**6. Polymeric nanoparticles functionalization and considerations for smart application**

provide some examples of various nanoparticles with different functionalization and different therapeutic uses based on the target, shown in Table 3. Therefore, the multi-functionalized nanoparticle over comes from the drawbacks of conventional therapy. In the latest study provided that more than 26 nanoparticle based therapeutic system have been approved for clinical treatment and several nanoparticles are under consideration [281]. In order to achieve the efficient nano-particulate system based therapeutics the nanoparticle synthesis and functionalization methods have to consider very carefully. Although several surface modified methods for various bio-applications have been reported previously, in this section highlight

**Nanoparticles Functionalization Drug Use Refs.** Human serum albumin Amino/acid group Doxorubicin Antineoplastic [260]

PLLA-b-PEG Folate targeted Doxorubicin Solid tumors [262] PEG-PE Lipid conjugated Paclitaxel Various cancers [263] PEG Lipid conjugated Tamoxifen Lung carcinoma [264]

Polymer-lipid hybrid Lipid conjugated Doxorubicin Solid cancer [265]

PAMAM dendrimers Folic acid ethotrexate Epithelial cancer [267]

PEG Serum protein Ellipticin Anticancer [266]

PEG Albumin bound Doxorubicin Various cancers [268]

PLGA Alendronate Estrogen Bone-osteoporosis [270]

Poly(DEAP-Lys)-b-PEG -b-PLLA Poly(lysine) Doxorubicin pH sensitive tumor [271] PLGA-b-PEG-COOH PSMA Anti cancer Prostate- cancer [272] PEG or PE particles Transferrin Oligonucleotide Brain- gene [273] PLLA-PEG Biotin Anti cancer Cancer therapy [274] Polystyrol Sc-TNF Anti cancer Cancer therapy [275] PLA Aptamer Anti cancer Prostate cancer [276] PE RGD peptides siRNA Vasculature cancer [277] mPEG/PLGA Peptidomimetics Anti cancer Brain cells cancer [278] PLA Galactose Retinoic acid Hepatocytes [279] PLGA MP lipid A Anti cancer Dentritic cells [280]

**Table 3.** Examples of various nanoparticles with different functionalization and therapeutic uses based on the target

conjugated Daunomycin Brain tumor [269]

cancer [261]

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Trimyristin Sterically stabilized Paclitaxel Ovarian, lung, breast

particular examples where this type of functionalization has been used.

PCL-b-trimethylene carbonate-

Micelles Biotin-antibody-

In this section provides the recent research on the preparation and functionalization of various polymeric hybrid nano-materials including nanoparticles and microparticles by various techniques. Several techniques have been developed for the functionalization of polymeric nanoparticles with different therapeutic applications. The polymeric nanoparticles have been studied for their enriched properties in biological systems, with the nature of the materials and whether it has the specific properties for chemical modification and functionalization of the nanoparticle developed from various materials including bio-macromolecules. There are several researchers have been studied for functionalization and surface modification of nanoparticles and it would not cover all this in this section; so, this section covers some examples of nanoparticles functionalization and some important criteria to consider the fabrication process. In addition, the richness of surface chemistry and potential biomedical applications are described. The polymeric nanoparticles surface functionalization are mainly two types, one is functionalization with biological (macro)molecules such as peptides, carbohydrates, lipids, fatty acids, proteins, and nucleic acids (genes, oligomers, aptamers, and ribozymes/DNAzymes); another one is functionalization with specific ligands such as monoor oligosaccharides (carbohydrates), folate receptor, antibodies and biotin are commonly used. This surface functionalization have been made by various modifications on preformed nanoparticles through adsorption, functional surfactants, emulsification, polymerization, covalently bounded functional molecules and various forms of bio-conjugation. There are few considerations for functionalization of polymeric nanoparticles properties such as: 1) the biomolecule ratio should controlled by calculating the number of conjugate sites presents in the nanoparticles with different applications, 2) due to the environment and electrostatic interac‐ tions the alignment of functionalization has been varying, so the non specific attachment should be avoided in the performed nanoparticles, 3) depends on the applications require‐ ments the nanoparticles bio-molecule distance should be maintained, 4) control the conjuga‐ tion moiety attachment/linking affinity to the performed nanoparticles, 5) should maintain the optimal efficiency of physiochemical characters and 6) it should be high reproducible for all batches. The above all criteria can fulfil the requirement of design and functionalization of nanoparticles for a controllable release profile that satisfies the desired application. And better protection against environmental factors and maximum optimal control is achieved if drug loading is carried out by encapsulation instead of adsorption on to the particle surface. With the combinations of these above criteria in the fabrication of nanoparticles are potential to increase the clinical therapeutics by reducing unwanted effects.

