Biomedical Applications of Nanostructured Polymeric Materials

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Biomedical Applications of Nanostructured Polymeric Materials Magdalena Stevanovi´c Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, Belgrade, Serbia

1.1 Introduction Polymeric materials in the nanometer scale, as well as their composites, are of great importance in the field of biomedicine. Development in this area has led to significant progress in terms of improvement in the field of already existing biomaterials as well as the synthesis of a new one with tailor-made properties and functionalities. Such materials include nanoparticles, nanocapsules, nanofibers, nanogels, nanocomposites, micelles, polymersomes, and dendrimers. These nanostructured polymeric materials have been widely exploited for different biomedical purposes, for instance, in controlled and targeted delivery of medicaments, bioimaging, regenerative medicine, gene therapy, etc. The advantages of special features of nanostructures increase the efficiency and accuracy of medical diagnosis, treatment, and observation at the level of individual molecules or molecular structures. Different active substances can be delivered by polymer particles. For these purposes and the preparation of such particles at the nanoscale, natural (chitosan, alginate, albumin, etc.) as well as synthetic polymers [polylactides (PLA), polyglycolides, poly(lactide-coglycolides), poly(ε-caprolactone) (PCL), and also tyrosine-derived polymers] can be used. However, natural polymers often lack consistency from batch to batch, which often makes them difficult for use in preparing biomaterials with reproducible properties and other desirable characteristics [1,2]. Conversely, synthetic polymers can be synthesized with high enough purity as well as reproducibility. One of the important basic requirements in drug delivery of medicaments is a spherical form of the polymer micro- and nanoparticles as well as for them to be narrow. The morphology of the particles has a crucial role in processes which occur between particles and cells. For intravenous administration of particles, the most important parameters are encapsulation efficiency and loading amount, the charge of the particles, and the dynamics of the release. Degradation is also a very important factor which influences the release of the active substance from polymer particles. Therefore it is crucial and necessary to examine the degradation process of such

Nanostructured Polymer Composites for Biomedical Applications. DOI: https://doi.org/10.1016/B978-0-12-816771-7.00001-6 © 2019 Elsevier Inc. All rights reserved.

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systems. It is also important to develop a process for the production of nanoparticles that will be environmentally friendly. This is, without doubt, a challenge and involves nontoxic materials and especially solvents, materials which are biodegradable, processes that require less energy, etc. All this presents challenges in the field of research of different nanostructured polymeric materials for biomedical applications. In this chapter different types of nanostructured polymeric materials, their production methods, characterizations, and applications are described. This chapter highlights innovative nanosystems and their applications in different biomedical fields and will also be a contribution to the development of commercial-scale production and further applications of nanostructured polymeric materials.

1.2 Nanostructured Polymeric Materials Various materials, including nanoparticles, nanocapsules, nanofibers, nanogels, nanocomposites, micelles, polymersomes, and dendrimers, are all used for different applications in biomedicine.

1.2.1 Nanoparticles Nanoparticles have been explored for more than a decade for numerous applications [1,2]. This approach offers several advantages compared to other systems for delivery of medicaments. Nanocarriers are used for (1) delivering immobilized active substances; (2) increasing the stability of drugs by chemical or physical means; (3) enhancing the solubility of drugs; (4) delivering a higher amount of medicaments to specific areas; and (5) conducting specific, targeted, treatments based on the ligands attached to the cells [1]. The most commonly used nanoparticles for such purposes are polymeric nanoparticles. Among polymers of natural origin, the most commonly used for preparing nanoparticles is chitosan. Chitosan is most often examined in the preparation of formulations for medical applications through the skin, that is, topical delivery. Chitosan is a water-soluble polysaccharide extracted from chitin. It may serve as a bioadhesive. Also, it can bind to mucoproteins that are negatively charged while chitosan is positively charged. This is important since it leads to prolonging of the circulation time of drugs based on chitosan and thus enhances their bioavailability [3]. From the literature, the most common methods for synthesis of nanoparticles from chitosan are ionic cross-linking, or covalent cross-linking [4], precipitation [5], polymerization [6], or self-assembly procedures [7]. Based on the techniques applied for the preparation of particles, their sizes vary from several nanometers to several hundred nanometers. Complexes of chitosan and drug are usually obtained through interactions among positively charged (cationic) chitosan and negatively charged (anionic) drugs [8,9]. By tailoring the degradation, it is possible to influence and control the drug-delivery release from chitosan-based nanoparticles. In this respect, such a system can

