**3. Modern methods for preparation of polymeric nanoparticles**

Recently, the polymeric nanoparticles have emerged as a most promising and viable technol‐ ogy platform for recognizing the targeted, environment-responsive and, multi-functional with navigated controlled drug delivery system. Polymer in smart drug delivery is a rapidemerging new technological discipline in which various therapeutic applications of nano products are expected to overcome the patient complaints in healthcare. Smart delivery will give new solutions for therapeutic interventions. There is great interest from the beginning in smart medicine of advanced and well-characterized bionanotechnological products that will be especially effective in fighting diseases like cardiovascular diseases [63], diabetes [64], cancer [65, 66], aging [67, 68], some chronic metabolic syndrome and various degenerative diseases and disorders [69, 70]. For example, the innovative smart polymers with nanoparticulate drug-delivery systems can obviously advances in therapeutics by guiding the drugs to target cells and reducing the adverse-effect/side-effect on well being. At present, some of the smart polymer with multi-functioned nanoparticle system approaches in clinical trials, and it shows promising outcome. Certainly the morbidity and mortality rate of disease affected patients could improve their lifestyle by the early course of smart therapeutic intervention. This smart intervention can be attained by developing high sensitivity and reliable smart drug delivery.

ous of delivery vehicles have been studied and reported recently, this chapter will cover same viewpoint and their brief discussion will be covered without attempting to all the work that has been done in this field. Various concepts are utilized in the design of delivery vehicles that are capable of ferrying multiple active ingredients in a self-controlled manner, with different release profile kinetics. The distinctive self-assembly of multifaceted nano‐ structures from an easy colloidal system has been of interest to design a material with distinctive characters for the use of drug delivery vehicles. The inter-and intra-molecular linkage via van der Waals interaction leads to dense-packed self-assembly periodic nanostructures. These structures could be colloidal particle or clusters, based on the assembly [84, 85]. The natural or semi-synthetic polymer-based self-assembled nanostruc‐ tures have inherent capacity of the nano-carrier for delivering many kinds of active ingredients, because of good biocompatibility and degradation/resorption properties [86]. In the sonication methods (Figure 2a), the self-assembled nanoparticle was achieved by probe sonication, the process has been done by cavitation, nucleation and reversible locking concept, the formed nanostructure have more flexibility in the nature [87]. In this selfassembled and core-shell particulate delivery systems, including water-soluble polymeric drug compounds conjugates [88], block polymeric micelles [89-93], long-circulating polymeric micelles [94, 95], nano encapsulations [96, 97], and core-shell nano-spheres [98, 99] have been synthesized by in situ two-step semi-batch emulsion polymerization technique (Figure 2b), as vehicle to target suitable dose of drugs in an accurate and controlled manner. Also the core-shell nano-spheres have been achieved for pH-respon‐ sive controlled release, and delivery of hydrophobic anticancer agents for acidic tumor tissues [100]. Recently Choi DH, et al have optimized electrodropping system to produce a homogeneous biocompatible core shell capsules for angiogenesis in dual delivery system [77], and they particularly focused on regenerative medicine. This electro-dropping system can overcome from the particle aggregation and drug encapsulation efficiency (Figure 2d). Coming to the micro-fluidics, the recent science and advanced technology of manipulat‐ ing micro/nano-scale volumes in micro-fluidic channels have significant impact on the various applications. Advances and inventions in micro-fluidics are awaited to enhance the preparation of polymer nanoparticles and shifting to clinical evaluation [101] most of the micro-fluidic systems for synthesis, polymer nanoparticles are still under development and they have the widest possible to develop because they are highly reproducible, easily modifiable and can be incorporated with other techniques [102]. Recently, various microfluidic systems provide rapid mixing without any stimulator, such as stirring or electric force; have been originated [103]. Among these various systems the flow-focusing [104], droplet mixers [105] are widely utilized and it enables micro-mixing within the micro channel [106]. The flow focusing squeezes the solvent stream between two anti-solvent streams, resulting in a rapid solvent exchange via diffusion take place (Figure 2c). The effectuation of these rapid mixing methods for the development of nanoparticles in continuous flow; the micro-fluidic system has been achieved the continuous flow, narrow sized, mono dispersed with high drug entrapment and better batch-to-batch uniformity in

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compared with conventional methods [107].

The rapid advancement in the above direction has been made with the initiation and development of more advanced alternative nanofabrication techniques to produce struc‐ tures in various nano-scales level of controlled manners. Drug loaded polymeric nanosystems can provide controlled release of both hydrophilic and hydrophobic drugs over a long period of time while minimizing unwanted side effects in the body. This involves the synthesis of various novel biocompatible polymers with well-defined nanometers to a few micro-meters structures using several modern techniques such as microelectromechanical systems [71] microfluidic systems [72-76], electrodropping system [77], microneedle based system [78-81], advanced high pressure homogenization, interfacial emulsion polymeriza‐ tion and combined systems. Figure 2 described the few modern techniques for polymeric nanoparticles preparation with various concepts. The physiochemical characters of polymeric nanoparticles have to be optimized based on the specific application. Various methods can be used to produce various nano-particulate systems with various polymers. The multifunctional polymeric nanoparticles developments such as environment-respon‐ sive micelles, colloids, nano hydrogel, core-shell nanoparticles, nano-spheres and coreshell nano-spheres with layer-by-layer assembly for single/dual or multi drug release have been achieved so far. In order to get the desired properties, the mechanism of formula‐ tion method plays a vital role. Thus, it is extremely beneficial to have synthesis mecha‐ nism at hand to approach multi-functional polymeric nanoparticles with exact physiochemical properties for a specific application.

**Figure 2.** Schematic diagrams represent the advanced techniques of preparation of polymeric nanoparticles

The smart delivery systems of target bio-molecules have been concentrated of recent researches for various interventions. Particularly, various proteins, peptide, growth factors and cytokine therapy for various diseases play a vital role in regulating cellular respons‐ es, and thus the design of multi-functional polymeric particles delivery vehicles are closely associated with the regulation of multiple cellular events, likewise a wide variety of target bio-molecules have been investigated in numerous literature reports [82, 83]. Also numer‐

ous of delivery vehicles have been studied and reported recently, this chapter will cover same viewpoint and their brief discussion will be covered without attempting to all the work that has been done in this field. Various concepts are utilized in the design of delivery vehicles that are capable of ferrying multiple active ingredients in a self-controlled manner, with different release profile kinetics. The distinctive self-assembly of multifaceted nano‐ structures from an easy colloidal system has been of interest to design a material with distinctive characters for the use of drug delivery vehicles. The inter-and intra-molecular linkage via van der Waals interaction leads to dense-packed self-assembly periodic nanostructures. These structures could be colloidal particle or clusters, based on the assembly [84, 85]. The natural or semi-synthetic polymer-based self-assembled nanostruc‐ tures have inherent capacity of the nano-carrier for delivering many kinds of active ingredients, because of good biocompatibility and degradation/resorption properties [86]. In the sonication methods (Figure 2a), the self-assembled nanoparticle was achieved by probe sonication, the process has been done by cavitation, nucleation and reversible locking concept, the formed nanostructure have more flexibility in the nature [87]. In this selfassembled and core-shell particulate delivery systems, including water-soluble polymeric drug compounds conjugates [88], block polymeric micelles [89-93], long-circulating polymeric micelles [94, 95], nano encapsulations [96, 97], and core-shell nano-spheres [98, 99] have been synthesized by in situ two-step semi-batch emulsion polymerization technique (Figure 2b), as vehicle to target suitable dose of drugs in an accurate and controlled manner. Also the core-shell nano-spheres have been achieved for pH-respon‐ sive controlled release, and delivery of hydrophobic anticancer agents for acidic tumor tissues [100]. Recently Choi DH, et al have optimized electrodropping system to produce a homogeneous biocompatible core shell capsules for angiogenesis in dual delivery system [77], and they particularly focused on regenerative medicine. This electro-dropping system can overcome from the particle aggregation and drug encapsulation efficiency (Figure 2d). Coming to the micro-fluidics, the recent science and advanced technology of manipulat‐ ing micro/nano-scale volumes in micro-fluidic channels have significant impact on the various applications. Advances and inventions in micro-fluidics are awaited to enhance the preparation of polymer nanoparticles and shifting to clinical evaluation [101] most of the micro-fluidic systems for synthesis, polymer nanoparticles are still under development and they have the widest possible to develop because they are highly reproducible, easily modifiable and can be incorporated with other techniques [102]. Recently, various microfluidic systems provide rapid mixing without any stimulator, such as stirring or electric force; have been originated [103]. Among these various systems the flow-focusing [104], droplet mixers [105] are widely utilized and it enables micro-mixing within the micro channel [106]. The flow focusing squeezes the solvent stream between two anti-solvent streams, resulting in a rapid solvent exchange via diffusion take place (Figure 2c). The effectuation of these rapid mixing methods for the development of nanoparticles in continuous flow; the micro-fluidic system has been achieved the continuous flow, narrow sized, mono dispersed with high drug entrapment and better batch-to-batch uniformity in compared with conventional methods [107].

