Polymer Nanoparticles For Smart Drug Delivery: Devasier Bennet and Sanghyo Kim

Chapter 8
Polymer Nanoparticles for Smart Drug Delivery

Devasier Bennet and Sanghyo Kim
Additional information is available at the end of the chapter
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1. Introduction
In the recent decades, polymers are widely used as biomaterials due to their favorable
properties such as good biocompatibility, easy design and preparation, a variety of structures
and interesting bio-mimetic character. Especially in the field of smart drug delivery, polymer
played a significant role because it can deliver therapeutic agents directly into the intended
site of action, with superior efficacy. The ideal requirements for designing nano-particulate
delivery system are to effectively be controlled particle size, surface character; enhance
permeation, flexibility, solubility and release of therapeutically active agents in order to attain
the target and specific activity at a predetermined rate and time. The smart drug delivery
systems have been successfully made by the advances in polymer science in the bio-nano
technology field. Recently, these advances have been found in various medical applications
for nano-scale structures in smart drug delivery. The smart drug delivery systems should
possess some important feature such as pre-scheduled rate, self controlled, targeted, predetermined time and monitor the delivery. The smart drug delivery system enhances the
polymer nanoparticle better stage to their therapy regimen. They are drug carriers of natural,
semi-synthetic, and synthetic polymeric nature at the nano-scale to micro-scale range. The
polymeric particles are collectively named as spheres and capsules. The most of the polymeric
nanoparticles with surfactants offer stability of various forms of active drugs and have useful
to smart release properties. There are numerous biological applications have been reported for
the nano-scale to micro-scale sized particles, such as site-targeted, controlled, and enhanced
bioavailability of hydrophobic drugs [1-4]. Due to the nanoparticles size the drugs have been
targeting into various applications, such as, various cancers targeting has been shown to be
promising [5]. Moreover, polymeric particles proved their effectiveness in stabilizing and
protecting the drug molecules such as proteins, peptides, or DNA molecules from various
environmental hazards degradation [2-4, 6, 7]. So these polymers are affording the potential
for various protein and gene delivery. Numerous methods had been available to fabricate
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Application of Nanotechnology in Drug Delivery
nanoparticles; it depends on the physical and chemical properties of polymer and active
ingredients. Most of the formulation techniques involve different mechanisms such as using
organic solvents, temperature, ultra-sonication and mechanical agitation which can degrade
the pharmaceutical active ingredients. So the nano-particulate system can be developed to
consider the formulation methodology should not damage the active pharmaceutical ingre
dients. There are numerous biodegradable and biocompatible polymers with different
physicochemical characters are offered to prepare smart nanoparticles, those polymeric nanocarriers can be natural or semi-synthetic or synthetic. Those nanoparticles can enhance the
systemic circulation half-life and minimize unwanted internalization and prevents the
denaturation of the therapeutically active moiety and could use to deliver the target agents.
Several polymer systems are approved by the U.S. Food and Drug Administration (FDA) for
human use. It is the belief that when inventions in fabrication can catch up with those in
materials, design and development of drug delivery system can enter a new generation of
enhancing clinical healthcare.
The most recent advances in the uses of carriers for sustained and targeted delivery, micro and
nano fabricated self-regulated devices [8], bio-recognizable systems; micro-needles for
transdermal drug delivery have shown the flexibility and enhanced permeability of these
polymeric materials. Ultimately the goal in smart drug delivery is the emergence of a micro
and nano-fabricated therapeutic drug release device with the capacity to enough hold and
release of various active agents on demand. In modern system the micro-electro-mechanical
systems give a distinctive possibility to produce micro-fabricated biomedical devices for
different intentions, from implantable systems to lab-on-a-chip systems. The constant and
prolonged drug release micro-fabricated systems have the several benefits, such as many active
ingredients could be stored in an nano form within the system and sustainably released, the
drug release is initiated by the dissolution and disintegration of outer membrane barrier by
an mechanical/electric stimuli, the most potential drugs could be released more specifically
with this technique, the complex drug release system such as simultaneous stable and
periodically could be attained for local therapy by the micro-fabricated system; it can be
achieved in high or low dose of drugs at the targeted site and increase the stability of drugs
by the membrane barrier for preventing water diffusion into the reservoirs [9]. Owing to the
advanced scientific sophistication of the controlled drug release system that has been achieved
till now, or that are in dynamic progress, this delivery model can be categorized into various
classes. The controlled drug delivery systems can be categorize four main mode of drug
delivery, such as (1) rate-programmed drug delivery, where drug diffusion from the system
has follow a specific release rate profile, (ii) activation-modulated drug delivery, where the
drug release is induced by various factors such as physical, chemical electrical or biochemical
modules, (iii) feedback-regulated drug delivery, where the rate of release is determined by
biochemical substance (triggering agent) concentrations, it is dependent on the concentration
exhibit in the target and (iv) site-targeting drug delivery systems, this is a complex process
that consists of multiple steps of diffusion rate and partitioning for the rate of drug release is
regulated by the specic targeting moiety, solubilizer and drug moiety. This chapter will brief
discussion on recent innovative nano-fabrication methods for novel drug delivery system.
Also, highlights some of these new technologies and consider their possibility ongoing clinical