Biomedical Applications of Nanostructured Polymeric Materials 3 enable the release of the drug over a period of several days to several months [10]. Alginate is also representative of natural polymers. It also belongs to the group of polysaccharides. Recently, Ibrahim et al. reported on the preparation of alginate nanoparticles with an immobilized drug, brimonidine [11]. This system has shown improvement in vivo regarding intraocular pressure when compared to commercially available brimonidine-tartrate eye drops [11]. In another study, the use of nanoparticles for immobilization of antimicrobial substances has been examined. For this purpose have been used chitosan and alginate. The system showed superior in vitro antimicrobial activity in comparison with benzoyl-peroxide [12]. The next representative of natural polymers is albumin. Albumin nanoparticles are nontoxic, biocompatible, and biodegradable carriers of different active substances [13,14]. These nanoparticles are often used for producing systems in controlled drug delivery [15,16]. They have gained significant attention in this field due to their high binding capacity. Recently, Das et al. illustrated that albumin nanoparticles containing aspirin achieved the release of aspirin in vitro for 72 h and have potential as a topical system for diabetic retinopathy [15]. In a study by Lomis et al., a method for obtaining human serum albumin nanoparticles with encapsulated anticancer drug paclitaxel was described. The synthesis was done by the emulsion evaporation method and high-pressure homogenizer. In vitro assessment of drug release and a cytotoxicity study were both done with breast cancer cells. After applying different concentrations of paclitaxel, dose-dependent toxicity on cells was demonstrated [16]. In a study by Lu et al., albendazole was loaded into particles, a conjugate of bovine serum albumin and polycaprolactone. The size of these nanoparticles was about 100 nm and they were prepared for the treatment of pancreatic carcinoma cells [17]. PCL is representative of synthetic polymers. It is extensively used for the production of nanocarriers. It is a biocompatible, biodegradable polymer which possesses suitable rheological characteristics, such as a low glass transition temperature [18]. Due to its semicrystalline nature, the degradation of PCL is slower than in other polyesters [degradation rates: poly(glycolic acid) . poly(lactide-co-glycolide) . poly(L-lactic acid) . PCL] [18]. As a consequence, PCL is often modified to adjust its biodegradability to meet the specifications of the targeted biomedical application [19,20]. PCL spherical micro- and nanoparticles have been synthesized by a physicochemical solvent nonsolvent technique and by employing different types of polyelectrolytes as stabilizers in synthesis at room and elevated temperatures. The particles with polyglutamic acid had spherical shapes, with smooth surfaces and size less than 1 μm [21]. Poly(lactic-co-glycolic acid) (PLGA) is also a biodegradable polymer widely used in medical devices and pharmaceutical formulations. It has many advantages, such as exceptional properties which make PLGA easy for operating. It is also easy to manipulate and tailor the degradation and biocompatibility of this polymer for specific applications. PLGA is an FDA-approved polymer for different purposes. It is a copolymer which may have different ratios of monomers in the chain and molecular weights. In PLGA nanoparticles it is possible to immobilize/encapsulate different active substances as well as to modify the surface of such particles to be site-specific in the body [22].

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Depending on the chosen materials, techniques for the synthesis of polymeric micro- and nanoparticles generally can be classified into several groups. These include polymerization of monomers, dispersion of preformed polymers, and coacervation [23]. PLGA can be produced as nanoparticles using different methods, such as emulsification-evaporation method [24 26], emulsification-solvent diffusion method [27,28], nanoprecipitation [29,30], and spray-drying [31]. With the aim of obtaining particles with smaller sizes, homogenization or centrifugation is very often employed [32 36]. In the literature, it can be seen that changing factors such as aging time (with nonsolvent), duration of centrifugation, etc., can affect the morphological characteristics of particles, such as size, uniformity, and agglomeration [36].