patients could improve their lifestyle by the early course of smart therapeutic intervention. This smart intervention can be attained by developing high sensitivity and reliable smart drug

The rapid advancement in the above direction has been made with the initiation and development of more advanced alternative nanofabrication techniques to produce struc‐ tures in various nano-scales level of controlled manners. Drug loaded polymeric nanosystems can provide controlled release of both hydrophilic and hydrophobic drugs over a long period of time while minimizing unwanted side effects in the body. This involves the synthesis of various novel biocompatible polymers with well-defined nanometers to a few micro-meters structures using several modern techniques such as microelectromechanical systems [71] microfluidic systems [72-76], electrodropping system [77], microneedle based system [78-81], advanced high pressure homogenization, interfacial emulsion polymeriza‐ tion and combined systems. Figure 2 described the few modern techniques for polymeric nanoparticles preparation with various concepts. The physiochemical characters of polymeric nanoparticles have to be optimized based on the specific application. Various methods can be used to produce various nano-particulate systems with various polymers. The multifunctional polymeric nanoparticles developments such as environment-respon‐ sive micelles, colloids, nano hydrogel, core-shell nanoparticles, nano-spheres and coreshell nano-spheres with layer-by-layer assembly for single/dual or multi drug release have been achieved so far. In order to get the desired properties, the mechanism of formula‐ tion method plays a vital role. Thus, it is extremely beneficial to have synthesis mecha‐ nism at hand to approach multi-functional polymeric nanoparticles with exact

physiochemical properties for a specific application.

**Figure 2.** Schematic diagrams represent the advanced techniques of preparation of polymeric nanoparticles

The smart delivery systems of target bio-molecules have been concentrated of recent researches for various interventions. Particularly, various proteins, peptide, growth factors and cytokine therapy for various diseases play a vital role in regulating cellular respons‐ es, and thus the design of multi-functional polymeric particles delivery vehicles are closely associated with the regulation of multiple cellular events, likewise a wide variety of target bio-molecules have been investigated in numerous literature reports [82, 83]. Also numer‐

delivery.

262 Application of Nanotechnology in Drug Delivery

## **4. Controlled drug delivery systems**

#### **4.1. Rate-programmed drug delivery systems**

The recent advances in smart drug delivery systems with rate-programmed drug delivery systems have been achieved by functionalization of rate-controlling surface. The transder‐ mal drug delivery have been achieved a new rate pre-programmed drug delivery system, transdermal patch which delivers a particular concentration of drugs to the blood circula‐ tion via the skin, it provides the therapeutic advantage to clinical levels. The rate-program‐ med drug delivery systems, the release of drug molecules from the rate controlling membrane system has been pre-programmed at particular rate kinetics. The rate control‐ ling membranes made from natural and semi-synthetic polymeric material and proves their ability to use as a rate controlling membranes in any dosage form even nano to microscale level particle embedded matrixes or implantable or transdermal patches. It must be simple, cost-effective, and flexible enough not to split or crack on bending or stretching. Recently, some of novel rate-controlling composite membranes have been developed as rate controlling barriers for transdermal application, with flexible and smooth surface nanopar‐ ticles embedded scaffold which could reduce the risk of wounding or being rubbed off during dressing, and thereby improves upon traditional dressings and its can provides better patient compliance [108, 109]. This is achieved by optimized system design, which determines the diffusivity of active agents across the membrane. This rate-programmed drug delivery system can be categorized by various controlling dependencies, such as (1): membrane permeation-controlled, (2): diffusion-controlled, (3): membrane/matrix hybridtype and (4): reservoir partition-controlled systems. The recent advance in the smart rateprogrammed drug delivery systems the polymer and their scaffolds play vital roles, such as greater drug-loaded nano/micro-particle encapsulation ability, overcome pre-systemic metabolism, enhanced bioavailability and environmental responsive properties for vari‐ ous applications. For selecting the polymers, need to consider some important key factors for pharmaceutical application such as reduced tensile strength [110], water vapor perme‐ ability rate, biocompatibility, non-toxic [111], anti-infective, controlled release [112, 113], flexibility, emollient, adhesion, spreadability and retention properties of the drug-loaded nano/micro-particle encapsulation scaffold or film preparation [114-116]. So it can prevent the immunogenesis, secondary damage to cells, disease recurrence and finally enhance patient compliance [117]. In this type of rate-programmed controlled drug delivery systems, a drug-loaded nano formulation or rate-controlled nano formulation can be either totally or partially loaded in the reservoir space whose surface is covered by the rate pre-program‐ med polymeric membrane. The pre-programmed polymeric membrane can be optimized and achieved by multi-functionalization with block copolymers. The scaffold or mem‐ brane can be produced by the homogeneous or heterogeneous non-porous polymeric compounds or a micro/nano-porous or semi-permeable material. The drug release profile should be at a constant pre-fixed rate. The release profile is controlled by a pre-program‐ med rate-controlling membrane; it's based on the molecules, diffusivity, partition coefficient, and dimension of the outer membrane. Also the rate of release is determined by the cross-linking ratio of the polymer network. The rate controlled release profile exists in many kind therapeutic formulations such as intrauterine devices [118], ocular insert [119, 120], some transdermal therapeutic system [109], polymer matrix, sub-dermal [121] and

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**Figure 3.** Schematic diagrams represent the rate controlled drug delivery systems of topical applications

The smart drug delivery with activation-modulated system has been achieved by external or environmental stimuli, these environmental responsive smart delivery systems achieved a lot more with double and multiple-responsive delivery system. The various activation/stimuli responsive drug delivery vehicles have been synthesized and tested, in various particle sizes, ranges from nanometers to a few micro-meters sized carriers for different routes of adminis‐ tration. The transdermal electro-activated or electro-modulated drug delivery has been established as an efficient model. In this group of activation-modulated controlled drug

*4.2.1. Environmental activation/stimuli responsive smart delivery system*

subcutaneous implantation [122-125].

**4.2. Activation-modulated drug delivery**

the cross-linking ratio of the polymer network. The rate controlled release profile exists in many kind therapeutic formulations such as intrauterine devices [118], ocular insert [119, 120], some transdermal therapeutic system [109], polymer matrix, sub-dermal [121] and subcutaneous implantation [122-125].