With the field of bio-nanotechnology, enormous new research on the synthesis of polymeric nanoparticle based top-down or bottom-up approaches have been recently developed. Recent developed polymeric systems engrafted nanoparticles provide the optimal characteristic of the functionalized nanoparticles for various therapeutic approaches in harsh environments such as in the acidic and alkali environment [259]. Also polymer nanoparticles are broadly used in several therapeutic applications, mostly cancer targeting and therapeutics. And we provide some examples of various nanoparticles with different functionalization and different therapeutic uses based on the target, shown in Table 3. Therefore, the multi-functionalized nanoparticle over comes from the drawbacks of conventional therapy. In the latest study provided that more than 26 nanoparticle based therapeutic system have been approved for clinical treatment and several nanoparticles are under consideration [281]. In order to achieve the efficient nano-particulate system based therapeutics the nanoparticle synthesis and functionalization methods have to consider very carefully. Although several surface modified methods for various bio-applications have been reported previously, in this section highlight particular examples where this type of functionalization has been used.

**6. Polymeric nanoparticles functionalization and considerations for smart**

In this section provides the recent research on the preparation and functionalization of various polymeric hybrid nano-materials including nanoparticles and microparticles by various techniques. Several techniques have been developed for the functionalization of polymeric nanoparticles with different therapeutic applications. The polymeric nanoparticles have been studied for their enriched properties in biological systems, with the nature of the materials and whether it has the specific properties for chemical modification and functionalization of the nanoparticle developed from various materials including bio-macromolecules. There are several researchers have been studied for functionalization and surface modification of nanoparticles and it would not cover all this in this section; so, this section covers some examples of nanoparticles functionalization and some important criteria to consider the fabrication process. In addition, the richness of surface chemistry and potential biomedical applications are described. The polymeric nanoparticles surface functionalization are mainly two types, one is functionalization with biological (macro)molecules such as peptides, carbohydrates, lipids, fatty acids, proteins, and nucleic acids (genes, oligomers, aptamers, and ribozymes/DNAzymes); another one is functionalization with specific ligands such as monoor oligosaccharides (carbohydrates), folate receptor, antibodies and biotin are commonly used. This surface functionalization have been made by various modifications on preformed nanoparticles through adsorption, functional surfactants, emulsification, polymerization, covalently bounded functional molecules and various forms of bio-conjugation. There are few considerations for functionalization of polymeric nanoparticles properties such as: 1) the biomolecule ratio should controlled by calculating the number of conjugate sites presents in the nanoparticles with different applications, 2) due to the environment and electrostatic interac‐ tions the alignment of functionalization has been varying, so the non specific attachment should be avoided in the performed nanoparticles, 3) depends on the applications require‐ ments the nanoparticles bio-molecule distance should be maintained, 4) control the conjuga‐ tion moiety attachment/linking affinity to the performed nanoparticles, 5) should maintain the optimal efficiency of physiochemical characters and 6) it should be high reproducible for all batches. The above all criteria can fulfil the requirement of design and functionalization of nanoparticles for a controllable release profile that satisfies the desired application. And better protection against environmental factors and maximum optimal control is achieved if drug loading is carried out by encapsulation instead of adsorption on to the particle surface. With the combinations of these above criteria in the fabrication of nanoparticles are potential to

increase the clinical therapeutics by reducing unwanted effects.