1.2.2 Nanocapsules All the above-mentioned polymers can be also used for the preparation of nanocapsules. Nanocapsules are a vesicular system in which active substances, solubilized in an aqueous or oil core, are covered by a polymeric membrane (wall material) [37,38]. The nanoencapsulation of therapeutic agents has been a research field widely explored with the utilization of a wide variety of wall materials in its composition. As wall materials in nanocapsules, synthesis materials such as casein micelles, whey protein, pectin, cellulose, etc. have been also used [39,40]. After preparing nanocapsules, the assessment of their stability is very important, mostly in relation to their characteristics, such as size, morphology, polydispersity index, zeta potential, pH, and release profile [37]. All these parameters mainly depend on the material and method chosen for their synthesis. The most efficient method to produce nanocapsules is determined by the physicochemical properties of the polymer and also the active compound to be nanoencapsulated [41]. Also, which polymer will be chosen in the synthesis mainly depends on the size of the required nanocapsules, aqueous solubility and stability, surface permeability, and the desired drugrelease profile [42]. For the characterization of nanocapsules, different techniques can be applied, such as dynamic light scattering, transmission electron microscopy, measurement of zeta potential, etc. Additionally, the selection of the organic solvent employed during nanocapsule preparation is also very important because of the risk to human health, restricting the application of nanocapsules. In a study by Charcosset et al., PCL nanospheres and nanocapsules were prepared using a ceramic membrane, with a high flux through the membrane and large membrane pore size distribution [43]. A similar method has been applied for the preparation of vitamin E-loaded nanocapsules but with a Shirasu porous glass membrane, which is especially intended for membrane emulsification and consequently offers a much sharper pore size distribution when compared with classical ceramic membranes [44]. Rice bran oil has been used for producing nanocapsules where PCL was used as the wall material [45]. This was done with the aim of evaluating its protective effect in the treatment of skin injury in mice induced by UVB radiation.

Biomedical Applications of Nanostructured Polymeric Materials 5 The authors concluded that 60% of the edema was inhibited by applying these nanocapsules [45]. PCL used in nanocapsule preparations increases solubility, stability, and applications of carotenoid compounds, such as bixin, lycopene, and β-carotene [46 49]. PLA is also used for the preparation of nanocapsules and encapsulation of many therapeutic agents. For example, PLA has been utilized for encapsulation of flavonoids by the solvent-evaporation method [50] and the nanoprecipitation method [51]. Different biologically active compounds, like quercetin, can be loaded together with medicaments applying PLGA as a wall/core material. In this manner, it has achieved synergistic therapeutic effects of these compounds and it has improved their efficiency [52]. PLGA has been also used for the encapsulation of a lipophilic substance, lutein, and this was done by the emulsion sonication-solvent evaporation technique [53]. The nanocapsules had sizes of about 200 nm and presented a controlled sustainable release of 66% for up to 72 h. A PLGA blend with chitosan (1:1, w/w) has been used for the production of nanocapsules containing α-tocopherol and γ-tocotrienol with the aim of evaluating their cellular uptake, antioxidative effect, and antiproliferative activity [54]. The nanocapsules including chitosan in their formulations were more efficient in interactions with cells than those with only PLGA. This is explained by the positive zeta potential of chitosan which leads to better internalization of nanoparticles in cells [54]. Chitosan also can be used as a wall material for bioactive compounds, but it is much more often used in combination with other polymers [55].

1.2.3 Nanofibers Delivering therapeutic agents in a continuous manner to the intended site can be also done by nanofibers. Nanofibers are also a very important nanostructured material that is presently applied for different biomedical purposes. Their properties can be optimized for precise requirements by surface adaptations, counting the attaching of functional ligands as well as biologically active molecules such as drugs, cytokines, proteins, etc. [56]. Nanofibers may act as an effective system for the regeneration of injured tissues and organs due to their appropriate permeability, high surface to volume ratio, low basis weight, and small fiber diameter [56]. Thus numerous nanofibrous materials are being explored for their potential in tissue engineering and regenerative medicine. There are several main approaches to the production of functional polymeric nanofibers such as vapor phase deposition, evaporation, sputter deposition, laser ablation, electrospinning, and wet chemical methods [56]. The electrospinning process has attracted significant attention because of its ability to generate fibers similar to the fibrous structures of the native extracellular matrix. The recent methods such as self-assembly [57], melt-fibrillation, centrifugal spinning [58], and nanolithography are restricted by their cost and production rate. As a consequence, producing nanofibers based on biomimetic approaches has gained much attention among researchers. The several typical biomimetic nanofibrous structures that have great potential for tissue engineering are