**Figure 3.** Schematic diagrams represent the rate controlled drug delivery systems of topical applications

#### **4.2. Activation-modulated drug delivery**

**4. Controlled drug delivery systems**

264 Application of Nanotechnology in Drug Delivery

**4.1. Rate-programmed drug delivery systems**

The recent advances in smart drug delivery systems with rate-programmed drug delivery systems have been achieved by functionalization of rate-controlling surface. The transder‐ mal drug delivery have been achieved a new rate pre-programmed drug delivery system, transdermal patch which delivers a particular concentration of drugs to the blood circula‐ tion via the skin, it provides the therapeutic advantage to clinical levels. The rate-program‐ med drug delivery systems, the release of drug molecules from the rate controlling membrane system has been pre-programmed at particular rate kinetics. The rate control‐ ling membranes made from natural and semi-synthetic polymeric material and proves their ability to use as a rate controlling membranes in any dosage form even nano to microscale level particle embedded matrixes or implantable or transdermal patches. It must be simple, cost-effective, and flexible enough not to split or crack on bending or stretching. Recently, some of novel rate-controlling composite membranes have been developed as rate controlling barriers for transdermal application, with flexible and smooth surface nanopar‐ ticles embedded scaffold which could reduce the risk of wounding or being rubbed off during dressing, and thereby improves upon traditional dressings and its can provides better patient compliance [108, 109]. This is achieved by optimized system design, which determines the diffusivity of active agents across the membrane. This rate-programmed drug delivery system can be categorized by various controlling dependencies, such as (1): membrane permeation-controlled, (2): diffusion-controlled, (3): membrane/matrix hybridtype and (4): reservoir partition-controlled systems. The recent advance in the smart rateprogrammed drug delivery systems the polymer and their scaffolds play vital roles, such as greater drug-loaded nano/micro-particle encapsulation ability, overcome pre-systemic metabolism, enhanced bioavailability and environmental responsive properties for vari‐ ous applications. For selecting the polymers, need to consider some important key factors for pharmaceutical application such as reduced tensile strength [110], water vapor perme‐ ability rate, biocompatibility, non-toxic [111], anti-infective, controlled release [112, 113], flexibility, emollient, adhesion, spreadability and retention properties of the drug-loaded nano/micro-particle encapsulation scaffold or film preparation [114-116]. So it can prevent the immunogenesis, secondary damage to cells, disease recurrence and finally enhance patient compliance [117]. In this type of rate-programmed controlled drug delivery systems, a drug-loaded nano formulation or rate-controlled nano formulation can be either totally or partially loaded in the reservoir space whose surface is covered by the rate pre-program‐ med polymeric membrane. The pre-programmed polymeric membrane can be optimized and achieved by multi-functionalization with block copolymers. The scaffold or mem‐ brane can be produced by the homogeneous or heterogeneous non-porous polymeric compounds or a micro/nano-porous or semi-permeable material. The drug release profile should be at a constant pre-fixed rate. The release profile is controlled by a pre-program‐ med rate-controlling membrane; it's based on the molecules, diffusivity, partition coefficient, and dimension of the outer membrane. Also the rate of release is determined by

#### *4.2.1. Environmental activation/stimuli responsive smart delivery system*

The smart drug delivery with activation-modulated system has been achieved by external or environmental stimuli, these environmental responsive smart delivery systems achieved a lot more with double and multiple-responsive delivery system. The various activation/stimuli responsive drug delivery vehicles have been synthesized and tested, in various particle sizes, ranges from nanometers to a few micro-meters sized carriers for different routes of adminis‐ tration. The transdermal electro-activated or electro-modulated drug delivery has been established as an efficient model. In this group of activation-modulated controlled drug delivery system, the release of active agents from the systems is activated by some physical, chemical, electrical, environmental condition or biochemical processes and/or facilitated by an energy supplied externally. The release profile has been controlled by the input energy. Based on the activation/stimulation process applied or energy type used, this activation-modulated controlled drug delivery system can be categorized into the various classes which are given in the Table 1. These stimuli-responsive materials show changes in the physicochemical character during the environmental condition changes. These changing properties can be fully utilized in smart delivery system, which certainly similar to the biological response behavior. Different types of body organs, different tissues and various types of cellular compartments might have great differences in every stimulus with great response. So that all the important cases considered in this chapter, deal with various environmental responsive smart delivery systems. Any specific behavioral changes in the system lead to a phase transition, these transitions will be key factors for the stimuli-responsive drug delivery system and some selected examples of applications are described in the Figure 4. The preclinical and clinical studies have demonstrated that drug-loaded polymeric nanoparticles has been well tolerated, extended systemic circulation, higher accumulation in the tumor sites through enhanced permeability and retention effect, minimized side effects and adverse effect, and/or higher bioavailability [153-155]. And most of the drug delivery systems are based on biodegradable polymer [156, 157]. Most of the environment-sensitive polymeric nano-particulate systems are leading to degradation and or disintegration by the internal or external local environmental stimulus such as pH, glucose, low oxygen content, ions, redox potential, and lysosomal enzymes; and then temperature, magnetic field, electric, ultrasound, and light respectively (Table 1).

sive release [169, 170]. Magnetically guided nano-carriers have been developed for the remote

controlled cancer therapy and diagnosis [171, 172]; also the core-shell nanoparticles have

demonstrated for improved tumor accumulation and antitumor therapeutic efficacy in various

**Based on Stimulus Mode Ref.**

Generate hydrodynamic pressure gradient

Creates vapor pressure, vaporizes at body temperature

Sonophoresis Utilizes ultrasonic energy to activate the delivery [132] Iontophoresis Electrical current to activate and diffuse the charged drug [133]

Deliver the drug in the ulcer stomach by floating delivery

Controlling the delivery of an ionic or an ionisable drug

Hydrolysis Hydrolysis-induced degradation of polymer chains Hydrolysis activate

Deliver the drug by enzymatic hydrolysis of polymers

Feedback-regulated delivery concept has been applied

Reversible phase separations through photo-irradiation

Shifting the hydrophilic/hydrophobic balance

Light Polymers undergo isothermal phase transitions by photon

Activated by hydration-induced swelling delivery

Electrically erodible matrix for delivery

pH Deliver the drug in the intestinal tract not in the stomach

Salt concentration Prepared by ionizable drug with ion-exchange resin

Enzyme Polymer chains fabricated with biopolymers

Biochemical Enzymatic-activated, biodegradation

Temperature Depends on the transition temperature

Equipped with a mechanically activated pump

Controlled through a gradient of osmotic pressure [126]

Forces the drug to release through the orifice [127]

First-pass elimination and pressure-sensitive delivery [130]

Magnetically activated, vibrate by an electromagnetic field [131]

the release of drug molecules [139]

[128] [129]

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[128] [126]

[134] [135]

[136] [137]

[128] [138]

[140] [141]

[142] [143]

[144] [145]

[146] [147]

Osmotic pressure Controlled through the permeability of water

Vapor pressure Pumping system contains vaporizable fluid

Hydration Utilized swellable polymer matrix

Electricity Electric-sensitive capsule

Magnetics Electromagnetism-triggering vibration mechanism

models.

Physical stimuli

Chemical stimuli

Biochemical stimuli

Environmental stimuli

Hydrodynamic pressure

A mechanical force

These activations grew to achieve smart, targeted drug release in a particular time (spatial and temporal control release) [158-160]. At this place we describe a few examples. Particularly, the acidic pH levels in the body vary according to the different body environments (site and the organ) such as tumor cells and tissues (pH 6.5-7.2), endosomes (pH 5.0-6.5), lysosomes (pH 4.5-5.0) and entire GI tract with different pH value as comparatively varied with normal physiological (pH of 7.4) conditions in blood and tissues. So, the pH-responsive nano system have been considered and formulated to release the active agents in pH sensitive targets such as cancer site or endo/lysosomal regions [161,162]. The cytosol and cell nuclei have surrounded with elevated redox potential (in reducing glutathione) it higher than normal body fluids and it have been developed for intracellular release of various active bio-molecules [163-165]. Additionally, the cancerous tissues are extremely low in oxygen content (hypoxia) with higher glutathione levels compared to normal tissues [166]. This has been targeted with hypoxiaresponsive polymeric nanoparticles. These internal stimuli-responsive nanoparticles have their own benefit of self-regulated drug delivery and effective target in clinical therapeutics. Also the external activated nanoparticles provide their own advantages such as high repro‐ ducible nature, also remote controlled delivery possible, then the release profile can be pulsatile delivered (means that switched on and off) possible [167]. On the other hand, the various light-responsive polymeric nanoparticles system has been developed for activating antitumor drug release [168]. Also numerous of temperature-sensitive multi-functionalized polymeric and copolymers nanoparticles have been formulated based on thermally-respon‐ sive release [169, 170]. Magnetically guided nano-carriers have been developed for the remote controlled cancer therapy and diagnosis [171, 172]; also the core-shell nanoparticles have demonstrated for improved tumor accumulation and antitumor therapeutic efficacy in various models.

