsulation and specific size and lamellarity is not always an easy task. The most important methods are known as thin-film method, sonication, injection methods, extrusion, microfluidization, reverse phase evaporation, dehydrated-rehydrated vesicles, giant vesicles, detergent depletion, and large unilamellar vesicles from cochleates. In recent years, drug delivery systems such as liposomes and microparticles have been used in clinic for the treatment of different diseases; from a regulatory point of view, a parenterally applied drug and drug delivery systems must be sterile and pyrogen free. Radiation sterilization is a method recognized by pharmacopoeias to achieve the sterility criteria of parenterals. It has the ability to kill microorganisms in therapeutic products. However, the performance of drug delivery systems might be also affected by the irradiation. Thus, the irradiation dose should be considered as one of the most critical points because some of the certain undesirable chemical and physical changes may accompany the irradiation, especially with the traditionally applied dose of 25 kGy. Its ionizing property may cause fragmentation of covalent bonds. The care must be paid to the applied dose. Sakar et al. performed research on the effects of gamma irradiation on different drug delivery systems, such as chitosan

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microparticles, liposomes, niosomes, and sphingosomes. According to the experimental data, it can be concluded that gamma irradiation can be a suitable sterilization technique for liposome, noisome, and sphingosome dispersions. When all irradiated drug carrier systems were taken into consideration, chitosan glutamate microparticles were found as the most radioresistant drug delivery system over the others [12]. Solid lipid particulate systems such as solid lipid nanoparticles, lipid microparticles, and lipospheres have been considered as alternative carriers for therapeutic peptides, proteins, and antigens. Solid lipid nanoparticles are an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes, and polymeric micro- and nanoparticles. Solid lipid nanoparticles combine advantages of the traditional systems but avoid some of their major disadvantages [13]. The mentioned lipid nanoparticles can be produced to incorporate hydrophobic or hydrophilic proteins and seem to fulfill the requirements for an optimum particulate carrier system. Proteins and antigens intended for therapeutic purposes may be incorporated or adsorbed onto solid lipid nanoparticles, and further administered by parenteral routes or by alternative routes such as oral, nasal, and pulmonary. Formulation in solid lipid nanoparticles confers improved protein stability, avoids proteolytic degradation, as well as sustained release of the incorporated molecules. Important peptides such as cyclosporine A, insulin, calcitonin, and somatostatin have been incorporated into solid lipid particles [14]. The efficiency for drug encapsulation of liposomes is enhanced with the increasing in stability of polyelectrolyte systems achieved through the alternate adsorption of several layers of natural polymers, such as anionic alginate and cationic chitosan on cationic nanosized phospholipid vesicles. The resulting particles were characterized for their size, surface charge, morphology, encapsulation efficiency, loading capacity, and release kinetics over an extended period of 30 days. The layer by layer deposition technique succeeded in building a spherical, monodisperse, and stable hybrid nanoparticulate protein delivery system with a cumulative size of about 383 nm and zeta potential surface charge of about 44 mV for five bilayered liposomes. The system offers numerous compartments for encapsulation, including the aqueous core and within the polyelectrolyte shell, demonstrates good entrapment and also sustained linear release of a model protein, bovine serum albumin, in vitro [15]. These developments have resulted in several clinical trials in such various areas like the delivery of gene medicines, the delivery of antiinflammatory drugs and anesthetics, as well as the delivery of anticancer, antifungal, and antibiotic drugs. Moreover, numerous liposomes (lipidic nanoparticles) are currently on the market, and many more are in the pipeline. Lipidic

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nanoparticles are known as the first nanomedicine delivery system which provided the possibility of transition from concept to clinical application. Now, they are consider as an established technology platform with remarkable clinical acceptance [16].

27.3 TISSUE ENGINEERING Tissue engineering, which can be actually considered as a multidisciplinary field, is rapidly emerging as a promising new approach in the restoration and reconstruction of imperfect tissues. It is also an evolving interdisciplinary field integrating materials science, biology, engineering, and medicine. In this regard, it focuses on the development of biological substitutes to restore, replace, maintain, or enhance tissue and organ function. From this perspective, scaffolds play a substantial role in supporting the cells to settle and guide their growth into a specific tissue. Therefore, designing scaffolds which are more favorable for cellular growth has a great importance. For example, a scaffold that harbors the desired features, such as biocompatibility, biodegradation, and porous structure, could serve as a template for bone tissue engineering. In that case, fibrous scaffolds, biopolymers, and hydrogels which are commonly used as scaffold materials are inherently soft in order to mimic the stiffness of natural tissues and thus often lack structural strength and support. However, bimetal alloys and bioceramics are too rigid and sometimes too hard for tissue engineering. Reinforcing of biodegradable polymers can also be an approach to overcoming some limitations of single applications of these materials like low stiffness, brittleness, and low toughness [17 21]. Moreover, a few studies have evaluated the mechanical properties of biodegradable polymer blends [22 26]. Nowadays, biodegradable polyesters are extensively studied as matrix materials in biocomposites reinforced with various materials for improving their performance. Biocompatible polymers with hydrolyzable chemical bonds are being used to produce safe, nontoxic fluorescent microspheres for material penetration studies. Due to their controlled release, grand bioavailability, less toxic properties, and better encapsulation, biodegradable nanoparticles have been used frequently as drug delivery vehicles. Therefore in order to extend nanotechnology, various nanoparticulate systems, controlled release, and improvement of therapeutic values of nanoencapsulated drugs, as well as general synthesis and encapsulation processes should be also considered in this field. Nanotechnology highlighted the impact of nanoencapsulation of various disease-related drugs on biodegradable nanoparticles such as poly(D,L-lactide-co-glycolide) (PLGA), polylactic acid (PLA), chitosan, gelatin, polycaprolactone, and poly-alkyl-cyanoacrylates [27].

A variety of natural, synthetic, and biosynthetic polymers such as poly(L-lactide) (PLLA), polyhydroxyalkanoate, poly(ε-caprolactone), polyglycolic acid, polyethylene glycol (PEG), polyesteramide, aliphatic copolyesters, aromatic copolyesters, starch, cellulose, regenerated cellulosed (RC), oxidized regenerated cellulose (ORC) chitin, chitosan, lignin, and proteins such as collagen (Col) and albumin are bio- and environmentally degradable. Biodegradability can therefore be engineered into polymers by the judicious addition of chemical linkages such as anhydride, ester, or amide bonds, among others. Based on pioneering research, nanotechnology has also been successfully used to produce biodegradable polymer materials with high performance. There are four main systems that require effective reinforcement in each composite. These are a large aspect ratio of reinforcing fillers (1), good dispersion of reinforcement materials (2), good alignment of fibers (3), and interfacial stress transfer between matrix and reinforcing fillers (4). In more recent times nanofibers made from materials such as alumina, glass, boron, silicon carbide, and especially carbon have been used as nanofillers in polymers. Utilization of carbon nanotubes (CNTs) as composite reinforcements for tissue engineering scaffolds to date has primarily been focused on enhancing their mechanical properties [28 30].