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aligned with random, spiral, tubular, and sheath membranes [59]. Presently, a diversity of natural polymers such as collagen, gelatin, silk, and synthetic polymers such as poly(L-lactic acid), poly(glycolic acid), PCL, and poly(lactic-co-glycolic) acid has been electrospun as biomimetic and temporal substrates to modulate various cellular activities [59].

1.2.4 Nanogels Nanogels are hydrogel particles at the nanometer scale. They are three-dimensional networks of hydrophilic polymers [60]. Hydrogels are cross-linked networks of hydrophilic polymers that retain a large amount of water and can be used for loading and release of therapeutics because of this feature [61 63]. Unlike the larger hydrogel particles, nanogels can be injected into the circulation to reach targeted organs and tissues. Therefore nanogels can deliver their drug contents locally as well as intracellularly [64 69]. They are biocompatible particles with high loading capacity for hydrophilic therapeutic agents. Also, their network protects the encapsulated substances against degradation as enzymes cannot penetrate to reach them [64 68]. Additionally, the progress in research of responsive nanogel delivery systems has led to particles that release their contents due to a certain physiological trigger inside cells, such as in the cytosol or endocytic compartments [60]. The properties of the nanogels such as size, cross-link density, or surface properties can be modified for specific applications. Nevertheless, it is difficult to immobilize and retain molecules which are smaller than the pore meshes in nanogels since the loaded molecules will be released from the particles during synthesis [67]. This can be overcome by increasing the cross-link density of nanogels to stably capture their payloads during gel synthesis. The therapeutics can be stably encapsulated within nanogels either in highly cross-linked nanogels or by strong electrostatic interactions with them to minimize their premature leakage. In such cases, the release of therapeutics will be mostly slow because of the hydrolytic degradation of cross-links, that is, the polymer network. Recently, nanogels have been produced with cross-links that can be broken by external stimuli such as pH, temperature, light, and ultrasound, etc., which causes rapid swelling and/or degradation and consequently faster release of the payload [67,68,70,71].

1.2.5 Nanocomposites Nanocomposites are composite materials where at least one component is in the nanometer scale. They have attracted significant attention as they usually possess better properties than the component materials individually, or they become multifunctional materials with more desirable properties [72]. Nanocomposites are usually comprised an organic matrix in which inorganic nanoparticles are dispersed. Organic matrix is made either from synthetic or natural polymers. Such polymeric nanocomposites exhibit improved mechanical, magnetic,

Biomedical Applications of Nanostructured Polymeric Materials 7 optical, thermal, etc. properties due to the combination of the desirable properties of the inorganic components, that is, large surface area, thermal stability, high surface reactivity, high mechanical strength, with the properties of the polymer, such as good processability, elasticity, flexibility, etc. [73]. For that reason, polymeric nanocomposites very often find applications in different fields [74,75]. This also leads to progress in research, not only in the field of polymeric nanocomposites but also in the design of new functional materials. Therefore all can result in customization of multifunctional materials with exceptional properties and highly sophisticated applications. A wide variety of approaches have been used to create polymer nanocomposites with improved structures, advanced properties, and prospective applications. Among these techniques, the self-assembly technique has been often used due to its simplicity, low cost, high precision, and flexibility [76 79]. Generally, the methods for obtaining polymeric nanocomposites most frequently mentioned in the literature include grafted polymer surface modification technique [79], spin coating [80], deposition based on chemical interactions like those between antigen and antibody [81], those with DNA hybridization [82], cross-linking [83], layer-by-layer assembly method [84], etc.