delivery system, the release of active agents from the systems is activated by some physical, chemical, electrical, environmental condition or biochemical processes and/or facilitated by an energy supplied externally. The release profile has been controlled by the input energy. Based on the activation/stimulation process applied or energy type used, this activation-modulated controlled drug delivery system can be categorized into the various classes which are given in the Table 1. These stimuli-responsive materials show changes in the physicochemical character during the environmental condition changes. These changing properties can be fully utilized in smart delivery system, which certainly similar to the biological response behavior. Different types of body organs, different tissues and various types of cellular compartments might have great differences in every stimulus with great response. So that all the important cases considered in this chapter, deal with various environmental responsive smart delivery systems. Any specific behavioral changes in the system lead to a phase transition, these transitions will be key factors for the stimuli-responsive drug delivery system and some selected examples of applications are described in the Figure 4. The preclinical and clinical studies have demonstrated that drug-loaded polymeric nanoparticles has been well tolerated, extended systemic circulation, higher accumulation in the tumor sites through enhanced permeability and retention effect, minimized side effects and adverse effect, and/or higher bioavailability [153-155]. And most of the drug delivery systems are based on biodegradable polymer [156, 157]. Most of the environment-sensitive polymeric nano-particulate systems are leading to degradation and or disintegration by the internal or external local environmental stimulus such as pH, glucose, low oxygen content, ions, redox potential, and lysosomal enzymes; and then temperature, magnetic field, electric, ultrasound, and light respectively

These activations grew to achieve smart, targeted drug release in a particular time (spatial and temporal control release) [158-160]. At this place we describe a few examples. Particularly, the acidic pH levels in the body vary according to the different body environments (site and the organ) such as tumor cells and tissues (pH 6.5-7.2), endosomes (pH 5.0-6.5), lysosomes (pH 4.5-5.0) and entire GI tract with different pH value as comparatively varied with normal physiological (pH of 7.4) conditions in blood and tissues. So, the pH-responsive nano system have been considered and formulated to release the active agents in pH sensitive targets such as cancer site or endo/lysosomal regions [161,162]. The cytosol and cell nuclei have surrounded with elevated redox potential (in reducing glutathione) it higher than normal body fluids and it have been developed for intracellular release of various active bio-molecules [163-165]. Additionally, the cancerous tissues are extremely low in oxygen content (hypoxia) with higher glutathione levels compared to normal tissues [166]. This has been targeted with hypoxiaresponsive polymeric nanoparticles. These internal stimuli-responsive nanoparticles have their own benefit of self-regulated drug delivery and effective target in clinical therapeutics. Also the external activated nanoparticles provide their own advantages such as high repro‐ ducible nature, also remote controlled delivery possible, then the release profile can be pulsatile delivered (means that switched on and off) possible [167]. On the other hand, the various light-responsive polymeric nanoparticles system has been developed for activating antitumor drug release [168]. Also numerous of temperature-sensitive multi-functionalized polymeric and copolymers nanoparticles have been formulated based on thermally-respon‐

(Table 1).

266 Application of Nanotechnology in Drug Delivery



*4.2.2. Dual and multi-stimuli responsive smart delivery system*

environment the drug release was taken place [175].

*4.2.3. Considerations for stimuli responsive targeted molecular systems*

In this chapter, provide the recent proposes and formulations of dual and multiple-stimuli responsive multi-functionalized polymeric nanoparticles and their promising targets in smart drug delivery in specific to the cancer therapy. With the booster development of the smart drug release and increase therapeutic efficiency of intelligent drug loaded nano-particulate system, polymeric nanoparticles that respond to dual and multi-stimuli, which have been aggressively reported. The double-response and multiple-responsive nano-particulate systems were described in the Table 2. It must be mentioned that the stimuli and responses happened at the same time at the same site or different mode. These dual and multi-stimuli responsive polymeric nanoparticles can provide control over the drug release profile, which leads to greater anti-tumor efficiency in vitro and in vivo models, and on the other side the nanoparticle formulation and drug loading under moderate conditions. In this section we describe a few examples. Especially, redox-responsive drug release multi-functionalized nanoparticulate system have been formulated based on temperature and reduction, dual responsive tri-block copolymers functionalized by increasing temperature above the lower critical solution temperature after that cross-linking [173, 174]. These multi-functionalized nanoparticulate systems were targeted to cancer cells and triggered by reduction oxidation mechanism, which leads to dissociate to release the active agents by de-crosslinking followed by disruption and degradation of nano-particulate system. pH/redox dual-stimuli multifunctionalized disulfide cross-linked micelles have been developed for increased drug release and accumulation in the cancer target, due to endo/lysosomal pH and intracellular redox

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These multi-functional polymeric nanoparticles are capable to face the current problems of nanoparticle drug formulations including formulation and drug encapsulation, prolong stability, cellular internalization, site-targetability, enhanced cellular uptake, and inside cell target and drug release. These dual and multiple-activation responsive characteristics have provided novel and enthusiastic power over drug release kinetics and greater efficiency. All the described studies in dual and multiple-stimuli responsive drug delivery systems are mostly trial and error models, because most them non-biodegradable carriers, low encapsulation, and nonviable to clinical therapeutics. To overcome all the unfavorable conditions, immediate efforts could be focussed to improvement of dual and multiple-stimuli responsive biocom‐ patible, biodegradable, non-toxic, and non-immunogenic smart polymeric nanoparticles that could effectively entrap and sustain the drug release in the systemic circulation, enhanced accumulation in the cancer target, and efficient release kinetics in response to more efficient external or internal stimuli. Moreover the smart polymeric nanoparticle system does not produce any secondary damage and any harmful to the healthy cells. In the case of clinical studies on dual and multiple stimuli responsive system shall be performed to obtain a real mechanism of action in anti-cancer target. In addition, the multi-functionalized smart poly‐ meric nanoparticles system construct with targeting ligands and shall be incorporated into dual/multiple stimuli responsive nanoparticles to be achieved multidrug resistant cancers by

**Table 1.** Overview of various stimuli responsive nano-carriers for smart drug delivery systems with mode of drug release applications

**Figure 4.** Schematic diagrams represent the activation-modulated drug delivery systems, which the polymeric nano‐ particle activated by various stimuli such as physical, chemical, biochemical, environment, and/or a combination of two or more.

#### *4.2.2. Dual and multi-stimuli responsive smart delivery system*

**Based on Stimulus Mode Ref.**

Micelles are reported pH and thermo-responsive

hypoxic conditions

Based on the polymer architecture

temperature/pH-responsive core

**Table 1.** Overview of various stimuli responsive nano-carriers for smart drug delivery systems with mode of drug

**Figure 4.** Schematic diagrams represent the activation-modulated drug delivery systems, which the polymeric nano‐ particle activated by various stimuli such as physical, chemical, biochemical, environment, and/or a combination of

Hydrophobically modified imidazole derivative was conjugated to the carboxymethyl dextran, it can release the hydrophobic agents under

Functionalization of pyrene-quaternized segments form a lightresponsive shell and the unquaternized segments form a

[148]

[149] [150]

[151] [152]

Hypoxia

268 Application of Nanotechnology in Drug Delivery

Two different responses

More than two responses

Dual-stimuli

Multi-stimuli

release applications

two or more.