With the field of bio-nanotechnology, enormous new research on the synthesis of polymeric nanoparticle based top-down or bottom-up approaches have been recently developed. Recent developed polymeric systems engrafted nanoparticles provide the optimal characteristic of the functionalized nanoparticles for various therapeutic approaches in harsh environments such as in the acidic and alkali environment [259]. Also polymer nanoparticles are broadly used in several therapeutic applications, mostly cancer targeting and therapeutics. And we

**application**

278 Application of Nanotechnology in Drug Delivery


**Table 3.** Examples of various nanoparticles with different functionalization and therapeutic uses based on the target

Functionalization is defined as the improving performance of nanoparticle by a chemical functional group on their surface. Some basic components of functionalized nanoparticle are enabling to increasing the multifunctional applications in the field of biomedicine; the basic components are diagnostic agent, targeting ligand, spacer group, therapeutic agents, and polymer nano-carrier with proper functionalization. Here we introducing two strategies for surface functionalization, first one is direct functionalization, where the functional ligand is a bi-functional compound. In this method, one of the reactive groups is used to bind to the nanoparticle surface and the second group contains the required active functionality. Another one is post-functionalization, here the strategy is not changeable and the nature of the functionalizing group cannot be compatible with good control over the size and dispersion of the nanoparticles in the solvent used for the fabrication. Commonly, the nano-carriers have been functionalized with various chemical functional groups such as thiols, disulfides, amines, nitriles, carboxylic acids, phosphines and bio-macromolecules [282-287], based on their application. The functionalization of nanoparticle is to modify their outer surface with other specific chemical agents based on the desired application. After functionalization the particle physiochemical character has been changed. Also, it is a very important step for control because it can change their size and self-organization during the formation and should not promote aggregation. The prepared polymeric nanoparticles have emerged promising technology platform for recognizing the target with navigated controlled drug delivery system. Figure 8 shows the various functionalizations of the nano-engines for the development of smart drug delivery systems (Left side) and pre-regulated nanoparticle recognizes the tumor cells not the healthy (right side). This therapeutic drug concentration reaches the tumor site not in the normal cells or tissues. Polymer base smart drug delivery can overcome the patient complaints in healthcare.

specific targeted delivery. For targeting brain delivery system the nanoparticles has been functionalized for specific or nonspecific binding mechanisms [303]. The fabrication and functionalization science has merged with software oriented technology for the development of controlled and targeted nanoparticle loaded micro-device system [304]. The recent trends in novel polymer and block co-polymer synthesis methods like radical polymerization and click chemistry has been provide well-desired multi functionality polymeric structures [305-312]. This is the potential method to fabricate the desired molecular weight polymer with well-defined characteristic features. This unique method of polymer synthesis gives the successful nano formulation for potential bio-application. The functionalized nanoparticles have been synthesized with potential biochemical moieties. Then these multi-functionalized nanoparticles have been examined for desired physicochemical property and biocompatibility.

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**Figure 8.** Schematic diagrams represent the various functionalizations of the nano-engines for smart drug delivery

**7. Recent developments, significant route of administration and targeting**

The route of administration of therapeutics is crucially important to cure the disease. Despite the invention of potential therapeutic moieties, the inefficient drug targeting by pills or injection on the appropriate site of the body limits therapeutics values to a larger extend. There

systems, which the pre-regulated nanoparticle recognizes the tumor cells not the healthy.

**strategies**

In polymeric based nano-composites fabrication, the nanoparticles is used as backbone to enhance the physiochemical characters [288-290] such as flexibility, smoothness, enough strength and stiffness, which are much essential in the field of tissue engineering and biomedical applications. The mechanical strength of polymer based nanocomposites is low due to the poor linkage between nanoparticles and the polymer, which leads to artificial defects in the composites [291-293]. It could be engineered with the appropriate interface to enhance the flexibility, smoothness, strength, stiffness and compatibility of the composite character [294]. The advanced functionalization of the nanocomposite have been prepared with suitable surface active agents, including anionic and non-ionic surfactants, it can lead to strong linkage between the nanoparticle and the polymer. The multi-functionalized nanocomposite enhances the physicochemical properties and no untoward effect on the biological system had been reported [295]. For the hydrophobic drug the phage display technique has been used for the functionalization [296], and the bioavailability have enhanced by post-polymerization. Additionally, the post-polymerization with copolymer produces efficient targeting in the extracellular compartment of the biological system [297-300]. With the nanoparticles the polymers like PEG establishes for prolonged systemic circulation [301, 302]. For the stimuli responsive targeted drug delivery has been achieved by the functionalization of suitable materials (light or magnetic or thermal or ionic responsive material). Particularly, the magnetic induction systems have been used with functionalized magnetic nanoparticles for cell or tissue specific targeted delivery. For targeting brain delivery system the nanoparticles has been functionalized for specific or nonspecific binding mechanisms [303]. The fabrication and functionalization science has merged with software oriented technology for the development of controlled and targeted nanoparticle loaded micro-device system [304]. The recent trends in novel polymer and block co-polymer synthesis methods like radical polymerization and click chemistry has been provide well-desired multi functionality polymeric structures [305-312]. This is the potential method to fabricate the desired molecular weight polymer with well-defined characteristic features. This unique method of polymer synthesis gives the successful nano formulation for potential bio-application. The functionalized nanoparticles have been synthesized with potential biochemical moieties. Then these multi-functionalized nanoparticles have been examined for desired physicochemical property and biocompatibility.