1.2.6 Micelles Micelles are aggregates formed in an aqueous solution by amphiphilic molecules (Fig. 1.1) [85]. Amphiphilic molecules have both polar or charged groups and nonpolar regions. In an aqueous solution, polar or ionic heads form an outer shell when they are in contact with water, while nonpolar tails are detached in the interior [85]. The type of obtained aggregate, the micelle, is determined by the length of the nonpolar tail, the nature and size of the polar or ionic head, the temperature, the acidity of the solution, the presence of added salts, etc.

Figure 1.1 Schematic representation of a micelle (A) and reverse micelle (B) in an aqueous solution.

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Micelles are formed in the aqueous medium only when the concentration of amphiphilic molecules reaches a certain level, that is, the critical micelle concentration. This can be seen by the changes to the solution in its chemical and physical appearance. In contrast, below this critical concentration, micelles will not be formed [85,86]. The process of micellization itself depends on two main factors, which are the tendency of the nonpolar tails to avoid contact with water as well as repulsion among the polar or charged heads. These are destabilizing effects on the aggregation process [85,86]. Micelles can be also formed in nonpolar organic solvents from amphiphilic molecules but, in that case, nonpolar tails will be exposed to the solvent while the polar heads will be in the interior of the aggregate to avoid contact with the solvent. These are so-called reverse micelles (Fig. 1.1) [85,86]. Micelles have been often used in drug delivery of medicaments as well as for other biomedical applications [87,88].

1.2.7 Polymersomes Polymersomes are also very attractive materials used for drug delivery and other biomedical applications due to their colloidal stability, tunable membrane properties, and ability to encapsulate a wide variety of active substances [89]. They are a class of vesicles made from synthetic amphiphilic block copolymers [90 93]. Polymersomes are hollow spheres containing an aqueous solution in the core surrounded by a bilayer membrane [89]. As is well described in a review article by Lee et al., this membrane is composed of hydrated hydrophilic coronas both at the inside and outside of the hydrophobic central part of the membrane separating and protecting the fluidic core from the outside medium [89]. The core can be used for the encapsulation of medicaments such as drugs, proteins, peptides, enzymes, DNA and RNA fragments, etc. [94 96]. The membrane can be used for the encapsulation of hydrophobic drugs within its hydrophobic core [97 99]. Polymersomes produced by means of biodegradable and/or stimuli-sensitive block copolymers that are responsive to various internal or external stimuli are of great interest for applications in drug delivery, medical imaging, etc.

1.2.8 Dendrimers Dendrimers represent a class of highly branched, monodispersed, synthetic macromolecules with well-defined composition and structure [1]. Dendrimer nanoparticles have applications in different areas, such as catalysis, electronics, and biomedical applications. [100]. The literature indicates that dendrimers very often used in nanomedicine are polyamidoamine, poly(L-lysine), polyesters, polypropylimines, poly(2,2-bis(hydroxymethyl)propionic acid), and amino-bis-(methylenephosphonic acid) scaffold dendrimers [100,101]. The surface chemistry of dendrimers can be modified easily, so it is possible to make nanoparticles with different characteristics. In a study by Perumal et al. it was shown that dendrimers could be

Biomedical Applications of Nanostructured Polymeric Materials 9 used to enhance the skin permeation of hydrophilic drugs [102]. Dendrimer properties such as size, surface charge, hydrophobicity, and molecular weight are key parameters guiding drug delivery [103].

1.3 Biomedical Applications All the above-described nanostructured polymeric materials have been used for a wide variety of different biomedical applications such as controlled drug delivery, bioimaging, tissue engineering, and regenerative medicine.