In this chapter, provide the recent proposes and formulations of dual and multiple-stimuli responsive multi-functionalized polymeric nanoparticles and their promising targets in smart drug delivery in specific to the cancer therapy. With the booster development of the smart drug release and increase therapeutic efficiency of intelligent drug loaded nano-particulate system, polymeric nanoparticles that respond to dual and multi-stimuli, which have been aggressively reported. The double-response and multiple-responsive nano-particulate systems were described in the Table 2. It must be mentioned that the stimuli and responses happened at the same time at the same site or different mode. These dual and multi-stimuli responsive polymeric nanoparticles can provide control over the drug release profile, which leads to greater anti-tumor efficiency in vitro and in vivo models, and on the other side the nanoparticle formulation and drug loading under moderate conditions. In this section we describe a few examples. Especially, redox-responsive drug release multi-functionalized nanoparticulate system have been formulated based on temperature and reduction, dual responsive tri-block copolymers functionalized by increasing temperature above the lower critical solution temperature after that cross-linking [173, 174]. These multi-functionalized nanoparticulate systems were targeted to cancer cells and triggered by reduction oxidation mechanism, which leads to dissociate to release the active agents by de-crosslinking followed by disruption and degradation of nano-particulate system. pH/redox dual-stimuli multifunctionalized disulfide cross-linked micelles have been developed for increased drug release and accumulation in the cancer target, due to endo/lysosomal pH and intracellular redox environment the drug release was taken place [175].

#### *4.2.3. Considerations for stimuli responsive targeted molecular systems*

These multi-functional polymeric nanoparticles are capable to face the current problems of nanoparticle drug formulations including formulation and drug encapsulation, prolong stability, cellular internalization, site-targetability, enhanced cellular uptake, and inside cell target and drug release. These dual and multiple-activation responsive characteristics have provided novel and enthusiastic power over drug release kinetics and greater efficiency. All the described studies in dual and multiple-stimuli responsive drug delivery systems are mostly trial and error models, because most them non-biodegradable carriers, low encapsulation, and nonviable to clinical therapeutics. To overcome all the unfavorable conditions, immediate efforts could be focussed to improvement of dual and multiple-stimuli responsive biocom‐ patible, biodegradable, non-toxic, and non-immunogenic smart polymeric nanoparticles that could effectively entrap and sustain the drug release in the systemic circulation, enhanced accumulation in the cancer target, and efficient release kinetics in response to more efficient external or internal stimuli. Moreover the smart polymeric nanoparticle system does not produce any secondary damage and any harmful to the healthy cells. In the case of clinical studies on dual and multiple stimuli responsive system shall be performed to obtain a real mechanism of action in anti-cancer target. In addition, the multi-functionalized smart poly‐ meric nanoparticles system construct with targeting ligands and shall be incorporated into dual/multiple stimuli responsive nanoparticles to be achieved multidrug resistant cancers by site targeting, site-specific, and rapid/sustained release, and we sure that dual and multiple stimuli responsive smart nano-particulate system going to be a good future in cancer therapy. **4.3. Feedback-regulated drug delivery**

responsive polymers.

The recent advances in smart delivery systems with feedback-regulation of drug release. This self-regulated or feedback-controlled drug delivery comes under closed-loop systems. The self-regulated system drug release rate is controlled by feedback information, without any external stimulation, and utilized several approaches to control the release rate [202-205]. The feedback-regulated drug delivery concepts were schematically depicted in Figure 5. The feedback-regulated drug delivery concept has been applied to the development of various controlled delivery systems such as bio-erosion regulated, bio-responsive regulated and selfregulating drug delivery systems. Among this one of the concepts has been involved in the smart controlled delivery systems. For that various research efforts are also in progress to develop such nanoparticles that contain drugs capable of a feedback-modulated drug release. The drug release is activated by a triggering agent, such as a biochemical substance, in the body via some feedback mechanisms. The release rate has been determined by triggering agent concentration. When the triggering agent is above a certain level, the release is activated. This can induce and stop the drug release. It would be a high potential benefits if they were delivered by a system that recognized the particular warning signal caused by disease affected part, then they estimated the magnitude ratio of the signal, and then acted to release the exact quantity of active drugs in response. This kind of drug delivery system required to fulfil the physiological need by means of some feedback mechanism. The self-regulated drug delivery systems utilize several approaches for the rate-control release: pH-responsive polymers, temperature-responsive polymers, enzyme-substrate reactions, antibody interactions, en‐ zyme-mediated, pH-dependent drug solubility nature, competitive binding mechanism and metal concentration-dependent hydrolysis. A hydrogel can swell in aqueous medium and retain their structure. The multi-functionalized polymer nanoparticle can be incorporated into hydrogel, such hydrogel used for the feedback-regulated drug delivery system. This hydrogels can protect the drug from dangerous environments such as enzymes and low pH in the stomach. This can control drug release through changing the network structure in response to particular stimuli, which can enable the sensor leads to reversible volume phase transitions upon small changes in the environment condition. For example, the polymers characterized by lower critical solution temperatures generally shrink, as the temperature is increased via lower critical solution temperature. Decreasing the temperature below lower critical solution temperature, the polymer can swell. Biomolecules can be encapsulated on or within the heat

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The sensor grafted in the delivery system can enable to mimic the recognition function of various bio-chemicals such as enzymes, cell mediated receptors and various proteins in human beings for maintaining the regulation and equilibrium. This approach is utilized for drug incorporated polymeric feedback controlled delivery systems, and this system approach is based on the observation that changes in control mechanisms, e.g.: pH or ionic strength or temperatures can affect large changes in drug solubility; this can be the main factor for control release rate. The external trigger molecule and polymer-bound enzyme can alter the pH inside the polymeric system. If the pH alteration happened inside the polymer system that can lead to changes in drug solubility, which is induces the diffusion or dissolution or disintegration,


**Table 2.** Overview of dual and multi-stimuli responsive materials for nano-carriers of various smart drug delivery systems

#### **4.3. Feedback-regulated drug delivery**

site targeting, site-specific, and rapid/sustained release, and we sure that dual and multiple stimuli responsive smart nano-particulate system going to be a good future in cancer therapy.

**Responses Stimulus Nanoparticles Ref.**

PEG-SS-PDEA polymersomes DS-g-PEG/cRGD nanoparticles Poly(b-amino ester)s-PEG micelles

mPEG-PAsp(MEA)-PAsp(DIP) micelles

Fe3O4 nanocarrier with peptide mimic polymers DOX-tethered Fe3O4 conjugates nanoparticles mPEG-b-PMAA-b-PGMA-Fe3O4 nanoparticles

T & redox EO-PAA-PNIPAAm polymersomes [190]

PMAA-based nanogels

Fe3O4-capped MSNs

Double pH PPC-Hyd-DOX-DA nanoparticles

MCM-TAA-Fe3O4-capped MSNs

Poly-b-amino ester ketal nanoparticles

pH & diols PEG-b-dendritic cholic acid telodendrimers nano-carriers containing

T & magnetic Pluronic with Fe3O4 nanoparticles [195] T & enzyme DNA-capped MSNs [196]

T/pH/redox PNIPAAm-SS-P(THP-protected HEMA) micelles [197] T/pH/magnetic P(NIPAAm-co-MAA) coated magnetic MSNs [198]

Light/pH/T Pyrene-functionalized poly (dimethylaminoethyl methacrylate)

**Table 2.** Overview of dual and multi-stimuli responsive materials for nano-carriers of various smart drug delivery

Fe(II) loaded PMAA crosslinked by N,N-methylene-bisacrylamide and N,N-bis(acryloyl)- cystamine [199]

Vesicles based on hosteguest complex formation between C4AS and MVC12 [200]

Cucurbit(8)uril micelles, methylviologene-functionalize PNIPAAm and naphthalene-terminated PDMAEMA [201]

boronic acid [194]

P(NIPAAm-co-DMAAm-co-UA) nanoparticles P(NIPAAm-co-AA)-b-PCL nanoparticles PLA-g-P(NIPAAm-co-MAA) nanoparticles P(NIPAAm-co-DMAAm)-b-PCL/PLA micelles PNIPAAm and PAA hollow nanogels

[176] [177] [178] [179] [180]