Functionalization is defined as the improving performance of nanoparticle by a chemical functional group on their surface. Some basic components of functionalized nanoparticle are enabling to increasing the multifunctional applications in the field of biomedicine; the basic components are diagnostic agent, targeting ligand, spacer group, therapeutic agents, and polymer nano-carrier with proper functionalization. Here we introducing two strategies for surface functionalization, first one is direct functionalization, where the functional ligand is a bi-functional compound. In this method, one of the reactive groups is used to bind to the nanoparticle surface and the second group contains the required active functionality. Another one is post-functionalization, here the strategy is not changeable and the nature of the functionalizing group cannot be compatible with good control over the size and dispersion of the nanoparticles in the solvent used for the fabrication. Commonly, the nano-carriers have been functionalized with various chemical functional groups such as thiols, disulfides, amines, nitriles, carboxylic acids, phosphines and bio-macromolecules [282-287], based on their application. The functionalization of nanoparticle is to modify their outer surface with other specific chemical agents based on the desired application. After functionalization the particle physiochemical character has been changed. Also, it is a very important step for control because it can change their size and self-organization during the formation and should not promote aggregation. The prepared polymeric nanoparticles have emerged promising technology platform for recognizing the target with navigated controlled drug delivery system. Figure 8 shows the various functionalizations of the nano-engines for the development of smart drug delivery systems (Left side) and pre-regulated nanoparticle recognizes the tumor cells not the healthy (right side). This therapeutic drug concentration reaches the tumor site not in the normal cells or tissues. Polymer base smart drug delivery can overcome the patient

In polymeric based nano-composites fabrication, the nanoparticles is used as backbone to enhance the physiochemical characters [288-290] such as flexibility, smoothness, enough strength and stiffness, which are much essential in the field of tissue engineering and biomedical applications. The mechanical strength of polymer based nanocomposites is low due to the poor linkage between nanoparticles and the polymer, which leads to artificial defects in the composites [291-293]. It could be engineered with the appropriate interface to enhance the flexibility, smoothness, strength, stiffness and compatibility of the composite character [294]. The advanced functionalization of the nanocomposite have been prepared with suitable surface active agents, including anionic and non-ionic surfactants, it can lead to strong linkage between the nanoparticle and the polymer. The multi-functionalized nanocomposite enhances the physicochemical properties and no untoward effect on the biological system had been reported [295]. For the hydrophobic drug the phage display technique has been used for the functionalization [296], and the bioavailability have enhanced by post-polymerization. Additionally, the post-polymerization with copolymer produces efficient targeting in the extracellular compartment of the biological system [297-300]. With the nanoparticles the polymers like PEG establishes for prolonged systemic circulation [301, 302]. For the stimuli responsive targeted drug delivery has been achieved by the functionalization of suitable materials (light or magnetic or thermal or ionic responsive material). Particularly, the magnetic induction systems have been used with functionalized magnetic nanoparticles for cell or tissue

complaints in healthcare.

280 Application of Nanotechnology in Drug Delivery

**Figure 8.** Schematic diagrams represent the various functionalizations of the nano-engines for smart drug delivery systems, which the pre-regulated nanoparticle recognizes the tumor cells not the healthy.