1.3.1 Drug Delivery There are various techniques for producing nanomaterials for drug-delivery systems, such as spray-drying, solvent evaporation, physicochemical solvent/nonsolvent method, electrospinning, etc. [104 107]. The synthesis of nanomaterials with natural or synthetic polymers extends the opportunity to protect the drugs from degradation in the gastrointestinal tract, which makes possible the delivery of drugs to various inflammatory sites [104]. In the micro- and nanosystems prepared from polymeric materials for controlled and targeted drug delivery, the drug and polymer are combined in a way that allows the release of drug in a predefined manner. The release process may occur constantly over a period of time, may be periodical, or it may depend on the environmental conditions such as temperature, pH, and the presence of enzymes. [23]. One of the main goals of such systems in controlled and targeted drug delivery is to find a balance, that is, to keep drug levels in the needed range, avoiding under- and overdosing, fewer administrations, increased patient adherence, and more effective therapies [104]. These systems significantly improve the drug level and as such can be used in different branches of medicine, that is, transdermal, dental, cardiovascular, etc. [104]. A recent study by Shi et al. examined the possibility of increasing the retention of RNA nanoparticles in the eye by using thermosensitive hydrogels [poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly (lactic-co-glycolic acid); PLGA PEG PLGA]. They examined particles with different morphological characteristics [108]. After 24 h postinjection, about 6% 10% of the fluorescence signal which originates from the larger nanoparticles (RNA square of 20 nm edge length and RNA pentagon of 10 nm edge length) persisted in the eye, while about 70% of the retinal cells restrained the smaller nanoparticles [108]. Based on the obtained results it was concluded that the larger nanoparticles were restrained in the cells of the retina, conjunctiva, cornea, and sclera, as well as in macrophages. Furthermore, the synthesis of RNA particles with the polymers enhanced retention of the nanoparticles in the eye [108]. Sanders et al. examined the activities of nanoparticles with the nucleic acid in vitreous and when they were PEGylated with the aim of advancing their behavior in vitreous and taking into account that this does not affect their transfection capacity [109].

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They concluded that PEGylation prevents nanoparticles from agglomeration in the vitreous, while the nanoparticles which were not PEGylated formed aggregates. PEGylation had a large influence on the performance of PEGylated nanoparticles in cells and therefore on their gene transfer efficiency [109]. Recently, Huu et al. presented an innovative nanosystem for the delivery of an active substance employing UV-degradable polymer. This approach allows noninvasively activated drug release by utilization of low-power light exposure [110]. Nanoparticles steadily preserve immobilized compound in the vitreous and can release the drug when they are activated by UV light. This can be prolonged for up to 30 weeks after injection. In this study, the release of nintedanib from nanoparticles was examined after their activation by light and it was shown that 10 weeks after their injection in rats they suppressed choroidal neovascularization [110]. ElMasry et al. [111] conjugated gelatin to fatty oleic acid (an acid that occurs naturally), by an amidation reaction. This was done with carbodiimide N-hydroxysuccinimide as activators with the aim of producing the conjugate of a gelatin and oleic acid. This compound was characterized by Fouriertransform infrared spectroscopy and 1H nuclear magnetic resonance spectroscopy. Additionally, a single-desolvation method has been used for the preparation of these nanoparticles. Also, the anticancer agent, sesamol, has been encapsulated into these nanoparticles and they have been further examined for transdermal delivery. The authors concluded that this system is effective for this purpose [111]. The aim of the study of Malinovskaja-Gomez et al. was to evaluate the in vitro system produced by nanoencapsulation and iontophoresis. PLGA has been used for the encapsulation of lipophilic model drug [112]. The system was prepared for transdermal delivery of the drug and has manifested stability in regards to colloidal properties when particles are exposed to iontophoretic current as well as when in contact with the skin barrier [112]. It has been shown that pulsed current iontophoresis could be an efficient option when compared with traditional constant current iontophoresis by enhancing transdermal permeation of drugs from nanoformulations [112]. Very recently, nanoparticles prepared from natural polymer chitosan were loaded with curcumin and examined for transdermal delivery. They have been optimized and evaluated ex vivo regarding interaction and delivery of curcumin through the skin. The study proved the ability of chitosan nanoparticles to deliver curcumin through the skin [113]. In the study by Takeuchi et al., PLGA nanoparticles loaded with donepezil hydrochloride were developed. Donepezil hydrochloride is a hydrophilic drug while PLGA is hydrophobic. During synthesis, the surfaces of PLGA particles were modified by cationic polymers, chitosan and hydroxypropyltrimonium, to give them a positive charge. The mean diameter of the particles was 117.7 6 60.6 nm [114]. Also, it was shown that in the case when iontophoresis was applied, the positively charged PLGA particles were 2.2-fold more effective regarding the delivery of the drug when compared to when unmodified, that is, negatively charged [114]. In a recent study, PLGA nanoparticles of 50 and 100 nm were prepared [115]. In this study indometacin was also encapsulated within the PLGA nanoparticles. These nanoparticles were further examined regarding their