[181] [182] [183] [184] [185]

[186] [187] [188] [189]

[191]

[192] [193]

Dual-stimuli

Multi- stimuli

systems

pH & Thermo

270 Application of Nanotechnology in Drug Delivery

pH & redox

pH & magnetic

pH/redox/ magnetic

T/redox/guest molecule

T/pH/guest molecule

The recent advances in smart delivery systems with feedback-regulation of drug release. This self-regulated or feedback-controlled drug delivery comes under closed-loop systems. The self-regulated system drug release rate is controlled by feedback information, without any external stimulation, and utilized several approaches to control the release rate [202-205]. The feedback-regulated drug delivery concepts were schematically depicted in Figure 5. The feedback-regulated drug delivery concept has been applied to the development of various controlled delivery systems such as bio-erosion regulated, bio-responsive regulated and selfregulating drug delivery systems. Among this one of the concepts has been involved in the smart controlled delivery systems. For that various research efforts are also in progress to develop such nanoparticles that contain drugs capable of a feedback-modulated drug release. The drug release is activated by a triggering agent, such as a biochemical substance, in the body via some feedback mechanisms. The release rate has been determined by triggering agent concentration. When the triggering agent is above a certain level, the release is activated. This can induce and stop the drug release. It would be a high potential benefits if they were delivered by a system that recognized the particular warning signal caused by disease affected part, then they estimated the magnitude ratio of the signal, and then acted to release the exact quantity of active drugs in response. This kind of drug delivery system required to fulfil the physiological need by means of some feedback mechanism. The self-regulated drug delivery systems utilize several approaches for the rate-control release: pH-responsive polymers, temperature-responsive polymers, enzyme-substrate reactions, antibody interactions, en‐ zyme-mediated, pH-dependent drug solubility nature, competitive binding mechanism and metal concentration-dependent hydrolysis. A hydrogel can swell in aqueous medium and retain their structure. The multi-functionalized polymer nanoparticle can be incorporated into hydrogel, such hydrogel used for the feedback-regulated drug delivery system. This hydrogels can protect the drug from dangerous environments such as enzymes and low pH in the stomach. This can control drug release through changing the network structure in response to particular stimuli, which can enable the sensor leads to reversible volume phase transitions upon small changes in the environment condition. For example, the polymers characterized by lower critical solution temperatures generally shrink, as the temperature is increased via lower critical solution temperature. Decreasing the temperature below lower critical solution temperature, the polymer can swell. Biomolecules can be encapsulated on or within the heat responsive polymers.

The sensor grafted in the delivery system can enable to mimic the recognition function of various bio-chemicals such as enzymes, cell mediated receptors and various proteins in human beings for maintaining the regulation and equilibrium. This approach is utilized for drug incorporated polymeric feedback controlled delivery systems, and this system approach is based on the observation that changes in control mechanisms, e.g.: pH or ionic strength or temperatures can affect large changes in drug solubility; this can be the main factor for control release rate. The external trigger molecule and polymer-bound enzyme can alter the pH inside the polymeric system. If the pH alteration happened inside the polymer system that can lead to changes in drug solubility, which is induces the diffusion or dissolution or disintegration,

The bio-responsive controlled drug delivery system, glucose-triggered insulin delivery has developed [214], the insulin is encapsulated within biocompatible polymer hydrogel scaffold comprising abundant NR2 functional groups present in the normal state. So in this state scaffolds are un-swollen and thus impermeable to insulin molecules. Enzymatically oxidized glucose is to form gluconic acid, this triggers the NR2 groups to form NR2 H+, it leads to swollen and insulin molecules deliver through the polymer membrane, and the amount of

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The reversible and competitive binding mechanism also has been reported to insulin delivery. This mechanism role is to activate and to regulate the release of drug in the target; also it depends upon the glucose level present in the systemic circulation. Insulin-sugar-lectin complex has been prepared and entrapped into the semi-permeable polymeric membrane to achieve controlled release. The diffused blood glucose has competitively bound to particular binding sites, then activates the complex to release insulin derivatives, and the release acted based on the concentration of glucose presented in the systemic circulation. By this way the self-controlled drug delivery has been achieved. A further improvement on insulin delivery, they used glycosylated insulin-concanavalin A complex and entrapped inside polymeric membrane and the release has been achieved by self-regulated mechanism, depends on the glucose concentration permeate into the system [215]. Again in the development of selfregulating insulin delivery has achieved by enzymatically controlled implantable glucosedependent insulin delivery systems [216]. Followed by various researches developed the different kinds of glucose-responsive insulin delivery [217-223]. Also the molecular imprinting technology developed system able to identify the specific compounds on the cell surface, and this can be appropriate for further developing and targeting the delivery system to specific tissues or cells. Recently, the pH-Sensitive polymer multi-functionalized with block copolymeric nanoparticles have been developed for the triggered release of paclitaxel within a tumor microenvironment which the polymer acted as a feedback-regulated drug delivery carrier [224], and this carrier have a reversed swelling behavior. Most recently, the feedback controlled drug delivery system has been developed for cerebral cortical disorders with a feedback controlled mechanism. Drugs have been delivered via subdural/subarachnoid space, then diffuse into neocortical tissue and this diffusion can be controlled by electrophysiological feedback, the cerebral cortical area is exposed to the drug, and they were optimized for the drug concentration, delivery, frequency of delivery [225]. Moreover, the molecular imprinting technology has a huge possibility for producing acceptable dosage forms in the feedbackregulated drug delivery systems. The application of molecular imprinting enables the design of new systems and also in polymer based device fabrications. The advances in the preparation of molecular imprinting as spherical uniform particles [226] and scaffolds [227] can increase the field application potentiality of several polymers in drug delivery system. Moreover, these

delivery has been controlled by glucose penetrating concentration.

imprinted delivery systems have not yet touched in clinical therapeutics.

The recent advances in the smart delivery systems with site-targeting drug release. A site targeted drug delivery systems are complex of multiple steps of diffusion and partitioning.

**4.4. Site-targeting drug delivery systems**

**Figure 5.** Schematic diagrams represent the feedback-regulated drug delivery systems

and rate of release has been changed accordingly. Many researchers have been developed a membrane to bypass the rumen but it allows the polymeric system to release the drug in the stomach via gastric retention mechanism [206]. Because of the polymer membrane it is impermeable to the rumen pH 7, but the swells and release at pH 4, which is the fourth stomach. Several studies have been performed on various polymers holding weakly acidic or basic functional groups in the polymeric backbone [207-112]. This polymeric system can swell or deswell by changing the pH of the environments. By this way the drug will release from a matrix or device, which is developed by pH dependent polymers and this system can provides controlled release rates.

The bio-erosion controlled drug delivery system comprises of a drug-encapsulated bioerodible scaffolds developed from biocompatible polymers (poly (vinyl methyl ether)), and were layered using immobilized urease. In a neutral pH the polymer erodes gradually, but in existing with urea, urea is metabolized by the system containing urea to form ammonia, it leads to increase the pH in the surrounding area, this increased pH degrade the polymer scaffolds then the drugs has been released [213], and some polymers require high pH to degrade.

The bio-responsive controlled drug delivery system, glucose-triggered insulin delivery has developed [214], the insulin is encapsulated within biocompatible polymer hydrogel scaffold comprising abundant NR2 functional groups present in the normal state. So in this state scaffolds are un-swollen and thus impermeable to insulin molecules. Enzymatically oxidized glucose is to form gluconic acid, this triggers the NR2 groups to form NR2 H+, it leads to swollen and insulin molecules deliver through the polymer membrane, and the amount of delivery has been controlled by glucose penetrating concentration.