27.3.1 Collagen Col is one of the tissue engineering scaffolds which is known as an essential structural and mechanical building block of various tissues. However, Col-based constructs reconstituted in vitro often lack robust mechanical stability, molecule binding capability, and fiber structure. For instance, Park et al. have coated Col multiwalled CNTs (MWCNTs) on Ti as a dental implant. They found that Col MWCNTs composite-coated Ti incorporated with MWCNTs compared to the Col-coated one showed relatively higher extent of cell proliferation observed after 5 days of cell culture due to the higher surface roughness. The MWCNTs incorporated in the composite could have also contributed to the cell viability and growth [31]. To enhance Col performances, Tan et al. developed 3D Col/MWCNTs composite constructs with two types of functionalized carboxylated nanotubes, covalently functionalized nanotubes and CNTs. These results showed that functionalized MWCNTs/Col composites, particularly MWCNT/Col composites could be promising materials, which provide structural support showing multifunctionality, mechanical stability, bundled fibril structure, and biocompatibility [32]. Hirata et al. showed that the MWCNT/Col surface shows strong cell adhesion. Therefore, the MWCNTcoated Col sponge is expected to be a useful 3D scaffold

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for cell cultivation. Also, their experimental results show that MWCNT coating appears to be effective for bone tissue engineering [33,34]. In another study, Mao et al. functionalized single-walled CNTs (SWCNTs) with Col (Col-SWCNTs) that retained the inherent properties of SWCNTs. Accordingly, the intracellular distribution, uptake, and cellular effects of the Col-SWCNTs were also investigated for culture of bovine articular chondrocytes. The Col-SWCNTs didn’t show obvious negative cellular effects and a high amount of SWCNTs were internalized by cells. They found that the internalized Col-SWCNTs were accumulated in the perinuclear region and remained in the cells for more than 1 week. It has observed that the adsorption of SWCNTs by extracellular matrix was considered to be an important step for cellular uptake of SWCNTs. Biomedical and biotechnological applications of SWCNTs will be facilitated by the high stability, easy cellular uptake, and long retention in cells of the ColSWCNTs [35]. Kikuchi et al. synthesized a hydroxyapatite (HAp) and Col composite by a simultaneous titration coprecipitation method using Ca(OH)2, H3PO4, and porcine atelocollagen as starting materials. The prepared composite showed a self-organized nanostructure similar to bone assembled by the chemical interaction between HAp and Col. The consolidated composite by a cold isostatic pressure of 200 MPa indicated a quarter of the mechanical strength of bone. It also indicated the same biological properties as grafted bone: The material was resorbed by phagocytosis of osteoclast-like cells and conducted osteoblasts to form new bone in the surrounding area. This HAp/Col composite having similar nanostructure and composition can replace autologous bone grafts [36].

27.3.2 Chitosan The chitosan was reinforced with nano-HAp (nHA) and considered for bone tissue engineering. Qualitative analysis via fluorescence microscopy showed cell proliferation in composite scaffolds was about 1.5 times greater than pure chitosan after 7 days of culture and beyond. The observations that are linked to the physicochemical properties, well-developed structure morphology, and superior cytocompatibility indicate that chitosan/nHA porous scaffolds are potential candidate materials for bone regeneration. Although it is necessary to further enhance the mechanical properties of the nanocomposite to be considered [37,38]. In order to increase the bioactivity, biodegradability, and biocompatibility of chitosan, Kong et al. combined HAp into chitosan scaffolds. The composite analysis results showed that after incubation in simulated body fluid on both of the scaffolds carbonate HAp was formed. With increasing the concentration of nHA in the

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composite, the quantity of apatite that formed on the scaffolds was increased. In comparison with neat chitosan, the composite with nHA could form apatite more readily than neat chitosan during the biomimetic process, which suggests that the composite possessed better mineralization activity. Furthermore, preosteoblast cells cultured on the apatite-coated scaffolds showed different behavior. On the apatite-coated composite scaffolds cells presented better proliferation than on apatite-coated chitosan scaffolds. In addition, alkaline phosphatase activities of cells cultured on the scaffolds in conditioned medium were assessed. The cells on composite scaffolds showed a higher alkaline phosphatase activity which suggested a higher differentiation level. On the other hand, that is to say composition of substrates could affect the apatite formation on them, and preloaded HAp can enhance the apatitecoating. It will also be significant in the preparation of apatite-coating polymer scaffolds for bone tissue engineering [39]. Saravanan et al. have developed a biocomposite scaffold containing chitosan/nHA/nanosilver particles (chitosan/nHA/nAg) by a freeze drying technique. In this study, it has found these composites have the potential in controlling implant-associated bacterial infection during reconstructive surgery of bone. Also, the nanocomposites have antibacterial activity and are nontoxic to rat osteoprogenitor cells and human osteosarcoma cell line [40]. In another research, Tripathi et al. showed that the prepared biocomposite scaffolds including Cu Zn alloy nanoparticles (nCu Zn) nHA and chitosan had no toxicity toward rat osteoprogenitor cells. Accordingly, the developed chitosan/nHA/nCu Zn scaffolds were seen as more useful and have potential applications over the chitosan/nHA scaffolds for bone tissue engineering. It is likely that the swelling, decreased degradation, and increased protein adsorption significantly increased the addition of nCu Zn in the chitosan/nHA scaffolds which led to increased antibacterial activity [41]. Pattnaik et al. combined nanoscaled silicon dioxide and zirconia (Zr) with chitosan under freeze drying conditions to fabricate another biocomposite scaffold. The newly developed scaffold had a porous nature with pore dimensions which were more suitable for colonization and cell infiltration. They found that the swelling and increased biodegradation, protein adsorption, as well as biomineralization properties of the chitosan/silicon dioxide/Zr decreased due to the presence of zirconia in this scaffold. The chitosan/silicon dioxide/Zr scaffold was also found to be nontoxic to rat osteoprogenitor cells. Thus, they suggest that chitosan/silicon dioxide/Zr biocomposite scaffold is a potential candidate to be used for bone tissue engineering [42]. Chitin, like chitosan, is the most widely accepted and applicable biodegradable and biocompatible

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macromolecule after cellulose. The incorporation of nanosized ZrO2 onto the chitin and chitosan scaffolds is predicted to enhance the osteogenesis of chitin and chitosan. A nanocomposite scaffold was fabricated by lyophilization technique using chitin chitosan with nano-ZrO2 by Kumar et al. Cell viability studies of prepared nanocomposite proved the nontoxic nature, also, cells were found to be attached to the pore walls and spread uniformly throughout the scaffolds [43]. Alginate was considered for improvement of chitosan for bone tissue engineering. In order to fabricate this kind of composite scaffolds, chitosan solution was mixed with nanosized HAp powders suspended in an alginate solution with an adjusted pH (usually .10) and then freeze-dried. In that case, higher content of the HAp can help the development of more differentiation and mineralization of the MC3T3-E1 cells on the composite scaffolds. The excellent mechanical characteristics and the monotonous pore structure of the Hap/chitosan composite scaffolds likely resulted from the use of the alginate solution at pH 10 as a dispersant for the nHA powders [44]. A novel nHA reinforced polymer composite scaffold with high amounts of porosity and well-controlled pore size and pore architectures was prepared using thermally induced phase separation techniques by Wei et al. They found that the introduction of HAp greatly increased the mechanical properties and improved the protein adsorption capacity. In a mixture of dioxane and water solving system, nHA-incorporated poly(L-lactic acid) (PLLA) scaffolds developed a fibrous morphology which in turn increased the protein adsorption threefold over nonfibrous scaffolds [45]. Due to their outstanding merits, natural polysaccharides have received more and more attention in the field of drug delivery systems. Polysaccharides especially seem to be the most promising materials in the preparation of nanometeric carriers. To date, four mechanisms have been carried out in order to prepare polysaccharides-based nanoparticles. They are categorized as ionic cross-linking, covalent cross-linking, polyelectrolyte complex, and the self-assembly of hydrophobically modified polysaccharides [46]. To assess the potential application of chitosan nanoparticles for ocular drug delivery by investigating their interaction with the ocular mucosa in vivo and also the toxicity of nanochitosan in conjunctival cell cultures, fluorescent chitosan nanoparticles were prepared by ionotropic gelation. The treated fluorescent chitosan nanoparticles were stable upon incubation with lysozyme and did not affect the viscosity of a mucin dispersion. In vivo studies showed that the amounts of fluorescent chitosan in cornea and conjunctiva were significantly higher for fluorescent chitosan nanoparticles than for a control fluorescent chitosan solution, these amounts being fairly

constant for up to 24 hours. Confocal studies suggest that nanoparticles penetrate into the corneal and conjunctival epithelia. Cell survival at 24 hours after incubation with chitosan nanoparticles was high and the viability of the recovered cells was up to 95% [47].