Biomedical Applications of Nanostructured Polymeric Materials 11 permeability through the abdominal skin of rats over 2 h. The amounts of PLGA nanoparticles loaded with indometacin were considerably higher when iontophoresis was applied than in the case of passively diffused nanoparticles and indometacin solution. Also, in the case of smaller PLGA/indometacin nanoparticles, the indometacin concentration was 1.7 times greater than in the case of larger ones. This is explained by the fact that smaller particles reached a deeper portion of the hair follicle when applying iontophoresis [115]. In the work of Al-Kassas et al., nanoparticles prepared from chitosan and dispersed within gels were examined with the aim of improving the systemic bioavailability of propranolol-HCl, and for transdermal drug delivery [116]. The authors produced these nanoparticles by ionic gelation technique and using tripolyphosphate as a cross-linking agent. Properties of the nanoparticles such as morphological characteristics, size, surface charge, shape, and drug-loading efficiency were evaluated. First, chitosan nanoparticles were freeze-dried and then dispersed within gels prepared from the poloxamer and carbopol. Thereafter properties such as rheological behavior were examined. Also, their adhesiveness was evaluated. The smallest particles were obtained with 0.2% chitosan. The study showed that the produced nanoparticles have the potential to increase the bioavailability and therapeutic efficacy of propranolol-HCl [116]. Choipang et al. investigated PLGA nanoparticles loaded with ciprofloxacin hydrochloride. The nanoparticles were prepared as an antibacterial agent and for treatment of infected pressure ulcers [117]. They used the double emulsion technique for this purpose. The particles were spherical, with sizes of about 600 900 nm. Additionally, PLGA nanoparticles loaded with ciprofloxacin hydrochloride were added into polyvinyl alcohol hydrogels prepared and cross-linked with gamma radiation. This material was evaluated as an antimicrobial agent with Escherichia coli and Staphylococcus aureus. Moreover, the cytotoxicity of the material was examined with human fibroblast cells and showed that the particles are nontoxic. The authors concluded that hydrogels loaded with PLGA/ ciprofloxacin hydrochloride may be used as materials in wound dressings with antimicrobial properties [117]. Docetaxel loaded within PLGA and PCL nanoparticles, which are coated with chitosan, were successfully developed by Badran et al. [118]. The synthesized nanoparticles were examined in the context of their physicochemical properties and loading efficiency, as well as in vitro degradation and release of the drug. The anticancer activity of docetaxel-loaded nanoparticles was assessed in a human HT29 colon cancer cell line utilizing MTT assay. The pharmacokinetics of the particles was monitored in Wistar rats and compared with docetaxel solution. Chitosan-decorated nanoparticles exhibited a significant increase in particle size and a switch of zeta potential from negative to positive. The in vivo study revealed significant enhancement in docetaxel bioavailability from chitosan-coated PLGA nanoparticles. The authors concluded that PLGA nanoparticles which are coated by chitosan showed high antitumor efficacy with colorectal cancer [118].