The reversible and competitive binding mechanism also has been reported to insulin delivery. This mechanism role is to activate and to regulate the release of drug in the target; also it depends upon the glucose level present in the systemic circulation. Insulin-sugar-lectin complex has been prepared and entrapped into the semi-permeable polymeric membrane to achieve controlled release. The diffused blood glucose has competitively bound to particular binding sites, then activates the complex to release insulin derivatives, and the release acted based on the concentration of glucose presented in the systemic circulation. By this way the self-controlled drug delivery has been achieved. A further improvement on insulin delivery, they used glycosylated insulin-concanavalin A complex and entrapped inside polymeric membrane and the release has been achieved by self-regulated mechanism, depends on the glucose concentration permeate into the system [215]. Again in the development of selfregulating insulin delivery has achieved by enzymatically controlled implantable glucosedependent insulin delivery systems [216]. Followed by various researches developed the different kinds of glucose-responsive insulin delivery [217-223]. Also the molecular imprinting technology developed system able to identify the specific compounds on the cell surface, and this can be appropriate for further developing and targeting the delivery system to specific tissues or cells. Recently, the pH-Sensitive polymer multi-functionalized with block copolymeric nanoparticles have been developed for the triggered release of paclitaxel within a tumor microenvironment which the polymer acted as a feedback-regulated drug delivery carrier [224], and this carrier have a reversed swelling behavior. Most recently, the feedback controlled drug delivery system has been developed for cerebral cortical disorders with a feedback controlled mechanism. Drugs have been delivered via subdural/subarachnoid space, then diffuse into neocortical tissue and this diffusion can be controlled by electrophysiological feedback, the cerebral cortical area is exposed to the drug, and they were optimized for the drug concentration, delivery, frequency of delivery [225]. Moreover, the molecular imprinting technology has a huge possibility for producing acceptable dosage forms in the feedbackregulated drug delivery systems. The application of molecular imprinting enables the design of new systems and also in polymer based device fabrications. The advances in the preparation of molecular imprinting as spherical uniform particles [226] and scaffolds [227] can increase the field application potentiality of several polymers in drug delivery system. Moreover, these imprinted delivery systems have not yet touched in clinical therapeutics.

#### **4.4. Site-targeting drug delivery systems**

and rate of release has been changed accordingly. Many researchers have been developed a membrane to bypass the rumen but it allows the polymeric system to release the drug in the stomach via gastric retention mechanism [206]. Because of the polymer membrane it is impermeable to the rumen pH 7, but the swells and release at pH 4, which is the fourth stomach. Several studies have been performed on various polymers holding weakly acidic or basic functional groups in the polymeric backbone [207-112]. This polymeric system can swell or deswell by changing the pH of the environments. By this way the drug will release from a matrix or device, which is developed by pH dependent polymers and this system can provides

**Figure 5.** Schematic diagrams represent the feedback-regulated drug delivery systems

The bio-erosion controlled drug delivery system comprises of a drug-encapsulated bioerodible scaffolds developed from biocompatible polymers (poly (vinyl methyl ether)), and were layered using immobilized urease. In a neutral pH the polymer erodes gradually, but in existing with urea, urea is metabolized by the system containing urea to form ammonia, it leads to increase the pH in the surrounding area, this increased pH degrade the polymer scaffolds then the drugs has been released [213], and some polymers require high pH to

controlled release rates.

272 Application of Nanotechnology in Drug Delivery

degrade.

The recent advances in the smart delivery systems with site-targeting drug release. A site targeted drug delivery systems are complex of multiple steps of diffusion and partitioning. Nowadays the site targeted drug delivery systems involve deep investigation as they are very eager to overcome the modern medical application [228]. A well-designed multi-functional‐ ized polymeric carrier for site-targeted drug delivery in the interventions of various diseases such as colon disease, kidney/renal disease, nasal disease and genitourinary disease has been reported recently [229-234]. A variety of both natural and synthetic water-soluble polymers have been used for biomedical applications. These polymers have been used routinely in biopharmaceutics because of the effectiveness in controlled drug release. The traditional formu‐ lations are not significantly efficient at targeting molecules, thus the new and smart drug delivery systems are being studied to overcome the problem. The goal of the smart drug delivery systems is to allow a localized drug delivery, at the same time; it does not affect the healthy tissues and no unwanted effects. The drugs composed of micro-or nano-sized particulate system, which is able to spread through the systemic circulation, and transport through various body organs and body areas such as arteries, veins, and capillaries and even cross membrane barriers. The nanoparticle transport and targeting tissue are the complex process, so the transportation and communication have been viewed by the molecular communication paradigm. This transport of drug-loaded particles in the human body has been viewed, where the nanoparticle has transported this information is conveyed by signaling molecule. This communication system provides a clear reading of particle diffusion, distribu‐ tion, disintegration over time throughout the biological system, which provides the impor‐ tance to the invention of a smart particulate delivery system. Initially, the kinetic Monte Carlo method [235, 236], have been used computer simulation to solve the communication system. Lately, researchers developed an analytical approach based on the abstraction of targeted particulate delivery systems as a communication mechanism. This information is passed between sender and receiver by intracellular and intercellular signalling [237]. Different kinds of molecular communication have been analyzed so far, which involve passive or active transport of molecules [238, 239]). The smart site targeted delivery system takes an advantage of the systemic circulation for the distribution of active drug particle from where it's ingested to the systemic circulation to a targeted site. Basically, the delivery systems have been made with purpose and intention to control the rate of release from the systems, but the transport of nanoparticle to the target site still needs more control. Preferably, the route of administration and nanoparticle transport should also be strong enough controlled.

kidney. The molecular weight and electric charge of polymers is one of the crucial role for effective renal clearance [245, 246], thus the active polymeric system can uptake and exists in the renal cells [247]. Especially the multi-functionalized polymeric nanoparticles showed higher uptake in glomerular mesangial cells [248, 249]. For nasal site-targeting specificity, the multi-functional particulate system design is the main role for site-targeting. So, design and preparation method has to be controlled according to the needs, the materials should be with quality of properties such as biocompatible, biodegradable, modifiable, mucoadhesive, antimicrobial, tumor or particular cell recognition, and maintain the drug release. In the example, N,N,N-Trimethyl chitosan nanoparticles achieved controlled intra nasal delivery to treat various diseases including hepatitis B and allergic rhinitis [250]. Also the amine func‐ tionalized chitosan has been shown their eminent characters such as biocompatible, enhanced solubility, strength, porosity, absorption efficacy, chemical tolerance, non-immunogenic and

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non-antigenic properties, and it has been used for various nasal delivery.

**Figure 6.** Schematic diagrams represent the site-targeting specificity particulate drug delivery systems

In this section also provides a few examples of site-targeted drug delivery systems, The ideal example is that the kidney site-targeted drug delivery systems, it acted as a smart delivery to enhance drug efficacy and safety in the therapeutics of kidney diseases. By this smart drug delivery treatment provides that reduces inflammation and reduce the formation of excess fibrous to proximal tubular cells, it can protect systemic infection and renal tubular inflam‐ mations. So targeting the renal proximal tubular cells is the novel and efficient routes to cure kidney disease [240-244]. Kidney-targeted drug delivery system can overcome from the various obstacles such as kidney transplantation, ureteral obstruction, diabetes, and other some important kidney disease. Figure 6 shows the kidney drug delivery of nano-particulate systems. Among all drug carriers the macromolecular carriers are extremely powerful targeting the kidney, because of the selective accumulation in the kidneys. Macromolecular carriers with prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. The molecular weight and electric charge of polymers is one of the crucial role for effective renal clearance [245, 246], thus the active polymeric system can uptake and exists in the renal cells [247]. Especially the multi-functionalized polymeric nanoparticles showed higher uptake in glomerular mesangial cells [248, 249]. For nasal site-targeting specificity, the multi-functional particulate system design is the main role for site-targeting. So, design and preparation method has to be controlled according to the needs, the materials should be with quality of properties such as biocompatible, biodegradable, modifiable, mucoadhesive, antimicrobial, tumor or particular cell recognition, and maintain the drug release. In the example, N,N,N-Trimethyl chitosan nanoparticles achieved controlled intra nasal delivery to treat various diseases including hepatitis B and allergic rhinitis [250]. Also the amine func‐ tionalized chitosan has been shown their eminent characters such as biocompatible, enhanced solubility, strength, porosity, absorption efficacy, chemical tolerance, non-immunogenic and non-antigenic properties, and it has been used for various nasal delivery.