27.3.3 Silica The preformation of silica nanoparticles as fillers in preparation of nanocomposite of polymers has much attention consideration, due to the increased in demand for new materials with adequate improved in thermal, mechanical, physical, and chemical properties of polymers. Recent developments in the synthesis of monodispersed, narrowsize distribution of nanoparticles by sol gel method provide a significant boost to the development of silica polymer nanocomposites [48]. Advanced bioanalysis, has driven the need to understand the biological effect and the medical effect of materials at the molecular scale. Bioconjugated silica nanoparticles have the potential to address this emerging challenge. Particularly, the intriguing diagnostic and therapeutic applications of silica nanoparticles in cancer and infectious disease, as well as uses in gene and drug delivery, have been found [49]. Mesoporous silica nanoparticles used as “nanocarriers,” have found many applications for delivery of drugs and other cargos to cells due to their ability to make porous, uniformly sized, and dispersible silica nanoparticles using colloidal chemistry and evaporation-induced self-assembly. They have an exceptionally high surface area which often exceed 1000 m2/g. Mesoporous silica nanoparticles have also this ability to independently modify pore size and surface chemistry. These characteristic features enable them to be loaded by diverse cargos and cargo combinations at levels exceeding those of other common drug delivery carriers such as polymer conjugates or liposomes. It is found that three interactions including hydrogen bonding, noncovalent electrostatic, and van der Waals forces are responsible for the main interactions between the cargo and the mesoporous silica nanoparticle internal surface. These features altogether provide a suitable substrate for preferential adsorption of the cargo to the mesoporous silica nanoparticle, allowing loading capacities to surpass the solubility limit of a solution or that achievable by osmotic gradient loading. Consequently, engineered biocompatibility and biofunctionality could be achieved by the fact that the mesoporous silica nanoparticles are able to modify their surface and interior independently. For instance, Tarn et al. have made an effort to develop mesoporous silica nanoparticles as biocompatible nanocarriers [50]. Their ultimate goal was to reach a kind of nanocarrier which could simultaneously display

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multiple functions including dispersibility, high binding affinity to a particular target tissue or cell type, high visibility/contrast in multiple imaging modalities, triggered or controlled release of cargo, and having the ability to load and deliver large concentrations of diverse cargos. They chemically conjugated fluorescent dyes or incorporated MNPs to mesoporous silica nanoparticles in order to provide high visibility/contrast for in vivo optical or magnetic resonance imaging (MRI). They have also made mesoporous silica nanoparticles with charged groups, polymer coatings, or supported lipid bilayers toward obtaining acceptable dispersibility which improves stability in saline solutions and decrease aggregation. High binding affinity to the target tissues or cells as well as loading and delivering the large concentrations of diverse cargos could be gained by enhancing passive bioaccumulation. In that case, mesoporous silica nanoparticle surfaces were modified with positively charged polymers via the enhanced permeability and retention effect. They have also chemically functionalized the mesoporous silica nanoparticles with specific ligands so that the final compound selectively binds to the receptors overexpressed in cancer cells. In order to develop new classes of responsive nanocarriers that actively interact with the target cell, encapsulation of mesoporous silica nanoparticles within reconfigurable supported lipid bilayers have been also studied. The hydrophobic drugs could be also retained via exploiting the tailorable surface chemistry and the high surface area of mesoporous silica nanoparticles. Finally, for achieving a triggered or controlled release of cargo, they have engineered dynamic behaviors by incorporating molecular machines within or at the entrances of mesoporous silica nanoparticle pores and by using lipid bilayers, ligands, or polymers. These modifications on mesoporous silica nanoparticles can provide a means to seal-in and retain cargo and to direct mesoporous silica nanoparticle interactions with and internalization by target cells. Moreover, application of mesoporous silica nanoparticles as nanocarriers in human requires low toxicity and biocompatibility. Hence, the innate porosity of the mesoporous silica nanoparticle surface reduces the gamut of electrostatic interactions or hydrogen bonding with cell membranes as those surfaces are coated with lipid bilayers or polymers. Furthermore, high rate of dissolution into soluble silicic acid species, which are found to be nontoxic, could be on hand by promoting low extent of condensation and the high surface area of the mesoporous silica nanoparticle siloxane framework. Potential toxicity is further mitigated by the high drug capacity of mesoporous silica nanoparticles, which greatly reduces needed dosages compared with other nanocarriers [50]. For biotechnological and biomedical applications of the surface-functionalized mesoporous silica nanoparticle

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materials, it is essential to control their structural properties and chemical functionalization. During the last decade, mesoporous silica nanoparticles have attracted great attention as efficient drug delivery carriers for biomedical applications. Therefore, they have shown a great potential for a variety of drug delivery applications, such as intracellular controlled release of genes, drugs, and other therapeutic agents, as well as the site-specific delivery [51,52]. It was found that the mesoporous silica nanoparticles are facilely tunable for multifuctionalization, controlled drug release and delivery, as well as for the purposes of drug loading. Meanwhile, the biosafety and in vivo drug efficiency of mesoporous silica nanoparticle-based nanodrug delivery systems, involving biocompatibility (including cytotoxicity, blood, and tissue compatibility) and pharmacokinetics (including biodistribution, biodegradation, retention, excretion, blood circulation) are also drawing increasing attention because of their clinical application prospects [53]. Lee et al. have synthesized highly versatile nanocomposite nanoparticles by decorating the surface of mesoporous dye-doped silica nanoparticles with multiple magnetite nanocrystals [54]. In this strategy, nanoparticles can benefit from the superparamagnetic property of the magnetite nanocrystals and can be used as a contrast agent in MRI. In the other words, optical imaging modality is achievable by using the dye molecule in the silica framework. Thus, a remarkable enhancement of magnetic resonance signal is possible by integrating a multitude of magnetite nanocrystals on the silica surface due to the synergistic magnetism. Moreover, it is easy to load an anticancer drug like doxorubicin in the pores and induce efficient cell death. There are a few reports which in T2 magnetic resonance and fluorescence imaging data showed that in vivo passive targeting and accumulation of the nanoparticles at the tumor sites was confirmed. Furthermore, when they treated tumor-bearing mice with doxorubicin-loaded nanocomposite nanoparticles, apoptotic morphology was clearly detected in tumor tissues. That means doxorubicin was successfully delivered to the tumor sites and its anticancer activity was retained well [54]. In order to develop an effective drug delivery system for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP), mesoporous silica nanoparticles have functionalized with boronic acid. In this case, boronic acid-functionalized mesoporous silica nanoparticle had the immobilized fluorescein isothiocyanate-labeled gluconic acid-modified insulin (FITC-G-Ins) proteins on their exterior surface. It lets them serve as caps to encapsulate cAMP molecules inside the mesopores of boronic acid-functionalized mesoporous silica nanoparticle. By the introduction of saccharides,

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release of both G-Ins and cAMP was then triggered. The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose . glucose . other saccharides. In fact, it seems to be a doublerelease system with unique features. That means actually the release of cAMP from mesopores of mesoporous silica nanoparticle can balance the decrease of FITC-G-Ins release in cycles, which are regulated by the gatekeeper effect of FITC-G-Ins. Furthermore, the cytotoxicity of cAMP-loaded G-Ins-mesoporous silica nanoparticle with four different cell lines was investigated by cell viability and proliferation studies. In addition, the cAMP-loaded FITC-boronic acidfunctionalized mesoporous silica nanoparticle with and without G-Ins capping were investigated by flow cytometry and fluorescence confocal microscopy to assess their cellular uptake properties. This glucose-responsive mesoporous silica nanoparticle-based double-release system shows promise in providing a new generation of self-regulated insulin-releasing devices [55].