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1.3.2 Bioimaging Nanoparticle-based imaging has an essential role in diagnosis and treatment. Molecular imaging involves noninvasive mapping of molecular and cellular processes related to disease progression in living systems [119]. Modalities in molecular imaging include positron emission tomography, single-photon emission computed tomography, ultrasonography, optical imaging, and magnetic resonance imaging. They vary in spatial resolution, depth penetration, and detection sensitivity [119]. Molecular imaging of tumors must be highly sensitive as concentrations of biological molecules abnormally expressed in tumor tissues are, in general, very low [119]. Nanomaterials are the ideal to achieve this, as they possess characteristics that improve imaging detection of biological targets, such as: the ability to amplify contrast signal by incorporating, for example, radionuclides, gadolinium ions; unique physicochemical properties such as surface plasmon resonance, magnetic properties, thermal or pH-responsive phase changes; and the ability to modulate pharmacokinetics through surface chemistry and to integrate multiple functions in a single scaffold [119]. Also, semiconducting polymer nanoparticles arise as innovative molecular imaging nano-agents in living animals because of their extraordinary optical characteristics including large absorption coefficients, tunable optical properties and controllable dimensions, high photostability, and the use of organic and biologically inert components without toxic metals [120]. A diversity of innovative polymer strategies, chemical alteration, and nanoengineering designs have been established to precisely adapt optoelectronic properties of semiconducting polymer nanoparticles to support fluorescence, chemiluminescence, and photoacoustic imaging in living animals [121]. In that manner and with imaging modalities, semiconducting polymer nanoparticles have shown that they are capable of imaging tissues, for instance, lymph nodes, vascular structures, and tumors. Also, it is possible to detect disease biomarkers such as reactive oxygen species and protein sulfenic acid as well as physiological indexes such as pH and blood glucose concentration. The potential of semiconducting polymer nanoparticles in cancer phototherapy including photodynamic and photothermal therapy is remarkable [121]. In a recent study by Xie et al., semiconducting polymers with self-quenched fluorescence were synthesized and transformed into semiconducting polymer nanoparticles for amplified photoacoustic imaging in living mice. The self-quenched process is induced by the incorporation of an electron-deficient structure unit into the backbone of semiconducting polymers, which in turn promotes nonradiative decay and enhances heat generation [122]. Such chemical alteration of semiconducting polymers leads to a 1.7-fold photoacoustic amplification for the corresponding semiconducting polymer nanoparticles. By virtue of the targeting capability of cyclic arginine-glycine-aspartic acid (cyclic-RGD), the amplified semiconducting polymer nanoparticles can effectively delineate tumor in living mice and increase the photoacoustic intensity of tumor by 4.7-fold after systemic administration [122].

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1.3.3 Tissue Engineering and Regenerative Medicine Regeneration has fascinated humans for centuries. The use of nanotechnology to improve current methods in tissue and organ regeneration has received increased attention over the years. In particular, nanomaterials offer interesting features to advance the field of regenerative medicine [123,124]. During this time, there has been increased interest in the development and direct administration of therapeutic agents to promote bone tissue regeneration [123]. However, direct administration often has limitations, including degradation, nonspecificity, and poor cell uptake. This results in the need to use amplified doses, which increases the risk of adverse effects. Nanocarriers may improve the pharmacokinetics of such agents while protecting them from degradation. In addition, they can be modified to allow for controlled drug delivery as well as specific cell and tissue targeting. In the field of tissue engineering as well as regenerative medicine, nanostructured polymeric materials provide mechanical support and biochemical signals to favor cell attachment and to moderate cell behavior [125]. The template from nature for these materials is the extracellular matrix. The extracellular matrix contains intrinsic biochemical and mechanical cues that control cell phenotype and function in development, homeostasis, and response to injury [125]. The use of different nanomaterials in tissue engineering has advanced from coating cell culture plates with purified extracellular matrix components to the design of biomimicking biomaterials.

1.4 Conclusion Nanostructured polymeric materials are very promising candidates for various biomedical applications. This is because of their extraordinary features, which come mostly from their size and consequently unique physicochemical properties. This chapter describes various types of nanostructured polymeric materials, such as nanoparticles, nanocapsules, nanofibers, nanogels, nanocomposites, micelles, polymersomes, and dendrimers, as well as their biomedical applications. This chapter will also be a contribution to the development of commercial-scale production and further applications of nanostructured polymeric materials.

Acknowledgments M.S. acknowledges support from the Ministry of Education, Science and Technological Development of the Republic of Serbia.

References [1] Goyal R, Macri LK, Kaplan HM, Kohn J. Nanoparticles and nanofibers for topical drug delivery. J Control Release 2016;240:77 92. [2] Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 2003;55:329 47.

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