Nowadays the site targeted drug delivery systems involve deep investigation as they are very eager to overcome the modern medical application [228]. A well-designed multi-functional‐ ized polymeric carrier for site-targeted drug delivery in the interventions of various diseases such as colon disease, kidney/renal disease, nasal disease and genitourinary disease has been reported recently [229-234]. A variety of both natural and synthetic water-soluble polymers have been used for biomedical applications. These polymers have been used routinely in biopharmaceutics because of the effectiveness in controlled drug release. The traditional formu‐ lations are not significantly efficient at targeting molecules, thus the new and smart drug delivery systems are being studied to overcome the problem. The goal of the smart drug delivery systems is to allow a localized drug delivery, at the same time; it does not affect the healthy tissues and no unwanted effects. The drugs composed of micro-or nano-sized particulate system, which is able to spread through the systemic circulation, and transport through various body organs and body areas such as arteries, veins, and capillaries and even cross membrane barriers. The nanoparticle transport and targeting tissue are the complex process, so the transportation and communication have been viewed by the molecular communication paradigm. This transport of drug-loaded particles in the human body has been viewed, where the nanoparticle has transported this information is conveyed by signaling molecule. This communication system provides a clear reading of particle diffusion, distribu‐ tion, disintegration over time throughout the biological system, which provides the impor‐ tance to the invention of a smart particulate delivery system. Initially, the kinetic Monte Carlo method [235, 236], have been used computer simulation to solve the communication system. Lately, researchers developed an analytical approach based on the abstraction of targeted particulate delivery systems as a communication mechanism. This information is passed between sender and receiver by intracellular and intercellular signalling [237]. Different kinds of molecular communication have been analyzed so far, which involve passive or active transport of molecules [238, 239]). The smart site targeted delivery system takes an advantage of the systemic circulation for the distribution of active drug particle from where it's ingested to the systemic circulation to a targeted site. Basically, the delivery systems have been made with purpose and intention to control the rate of release from the systems, but the transport of nanoparticle to the target site still needs more control. Preferably, the route of administration

274 Application of Nanotechnology in Drug Delivery

and nanoparticle transport should also be strong enough controlled.

In this section also provides a few examples of site-targeted drug delivery systems, The ideal example is that the kidney site-targeted drug delivery systems, it acted as a smart delivery to enhance drug efficacy and safety in the therapeutics of kidney diseases. By this smart drug delivery treatment provides that reduces inflammation and reduce the formation of excess fibrous to proximal tubular cells, it can protect systemic infection and renal tubular inflam‐ mations. So targeting the renal proximal tubular cells is the novel and efficient routes to cure kidney disease [240-244]. Kidney-targeted drug delivery system can overcome from the various obstacles such as kidney transplantation, ureteral obstruction, diabetes, and other some important kidney disease. Figure 6 shows the kidney drug delivery of nano-particulate systems. Among all drug carriers the macromolecular carriers are extremely powerful targeting the kidney, because of the selective accumulation in the kidneys. Macromolecular carriers with prodrugs play crucial roles in targeting drugs to particular target cells in the

**Figure 6.** Schematic diagrams represent the site-targeting specificity particulate drug delivery systems

#### **4.5. Targeting strategies for kidney diseases**

Macromolecule is a very large molecule, which can accumulate in the kidneys. Generally, the molecular weight of the macromolecular vehicle is bigger than that of the prodrugs, so this kind of system can achieve the goal. Pro-drugs have the ability to select the target in the kidney because it can release the active drug by the action of renal enzymes. The various strategies of kidney-targeted drug delivery systems has to be considered such as biodynamical strategy of renal artery perfusion, macromolecular carriers which includes enzymes, immune proteins and peptide hormones, pro-drugs which includes folate, sugars, and amino acids, and other strategies including various nano-particulate systems. The molecular weight and charge [245, 246] of polymers is the main factor, it can influence their distribution in various organs including kidney. In general, increasing the molecular weight of polymers leads to decreases urinary clearance. Some of the polymers have been eliminated rapidly from the systemic circulation but it does not excrete from the kidney, and its accumulated in the renal systems. So it clearly proposed that the selection of effective and active multi-functionalized polymeric nanoparticles can uptake by the particular kidney cell types. So the selection of polymers is one of the prime strategies for consideration to achieve the efficient kidney targeting. These new possibilities to develop kidney targeting conjugates and other nano-particulate drug delivery systems. Including various polymers based nanoparticles give excellence strategies to achieve the goal of targeting drugs to the various renal diseases.

safety of the drugs, and when it should be reached. Described all above application strategies

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**5. Bioengineered materials: Ideal and recent advances for drug delivery**

Engineered materials have been utilized for developing smart drug delivery systems. Design and multi-functionalities fabricate of efficient smart drug delivery systems are vitally neces‐ sary for medicine and healthcare development. In the material science field provides biode‐ gradable, biocompatible, environment-responsive, and highly effective novel polymeric system for targeted delivery. Nanotechnology provides bottom-up and top-down nanofabri‐ cation with size controlled and multi-functionality of particulate for targeted delivery. New materials invention and advanced technology have been synergistically achieved in drug delivery so far. The essential goals of medical pharmacology provide the right medicine, right dosage, and right route at the right time to the right patient, so more research need to optimize the therapeutic efficacy of the drug. This is the essential principles is behind the smart drug delivery. A smart, controlled delivery system needs synergistic consideration of several factors; these have been summarized in Figure. 7. It is difficult to get all consideration factors in a smart controlled delivery system due to other influencing factors. Also high quality, reliability, efficiency and reproducibility are the most significant issue while designing such a smart system. Also the smart systems have to induce the drug release and stop the release by their own manner. It would be highly benefited, if the system recognizes the disease affected part, estimated the disease affected ratio, and then acted to release the exact quantity of active drugs. This kind of drug delivery system can fulfil the medicine and healthcare requirements.

**Figure 7.** Requirements of several factors for simultaneous consideration to design a polymeric nanoparticle for the

have a significant interest in targeting drugs into specific regions [257, 258].

**systems**

smart drug delivery system

**5.1. Nano-engines of drug delivery systems**

#### **4.6. Common strategies for smart polymeric particulate targeted delivery**

The ideal proposed model for site-targeting delivery is fabricated from a biocompatible, nonimmunogenic and biodegradable polymer and acts as the central of support to three main characteristics of attachments such as site-specific targeting moiety, solubilizer and drug moiety, which should have drug delivery capacity, capable of transport and active molecule should bonded to the polymer via spacer, and the linkage is cleaved by particular enzyme(s) at the final targeted site respectively. In order to develop a new polymeric vehicle for a particular drug, the polymer distribution in the systemic circulation has to be analyzed since it's right away affects on activity of drugs. For controlling the systemic distribution of drugs, we need to consider minimum two strategies which are active or passive targeting. Previously, the drug is delivered to target site using some specific antibodies, which are specific to target cell-surface [251-254]. This method gives efficient targeting to tumor site; however, the antibodies can produce immunogenic activity. But, the passive targeting with bio-polymers vehicles cannot produce immunogenicity or toxicity, this might enhance the active molecule efficacy, such as increased half-life by increased size of the nano-particulate complex, increased permeability at the targeted area and polymer vehicle interacts to the body organs. Those elements must be increase the absorption of the drug molecule; which minimize the dosage and low unwanted effects [255, 256]. Moreover, in the advanced fabrication of molecular imprinting technology can provide efficient smart polymeric systems with the ability to recognize specific bio active molecules. This advanced fabrication technology has tremendous possibility to meet the requirements for satisfactory dosage forms developments. Depends upon the particular application the fabricated systems can decide the delivery, efficiency, safety of the drugs, and when it should be reached. Described all above application strategies have a significant interest in targeting drugs into specific regions [257, 258].