27.3.4 Poly(L-Lactide) PLLA is an high-performance biodegradable and biocompatible homopolymer, as the model polymer for the present reasons: (1) the PLLA crystallizes quite slowly, even if CNTs are incorporated and there is a relatively long time to nucleate, which provides the possibility of online determination of its structure; (2) the neat PLLA crystallization has been extensively investigated and some of the mechanisms underlying this phenomena are widely accepted. Preexisting research has established a valuable foundation for investigation of the PLLA nanocomposite conformation [22,24,25]. The thermomechanical properties of PLLA biodegradable polymer reinforced with PLLA grafted from MWCNTs (MWCNT-g-PLLA)s is characterized. For this purpose, MWCNTs have been covalently grafted by the PLLA chains from their sidewall of aminated. Then, the MWCNT-g-PLLAs/PLLA composite films are prepared by solution casting using chloroform as solvent. The formed films show that the MWCNT-g-PLLAs are well dispersed in PLLA matrix. Increasing the concentrations of MWCNT-g-PLLAs up to 2 wt% led to gradually enhancement of the mechanical properties of PLLA. Differential scanning calorimetry analysis also revealed the MWCNT-g-PLLAs increase the melting point and the glass transition temperature of PLLA. In addition, the dynamic mechanical analysis results show that incrementing the concentrations of MWCNT-g-PLLAs is also accompanied by increasing Young modulus and the transition temperature of PLLA. The chain stiffness in the amorphous phase of PLLA can also increase due to the van der Walls force and the homogenous dispersion of MWCNT-g-PLLAs between the PLLA matrix chains and

the grafted PLLA chains on the sidewall of MWCNTs. In addition, the crystallinity of PLLA could be increased because of the MWCNT-g-PLLAs being heterogeneous nucleation agents. Application of radiation sterilization process by high-energy radiation such as gamma, X-ray, and electrons has been successfully utilized for modification and sterilization of sensitive biodegradable and biocompatible polymer composites. The effect of gamma irradiation on mechanical and thermal properties of PLLA reinforced with MWCNT-g-PLLAs was characterized by Nabipour Chakoli et al. It is found that the gamma irradiation increases the tensile modulus and tensile strength, while decreasing the elongation at the break of PLLA. The melting point of PLLA composites decreases by increasing the irradiation dose, while the melting enthalpy increases. Additionally, it is found that if the γ irradiation of composites increases to higher than 50 kGy, the rigidity and brittleness of composites that have higher concentrations of functionalized MWCNTs increase gradually [18,56].

27.3.5 Poly(D,L-Lactide-co-Glycolide) Another nanocarrier which has been extensively investigated for sustained and targeted/localized delivery of different agents including peptides and proteins, plasmid DNA, and low-molecular-weight compounds, is poly[D,L-lactide-co-glycolide] (PLGA)-based nanoparticles. Although PLGA was introduced many years ago, the role of nanoparticles in the mechanism of intracellular uptake, their trafficking and sorting into different intracellular compartments, as well as their mechanism of action for enhanced therapeutic efficacy of nanoparticleencapsulated agent at cellular level has been more recently considered [10]. Moreover, it was well characterized that PLGA nanoparticles showed a more effective function in in vitro and in vivo assays compared to industrial nanoparticles of a similar size range such as ferrous oxide, fumed silica, and zinc oxide. The cell viability after exposure to PLGA nanoparticles was also conducted by an in vitro cytotoxicity study via a WST assay. Both PLGA and amorphous fumed silica particles and ferrous oxide showed a cell viability of greater than 75%, but it was significantly reduced for zinc oxide particles. There were no specific anatomical pathological changes or tissue damage in the tissues of Balb/C mice obtained by histopathological evaluation during the in vivo toxicity assays. The continued tissue distribution and retention of oral administrated PLGA particles were also analyzed for 7 days. The brain, heart, kidney, liver, lungs, and spleen were those organs with high accumulation of the particles even after 7 days. A mean percentage of the particles in the liver (40.04%), 25.97% in the kidney, and 12.86% in the brain were localized.

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The lowest percentage was observed in the spleen. Thus, based on these assays, it can be concluded that the toxic effects observed with various industrial nanoparticles will not be observed with particles made of synthetic polymers such as PLGA when applied in the field of nanomedicine. Furthermore in order to avoid higher particle localization in the liver, surface modification of the particles should be considered [57]. The carboxy-terminated poly(D,L-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG COOH) polymer nanoparticles were developed by Cheng et al. and the effects of altering the present parameters on the size of nanoparticles (NPs): (1) polymer concentration; (2) drug loading; (3) water miscibility of solvent; and (4) the ratio of water to solvent was studied. They found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient 5 0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the prostate-specific membrane antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in aLNCaP (PSMA 1 ) xenograft mouse model of prostate cancer. The surface functionalization of NPs with the A10 PSMA Apt significantly enhanced delivery of NPs to tumors vs equivalent NPs lacking the A10 PSMA Apt (a 3.77-fold increase at 24 hours; NP-Apt 0.83% 6 0.21% vs NP 0.22% 6 0.07% of injected dose per gram of tissue; mean 6 SD, n 5 4, P 5 0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies [58].

in pristine MWCNTs by introducing the aromatic amine groups on the side wall of MWCNTs. The MWCNTNH2s was reacted with neat ORC in order to modify the neat ORC. The hydrophilicity test results revealed increasing the concentration of MWCNT-NH2s in composites could result in significant increment in water uptake of MWCNT-NH2s/ORC composites. The hemostatic evaluation of MWCNT-NH2s/ORC nanocomposites on the liver of rabbits shows that the aminated MWCNTs increases the rate of blood stopping and hence decreases the blood loss from injured sites on the rabbits liver [21].

27.3.6 Cellulose

27.4 NANOPHARMACUTICALS

In order to prepare a kind of RC film coated with copper (Cu) nanoparticles, cellulose-cuprammonium solution was coagulated in aqueous NaOH and followed by a reduction reaction in aqueous NaBH4. In that case, during the coagulation of cellulose-cuprammonium solution the Cu21 ions can migrate from the inner to the surface of the RC films and then convert to Cu0 through the reduction reaction. So, Cu nanoparticles were found to be firmly embedded on the surface of the RC films. It has been found that the RC films coated with Cu nanoparticles have potential antibacterial activity against Escherichia coli and Staphylococcus aureus. The efficacy of this nanoparticle is remarkable—a dramatic reduction of viable bacteria could be observed within 0.5 hours of exposure, and all of the bacteria were killed within 1 hours [59]. In a research study, Nabipour Chakoli et al. found that incorporating aminated MWCNTs (MWCNT-NH2)s with ORC can lead to the enhancement of the hemostatic properties. They tried to construct an amino functional group

Nanobiotechnology involves the biological systems that are manufactured at the molecular level. Nanobiotechnology is a multidisciplinary research field that has fostered the development of nanoscaled pharmaceutical delivery devices. Also, nanotechnology-based pharmaceuticals offer applicable and adequate solutions to fundamental problems in the drug technology ranging from poor water solubility and poor water dispersibility of drug compounds to a lack of target specificity. Additionally, nanotechnology should reduce the cost of drug extraction, design, manufacturing, and development. Many kinds of nanoparticles have been used as strategies to deliver conventional pharmaceuticals or substances such as peptides, recombinant proteins, vaccines, and nucleotides. Nanoparticles and other colloidal pharmaceutical delivery systems modify many physiochemical properties, thus resulting in changes in drug distribution in the human body and other pharmacological processes. These changes can lead to nanopharmaceutical delivery at

27.3.7 Bioceramics Calcium phosphate ceramics, cements, and silica-based glasses which are known as bioceramics are widely used as components of implants for teeth and bone restoration. Nowadays, incorporation of drugs within them or on their functionalized surfaces is provided by the new chemical strategies and the other advanced processing methods. In this regard, bioceramics act as local drug delivery systems to cure osteoporotic fractures, large bone defects, bone tumors, and also bone infections. However, developing the new mesoporous nanoceramics as suitable carriers for drug delivery has also paved the way for cancer therapeutic purposes. Mesoporous silica nanoparticles might be used as specific vehicles that are able to release the drug selectively within specific cancerous cells. Stimuliresponsive systems can be obtained when the pores are closed with molecular nanogates. Thus it leads to drug being released at will by supplying external stimuli such as magnetic fields, ultrasound, or light [60].

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specific sites and reduce the side effects in the body. Therefore, nanoparticles can improve the therapeutic efficiency since they are excellent carriers for biological molecules, including enzymes, recombinant proteins, and nucleic acid [61]. Novel horizons in the pharmaceutical nanotechnology can be achievable for diagnosis, imaging, and therapy by the development of inorganic systems. In fact, their high surface area to volume ratios and their nanometer-size mainly allow for specific functions that are not possible in the micrometer-size particles [62]. For example, the CRLX101 is a nanopharmaceutical which was developed by covalently conjugating camptothecin to a linear, cyclodextrin-PEG copolymer that self-assembles into nanoparticles. As a nanosize drug carrier system, the cyclodextrinpolymeric nanoparticle technology has unique design features and capabilities. Specifically, CRLX101 preclinical and clinical data confirm that cyclodextrin-PEG can introduce not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of conjugating camptothecin, but also, can present unique biological properties that enhance conjugating camptothecin pharmacodynamics and efficacy [63]. The CRLX101 (Cerulean Pharma, Inc., Cambridge, MA, USA), a novel tumor-targeted nanopharmaceutical platform containing camptothecin as its payload, has been shown in preclinical models to target HIF and is synergistic with bevacizumab. They combined CRLX101 with bevacizumab in order to determine the safety and the recommended phase 2 dose of the combination, and to determine its preliminary therapeutic activity in this setting [64]. Compared with traditional small molecule drugs, small interfering RNA therapeutics have potential advantages including high specificity and the ability to inhibit otherwise “undruggable” targets. For example, bevacizumabs, which showed short plasma half-lives in vivo, can induce a cytokine response, leading to poor cellular uptake. While, the stability of bevacizumab against nuclease degradation and its permeability and retention (electron paramagnetic resonance) effect, which improve site-specific delivery, can be enhanced by formulating bevacizumab into nanoparticles. Existing delivery systems generally suffer from poor delivery to tumors. Sevenson et al. described the formation and biological activity of polymeric nanopharmaceuticals based on biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) conjugated to bevacizumab via an intracellular cleavable disulfide linker (PLGA bevacizumab). Additionally, these PNPs contain (1) PLGA conjugated to PEG for enhanced pharmacokinetics of the nanocarrier; (2) a cation for complexation of bevacizumab and charge compensation to avoid high negative zeta potential; and (3) neutral PVA to stabilize the PNPs and support the PEG

shell to prevent particle aggregation and protein adsorption [65]. Alloxan is an environmental food contaminant that causes DNA damage in living cells and induces hyperglycemia. Pelargonidin, an active ingredient found in extracts of various fruits and vegetables, has been nanoencapsulated with PLGA and tested for efficacy in the prevention of alloxan-induced DNA damage in L6 cells in vitro. Glucose uptake, reactive oxygen species generation, glucose transporter 4, glucokinase levels, and mechanism of activation of DNA repair proteins, such as PARP and p53, have been studied in alloxan-induced L6 cells. The interaction between drug and DNA has been analyzed using calf thymus DNA as a target through circular dichroism and melting temperature profile. Pretreatment with both Pelargonidin and/or nanoencapsulated Pelargonidin was effective in reducing alloxan-induced oxidative stress and showed favorable effects for protection against DNA damage by activating DNA repair cascades. Results suggested a B10-fold increase in efficacy of nanoencapsulated Pelargonidin than Pelargonidin in the prevention of alloxan-induced oxidative stress and DNA damage [66]. Conjugation of nanomedicine and radiopharmacy creates a new research and technology area that is named nanoradiopharmacy. The nanoradiopharmacy has great advantages in disease diagnosis and control and subsequent therapy, due to the ability to develop molecular diagnostics for the early detection of disease as well as the ability to develop increasingly personalized and individualized treatments. Nanostructured materials have attracted considerable attention because of their high surface area to volume ratio resulting from their nanoscale dimensions. This class of sorbents is expected to have a potential impact on enhancement of the efficacy of radioisotope generators for diagnostic and therapeutic applications in nuclear medicine [67]. Radiolabeled nanoparticles represent a novel class of radiopharmaceutical agents with great potential in cancer research. The radiolabeled nanoparticles can be used for specific tumor imaging or for effective tumor treatment by specific radiation. Technetium-99m-rhenium-sulphide colloids with the particle size of 10 80 nm can be used for bone marrow scintigraphy, lymphoscintigraphy, and detection of inflammation. A technetium pyrophosphate complex is prepared, followed by reaction with freeze-dried rhenium sulphide at 100 C for 15 30 minutes. A technetium-99m nanocolloid of similar particle size can prepared from human serum albumin as well [68 71]. The biodistribution of colloidal albumin depends on particle size. More than 95% of the particles of nanocolloidal albumin are smaller than 80 nm and less than 4% of the particles are 80 100 nm. Only 1% is larger than 100 nm [72].

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Nanocolloidal albumin is licensed in European countries for lymphoscintigraphy and bone marrow scintigraphy. On the other hand, microcolloidal albumin is licensed for scintigraphy of liver and spleen of human body. With regard to 68Ge/68Ga generators, it is necessary to consider that most of the commercially available 68 Ge/68Ga generator systems are not optimally designed for direct applications in a clinical context. Rubel Chakravarty et al. have developed a nanozirconia-based 68 Ge/68Ga generator system for accessing 68Ga amenable for the preparation of radiopharmaceuticals. The compatibility of the product for preparation of 68Ga-labeled DOTA-TATE under the optimized reaction conditions was found to be satisfactory in terms of high labeling yields (.99%). The generator gave a consistent performance with respect to the elution yield and purity of 68Ga over a period of 1 year [73]. In another research, the 188 W/188Re generator for chromatographic separation of 188 Re using an acidic alumina column was optimized using nanoalumina [74].

27.4.1 Cancer Conventional drug delivery systems included several limitations such as poor oral bioavailability, nonspecific targeting and biodistribution, low therapeutic indices, and lack of water solubility. As nanotechnology is developing, cancer nanotherapeutics is also rapidly progressing and is being implemented as intelligent drug delivery systems to solve the limitations of conventional drug delivery systems. During the last decade, nanoparticles have been designed for surface characteristics and optimal size. In that case, their circulation time in the bloodstream has increased and led to improvements in the biodistribution of cancer drugs. The unique pathophysiology of tumors, such as the tumor microenvironment, retention effect, and their enhanced permeability, allow the nanoparticles to carry their loaded active drugs and selectively release them to cancer cells. Other active targeting strategies using selective antibodies or ligands against tumor targets can also amplify the specificity of these therapeutic nanoparticles beside this passive targeting mechanism. Moreover, nanoparticles have been found to be more effective against overcoming or at least reducing drug resistance, which is known as another obstacle that prevents the efficacy of both conventional chemotherapeutic agents and molecularly targeted agents. High accumulation of nanoparticles in cells without being recognized by P-glycoprotein should be considered as a main reason for this feature. In fact, this is one of the main mediators of multidrug resistance, resulting in the increased intracellular concentration of drugs can remove or reduce. Thus, the next generation of nanoparticles, included multiplex and multifunctional ones facilitating tailored and

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personalized cancer treatment, are on the horizon and are now being actively investigated [75]. In this regard, nanoparticles and liposomes are emerging technologies for the rational delivery of chemotherapeutic drugs in the treatment of cancer. The use of these newly developed nanoliposomes offers more importantly lower systemic toxicity, controlled and sustained release of drugs, and improved pharmacokinetic properties. Recently, bothliposomal Doxil and albumin-nanoparticlebased Abraxane, which are commercial available, have attracted much attention in this exciting and innovative field. In addition, better treatment of multidrug-resistant cancers and lower cardiotoxicity could be achieved by the recent advancement in liposome technology. However, nanoparticles also offer new avenues for curing the breast cancer as well as increased precision in chemotherapeutic targeting of prostate cancer [76]. Albumin has been known as a versatile protein carrier for drug delivery because of its nontoxicity, nonimmunogenicity, biocompatibility, and biodegradability features. Thus, it is an ideal material for the fabrication of nanoparticles for drug delivery. Many reports have shown that albumin nanoparticles have high binding capacity of various drugs and are also being well tolerated without any serious side-effects. Accordingly, specialized nanotechnological techniques including desolvation, emulsification, thermal gelation, and recently nanospray drying, nabtechnology, and self-assembly have been investigated to fabricate albumin nanoparticles [77,78].

27.5 NANOBIOSENSORS Nanotechnology and nanobioscience are taking increasingly important roles in the development of biosensors. The high quality of sensitivity and performance for biosensors is being achieved by the application of nanomaterials for their construction. The use of nanomaterials has allowed the introduction of many new signal transduction technologies in biosensors. Because of their submicron dimensions, the nanosensors, nanoprobes, and other nanosystems have allowed simple and rapid analyses in the human body. Portable instruments that are applicable for analyzing multiple components are becoming available [79]. Recent progress in nanooptics has paved the route toward the development of highly sensitive and label-free optical transducers using the localized surface plasmon resonance of metal nanostructures. Direct colorimetric assays reaching sensitivities in the zeptomolar range, or miniaturized multiplexed sensors constitute cutting-edge research in the localized surface plasmon resonance biosensing field. The unique physical, chemical, and physiological properties of nanoparticles make them extremely

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suitable for designing new and improved sensing devices, especially electrochemical sensors and biosensors. Many kinds of nanoparticles, such as metal, metal oxide, and semiconductor nanoparticles have been used for constructing electrochemical sensors and biosensors, and these nanoparticles play different roles in different sensing systems. The important functions provided by nanoparticles include the immobilization of biomolecules, the catalysis of electrochemical reactions, the enhancement of electron transfer between electrode surfaces and proteins, labeling of biomolecules, and even acting as reactant [80,81]. There are different types and properties of underresearched nanobiosensors and nanomaterials. The nanomaterials can be integrated in diagnostic paper-based biosensors for the detection of proteins, nucleic acids, and cells [82]. For biochemical sensing, there are nanotube and nanoparticle-based electrodes relying on aligned nanotube arrays, direct electron transfer between biomolecule and electrode, novel binding materials and mass production technology; and nanoscale materials as biomolecule tracers, including gold nanoparticles (AuNPs), quantum dots for DNA and protein multiplexing, novel nanobiolabels such as apoferritin, liposomes and enzyme tags loaded CNTs [83]. CNTs have a valuable optical transitions in the nearinfrared region. Hence, this effect makes CNTs as poetical imaging agents with higher resolution and greater tissue depth for near-infrared fluorescence microscopy and optical coherence tomography [20,84 86]. In a study by Cherukuri et al., CNTs were successfully monitored in phagocytic cells and intravenously administered into mice using near-infrared fluorescence [87]. Given that CNTs are highly sensitive to Raman scattering, there has been extensive use of Raman spectroscopy to characterize the structural features. The characteristic Raman signatures of CNTs have also been utilized as cellular probes. For example, Liu et al. detected CNTs in various tissues after intravenous delivery into mice using Raman spectroscopy [88]. Another class of nanobiosensors are highly emissive inorganic organic nanoparticles with core shell structures fabricated by a one-pot, surfactant-free hybridization process [89]. In this study, tetraphenylethene was treated by silole-functionalized siloxanes under a surfactant-free sol gel reaction followed by reactions with tetraethoxysilane to afford fluorescent silica nanoparticles FSNP-1 and FSNP-2, respectively. Finally, the produced fluorescent silica nanoparticles are surface-charged, uniformly sized, and colloidally stable. It is also possible to gain tunable diameters in the range of 45 295 nm for the fluorescent silica nanoparticles by changing the reaction conditions. The nanoparticles strongly emit in the visible vision whereas their TPE and silole precursors are nonemissive.

It could result in the novel aggregation-induced emission characteristics of the silole aggregates and tetraphenylethene in the hybrid nanoparticles. The fluorescent silica nanoparticles pose no toxicity to living cells and can be utilized to selectively image cytoplasm of HeLa cells [89].

27.6 METALLIC NANOPARTICLES Up to now, the most widely used metallic nanoparticles in biological and biomedical applications have been gold (Au), silver (Ag), copper (Cu), platinum (Pt), selenium (Se), gadolinium (Gd), palladium (Pd), iron oxide (Fe2O3), zinc oxide (ZnO), and titanium oxide (TiO2). Nanomaterials can be synthesized and modified with appropriate functional groups that would allow them to bind with drugs, antibodies, and ligands which are the substances of high interest in the biomedical field.

27.6.1 Gold Nanoparticles (AuNPs)-Based Nanomaterials AuNPs are known to contain many attractive features, such as excellent biocompatibility, catalytic and optical properties, and unique electrical behavior. Recently, AuNPs have been highlighted in biological imaging as a contrast agent due to their unique optical property. The stability and dispersion of AuNPs in solution play a key role for biosystems. The AuNPs have been broadly applied into lateral flow immune chromatographical assay and enzyme-linked immunosorbent assay, which is a well-established technology for analysis of the target analytes in food safety, clinical diagnosis, environmental monitoring, medical science, and so on. The AuNPs showed an important role in improving sensitivity of the electrochemical sensors for the sensitive detection of small organic molecules. Especially, when AuNPs make new composited conducting polymers or carbon nanomaterials, they can be used to increase electrochemical efficiency. Moreover, it deserves noting that the carbon nanomaterials can be decorated with metal NPs due to the integrated property of two components with enhanced electrical conductivity and better catalytic activity [90,91]. One of the most significant features of AuNPs is the localized surface plasmon resonance. The AuNPs and graphene-based materials are the frequently used nanomaterials in the field of electrochemical biosensors for detection of biomolecules because they have excellent electrical signal amplification and also show the versatile functionalization chemistry. Recently, hybrid nanomaterial sensors based on AuNPs distributing on reduced graphene oxide (GO) or the surface of GO have also

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attracted the attention of many scientists who work in this area [92,93]. Biological imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate targeted therapy [94]. AuNs have been considered as one of the best contrast agents for disease diagnosis, and functionalization of AuNs becomes essential for application of AuNPs in computed tomography (CT), X-ray, and surface enhanced Raman scattering (SERS) imaging. The results indicated that AuNPs had great size-dependent enhancement on CT imaging and radiotherapy (RT) in the size range of 3 50 nm. Interestingly, AuNPs with a size of B13 nm could simultaneously possess superior CT contrastability and significant radioactive disruption. AuNPs have been studied as potential contrast agents for X-ray imaging, because they are nontoxic and have a higher atomic number and X-ray absorption coefficient compared with typical iodine-based contrast agents [95]. AuNPs have been widely used in SERS-based immunoassays of biomolecules like cells, protein, and DNA. However, challenges still remain with amplification of SERS signals due to the extremely small cross-section of Raman scattering. Indeed, a big disadvantage of using AuNPs as the optical contrast agents is their high photothermal conversion efficiency under resonance excitation, which may perturb or even damage the biological species being imaged [96]. Thus, to minimize unwanted heating in bioimaging applications, laser irradiation time is typically set to be in the range of 0.1 10 seconds, which either lowers the SERS signal contrast or is simply not suited for image-guided tumor resection in intraoperative settings, considering the longer timescales (1 2 hours) associated with such procedures [97,98]. The gold nanoshell-antibody complex can be used to ablate breast cancer cells [99]. Nanoshells have a core of silica and a metal outer layer. They can preferentially concentrate in cancer lesion sites through enhanced permeation retention. A near-infrared laser illuminates the tissue, and the light will be absorbed by the nanoshells to generate an intense heat that destroys only the cancer cells without damaging the surrounding healthy cells [100]. Nanoparticles have already been used for targeted drug delivery, which enables much earlier detection [101] and immediate treatment of cancer. The AuNPs have also been explored as radiosensitizers for cancer treatment. While major research in this area focuses on particles in micrometers or AuNPs with a diameter of less than 2 nm, recent results suggest the highest cellular uptake has been seen for nanoparticles with a diameter of 50 nm. Most of the in vitro studies have focused on the radiosensitization properties of nanoparticles in the 14 74 nm size range. In fact, there is a direct connection between the radiosensitization and the number of AuNPs internalized within the cells. Compared

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to AuNPs with size ranges 14 and 74 nm (1.20 and 1.26, respectively), AuNPs with 50 nm in diameter showed the highest radio sensitization enhancement factor (REF) (143 at 220 kVp). However, the REF for lower (105 kVp) and higher energy photons (6 MVp) obtained 1.66 and 1.17, respectively, using 50 nm AuNPs. Quantification of DNA double-strand breaks has been done using radiationinduced foci of γ-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized AuNPs [102].

27.6.2 Silver Nanoparticles (AgNPs)-Based Nanomaterials Silver nanoparticles (AgNPs) have antimicrobial activity. They are used as antimicrobial agents. Colloidal silver is a proven killer of bacteria [103]. It is a far more efficient antibiotic than any allopathic pharmaceutical. Colloidal silver is effective in killing 650 bacteria in less than five minutes, at most in concentrations of five to six parts per million (ppm). AgNPs also find application in topical ointments and creams used to prevent infection in burns and open wounds. AgNPs were found to be nontoxic on live cells, and induced apoptosis on cancerous HT [104 106]. Apt-based AgNPs are used in intracellular protein imaging and single nanoparticle spectral analysis, Here, AgNPs acts as an luminophore and the Apt as a biomolecule-specific recognition unit [107 109]. Among the noble metal nanoparticles, AgNPs show a series of features such as high surface-to-volume ratio, adequate and tunable morphology, simple synthesis routes, and intracellular delivery system [110 113]. The prominent biomedical applications of AgNps are found to be anticancer therapy [105,106], catalysis [108], antimicrobial activities [109,114], antibacterial activities [115 119], antifungal treatments [120], antiviral activities [121 123], wound healing [124], wound dressing [125], implanted material [126], tissue engineering, and medical devices (catheters, prostheses, vascular grafts). There are also diagnostic applications in biosensing [127], antipermeability agent (in management of diabetic retinopathy), and dental preparations [128 130]. A rapid development of gadolinium-based nanoparticles has been observed due to their attractive properties as MRI-positive contrast agents. In addition to these imaging properties, it has been recently shown that they can act as effective radio sensitizers under different types of irradiation (RT, neutron therapy, etc.). Liposomal-based gadolinium (Gd) nanoparticles have elicited significant interest for use as blood pool and molecular MRI contrast agents. GdNPs are used in neutron capture therapy to treat

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tumors. Theranostic MRI is now receiving a growing interest in imaging-guided drug delivery, monitoring treatment and personalized administration [131], and anticancer treatments [132]. Recently, Emam et al. have developed a totally green, one-pot, and quite simple methodology for the synthesis of AgNPs as a colloidal solution without containing stabilizing and reducing agents [133]. The use of a removable reducing agent to produce merely AgNPs can be considered as the unique advantage of this method. Existence of cellulose fibers with reducing features and insolubility property make them the preferred potential removable reducing agents. In this study, they used three different cellulosic fibers with different degrees of polymerization, named lyocell, viscose, and cotton fibers. The order for obtaining the best results for this strategy to prepare AgNPs was viscose fiber . cotton fiber . lyocell fiber. The small particle size (mean 5 9.5 nm) and the highest surface plasmon resonance peak for AgNPs were obtained for AgNPs were produced by using viscose fiber after 15 minutes. Increasing the carboxyl content of cellulose fibers after treatment with AgNO3 could be considered as an indicator for the conversion of reducing groups of cellulose to carboxylic groups by the reduction of Ag1 to Ag0. Approximately 30% of AgNPs were aggregated and precipitated after storage for 2 months. The prepared AgNPs were more convenient to use in the medical and biomedical fields as the pure solution does not contain any other chemicals or reducing or stabilizing agents [133].

dielectric, magnetic, optical, imaging, catalytic, biomedical, and bioscience properties. The prominent biomedical applications of PtNPs are found to include therapeutic effects [144], anticancer therapy [145], antitumor applications [146], contrast agent in medical imaging [147], antimicrobial activity [148], antibacterial activities [149], antioxidant effects [148], cancer chemotherapy [150], biosensors and intracellular analysis [151], photothermal therapy [152], as biocatalysts [153], and as biomarkers [153 155].

27.6.5 Selenium Nanoparticles (SeNPs)Based Nanomaterials The major biomedical applications of selenium nanoparticles include targeted drug delivery [156 158], drug delivery vehicles and artificial enzymes [159,160], anticancer therapy [161 163], antibacterial activities [164], biosensors, and intracellular analysis [165].

27.6.6 Palladium Nanoparticles (PdNPs)Based Nanomaterials The major biomedical applications of palladium nanoparticles include targeted drug delivery [166,167], anticancer therapy [168,169], antimicrobial activities [170], biosensors and intracellular analysis, hydrogen sensors [171,172], biocatalysts [173], and calalysis [174].

27.6.7 Metal Oxides-Based Nanomaterials 27.6.3 Copper Nanoparticles (CuNPs)-Based Nanomaterials The Biomedical applications of copper nanoparticles are found to be mainly in medical diagnosis [134], antibacterial and antifungal activities [135,136], molecular imaging [137], cancer imaging and cancer therapy [138], photothermal ablation of tumor cells [139], theranostic applications [140], and as catalysts [141 143].

27.6.4 Zinc Nanoparticles (ZnNPs)-Based Nanomaterials Zinc nanoparticles, nanodots, or nanopowder are spherical or faceted high surface area metal particles. They are typically 20 40 nm with a surface area in the range of 30 50 m2/g. Zinc nanorods are elongated particles ranging from 10 to 120 nm with specific surface area of 30 70 m2/g. ZnO NPs are used as antimicrobial, antibiotic, and antifungal (fungicide) agents by incorporating them in coatings, bandages, nanofiber, nanowire, plastics, alloy, and textiles. They possess suitable electrical,

MNPs are characterized by biodegradation, biocompatibility, and safety for human ingestion. It is essential that surface modifications made on MNPs are stable enough to resist the effects of salts and proteins in the physiological environment as well as allowing them to become water-soluble for biomedicine applications. Super paramagnetic iron oxides nanoparticles (SPIONs) are biocompatible among all types of nanoparticles. They have received much attentions for drug delivery applications based on the proper surface architecture and conjugated targeting ligands/proteins [175 178]. The major areas of applications of SPIONs are found to include targeted drug delivery [179,180], anticancer therapy [181,182], diagnosis and treatment of cancer [179], contrast agent in medical imaging [183], tissue engineering, target liver tumors and metastasis, ultrasensitive molecular imaging, cancer treatment by hyperthermia [184], antimicrobial activities [185,186], biosensors and intracellular analysis [187], and photothermal cancer therapy [188,189]. The unique properties of iron oxide MNPs are suitable for use in biocatalysis and bioseparation areas [190,191].

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Zinc oxide is an inorganic white powder. It is insoluble in water. It is present in the Earth’s crust as the mineral zincite. Zinc oxide is commonly found in medical ointments where it used to treat skin irritations. Zinc oxide is being used in semiconductors, concretes, ceramic and glass compositions, and even cigarette filters. Zinc oxide has become one of the most important ingredients in ointments, creams, and lotions to protect against sunburn and other damage to the skin caused by ultraviolet light (sunscreen) [192,193]. The prominent biomedical applications of ZnO NPs are found to include targeted drug delivery-destruction of tumor cells [194,195], bioimaging and drug delivery [196], tumor detection [197,198], anticancer therapy [199], contrast agent in medical imaging [200], antimicrobial activities [201], biomarkers [202], and biosensors [203 206].

27.6.8 Carbon-Based Nanomaterials Another important and novel category of nanomaterials that has been investigated extensively in drug delivery systems is CNTs. It has been seen that CNTs can interact with various biomacromolecules like DNA and proteins by physical adsorption mechanisms. Moreover, in order to conjugate covalently targeting moieties or therapeutic molecules to CNTs, several chemical modification schemes have been developed [207,208]. In a recent study, Zheng et al. introduced an important insight into the interactions between DNA molecules and CNTs [209]. In that case in the presence of single-stranded DNA, CNTs could disperse effectively in aqueous media. To date, the enhancement of mechanical properties of CNTs might be counted primarily for their using as composite reinforcements for tissue engineering scaffolds [29]. More recently, researchers have turned their attention to utilizing the multifunctional nature of CNTs in engineering tissue scaffolds. Most notably, CNTs have been incorporated to fabricate electrically conductive scaffolds.

27.6.9 Graphene Nanomaterials As has similarly been done with CNTs, several biomedical applications, including drug delivery systems, scaffold reinforcements, and injectable cellular labeling agents, have been explored using GO [210]. For example, functionalization of GO with folic acid, known to be a cancer targeting molecule, as well as loading of doxorubicin and camptothecin, known to be cancer drugs, onto the large surface area of GO via π π stacking have been reported by Zhang et al. [211]. New drug-loaded folic acid-GO showed an improved anticancer activity and cancer targeting capability compared with drugs delivered alone or drugs carried with unmodified GO. In addition, poly(ethylene glycol)-conjugated GO with targeting molecules

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could be used as a cellular sensor by utilizing the intrinsic photoluminescence property of GO at the near-infrared region [212].

27.6.10 Nanohydroxyapatite nHA is a bioceramic material widely used as a bone graft substitute owing to its biocompatibility and osteoconductive properties. nHA with chitin, chitosan, Col, gelatin, fibrin, PLA, polycaprolactone, poly(lactic-co-glycolic) acid, polyamide, polyvinyl alcohol, polyurethane, and polyhydroxybutyrate-based composite scaffolds have been explored in the present review for bone graft substitute. This article further reviews the preparative methods, chemical interaction, biocompatibility, biodegradation, alkaline phosphatase activity, mineralization effect, mechanical properties, and delivery of nHA-based nanocomposites for bone tissue regeneration. The nHA-based composite biomaterials have proved to be promising biomaterials for bone tissue engineering [213]. The researchers synthesized nHA by sol gel method, and then functionalized HAp nanoparticle by use of 3aminopropyl trimethoxysilane (APTMS), to improve the loading and control release of sulfasalazine drug bonded to APTMS. The drug release patterns from sulfasalazineloaded HAp nanoparticles at pH 8 for 6 hours, sulfasalazine-loaded functionalized HAp nanoparticles (sulfasalazine loaded HAp-APTMS) at pH 8 as in the intestine for 48 hours. Moreover, the functionalized HAp showed relatively slower release rate of sulfasalazine compare with nonfunctionalized Hap, because of the strong ionic interaction between the NH2 group in sulfasalazine in HAp-APTMS. On other side, the functionalized HAp loaded more drug than pure HAp [214].

27.6.11 Magnetic Nanoparticles MNPs are a class of nanoparticle which can be manipulated using a magnetic field. MNPs can be conjugated with any protein, drug, and gene, and MNPs can serve as contrast agents for MR imaging by changing the MRI signal. Additionally, they serve as a therapeutic tool by improving drug delivery to the target organ. Controlled release of drugs from nanostructured functional materials, especially nanoparticles, is attracting increasing attention because of the opportunities in cancer therapy and the treatment of other ailments. The potential of MNPs stems from the intrinsic properties of their magnetic cores combined with their drug loading capability and the biochemical properties that can be bestowed on them by means of a suitable coating [215]. Targeting specific sites in vivo for the delivery of therapeutic compounds presents a major obstacle to the treatment of many diseases. One targeted delivery technique

514 PART | VI Engineered Nanomaterial in Biomedical and Pharmaceutical Industry

that has gained prominence in recent years is the use of MNPs. In these systems, therapeutic compounds are attached to biocompatible MNPs and magnetic fields generated outside the body are focused on specific targets in vivo. The fields capture the particle complex resulting in enhanced delivery to the target site [216]. MNPs are used for in vivo applications like contrast agents in MRI techniques for tumor therapy or cardiovascular disease. SPIONs are very promising nanoparticles for these applications that can be targeted through external magnets. However, the SPIONs are coated with biocompatible materials that can be functionalized with plasmids, proteins, and a wide variety of drugs [217]. Most of the applications of biomaterial magnetic particle hybrid conjugates involve the concentration, separation, regeneration, mechanical translocation, and targeting of biomolecules, such as proteins, DNA/RNA, and of cells. Ferrite-nanoparticles are the most explored MNPs to date. Just like nonmagnetic oxide nanoparticles, the surface of ferrite nanoparticles is often modified by surfactants, silicones, or phosphoric acid derivatives to increase their stability in solution [218,219]. The important advantage of ferromagnetic materials (Fe3O4) and magnetite (γ-Fe2O3) in comparison with other materials with a high magnetic moment is the possibility for in vivo diagnosis and therapy. Other materials, such as cobalt and nickel, can cause oxidative stress or long-term changes in enzyme kinetics. Hence, their use should be limited in biomedical applications. The use of MNPs as drug carriers in targeted therapy provides huge opportunities in cancer treatment, as the use of such carriers considerably reduces the side effects of conventional cancer therapies such as chemotherapy.

5. The toxicity of nanoparticles and the limitation of each kind of nanoparticles have not been clarified up to now. Hence, it is necessary to consider the risk for application of nanomaterials for patients.

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