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transformation of nanoparticles, which the particles are well-controlled formulated. This

chapter will be followed by a more detailed novel drug delivery system development from a
polymeric material viewpoint and their various bio-applications will be covered without
attempting to all the work that has been done in this field.
Over a decade, investigators have appreciated the enrichment of potential uses of bionanotechnology in offering huge advancements in novel drug delivery and targeting. The
novel drug delivery platform that provides diminishes toxicity and enhances therapeutic
efficacy gives most possible benefits to clinical levels. In approaches to drug delivery systems
the route of administration is one of the crucial roles of drug targeting. These nanoparticles
can be used for various routes, including oral, nasal, transdermal, parenterals, pulmonary,
ocular, etc. Nonetheless, the oral route is most convenient, preferred, and in several cases, also
its cost-effective, but it does not cross easily some biological barrier; also easily degraded by
various body fluids, then rapid hepatic clearance and other organs. So the drug delivery
systems focus on overcoming the various membrane barriers, such as the blood brain barrier,
tight junction barrier, to achieve the effective drug target and enhance the efficacy. To find an
alternative and satisfiable route of administration for the effective drug delivery system should
overcome the digestive tract problems, where the degradation could take place via acidhydrolysis, enzymatic degradation and bacterial fermentation in the alimentary canal. This
chapter will cover the more detailed novel route of administration and development from a
polymeric material viewpoint and their brief discussion will be covered without attempting
to all the work that has been done in this field.
2. General methods for polymeric nanoparticles preparation

Recently, various kinds of polymers are used to prepare the polymeric nanoparticles, among
this all polymer biodegradable polymers and their co-polymers such as di-block, tri-block,
multi-block or radial block copolymer structures have been generally used to prepare poly
meric nanoparticles and to encapsulate the active ingredients. These multi-functionalized
polymeric nano-carriers include micelles, capsules, platelets, fibers, spheroids colloids,
dendrimers, core-shells, nanoparticle incorporated polymer matrixes, etc. The first polymeric
nanoparticles were developed between the year of 1960 to 1970 for the therapeutic application,
and this were Micelles[10-12].The micelles are formed by polymerisation methods, commonly
the formation of polymer nano-carriers during the polymerization of monomers [13-16]. Then
the various advanced polymerization techniques have been developed for the preparation
polymeric based nanoparticles, and the nanoparticles were stabilised using various surfactants
[1, 9]. The stabilised drug loaded nanoparticles consist of drug and non-toxic biocompatible
polymer with stabilizing agents, the biocompatible polymer is either biodegradable or nonbiodegradable. Numerous techniques are available for the preparation of the polymeric
nanoparticles and mainly top-down and bottom up processes. The polymer nanoparticle drug
carriers can be further categorized into nano/micro-capsules and nano/micro-spheres depends
on the size and structure [1, 9, 17-19]. The fine particles are 100 - 2,500 nm and ultrafine particles
are 1 to100 nm in size, and are collectively known as nanoparticles. 50 to 300 nm sized
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nanoparticle have been prepared by emulsion polymerization method [20]. Drawbacks in

polymerization techniques are evolving noxious factors such as toxic, reactive residues, unreacted monomers, the risk of a chemical reaction and the formation of unwanted oligomers
[1], and these drawbacks are overcome by using preformed polymers for the polymerization
process [1]. Generally the drug loaded nanoparticles were prepared by dissolving the drug
and polymer into the water-immiscible organic solvents and producing a nano-emulsion, as
an example by probe-sonication method. The organic solvent is removed by using elevated
temperature or reduced pressure [21-23], as an example of rotary evaporation method, and
the nanoparticle is washed and collected by certification. Followed by various changes and
improvements of the emulsification techniques have been reported [24-29]. For example, the
sonication process is a crucial step in the preparation of the sensitive drug loaded nanoemul
sion, and the sonication process can increase the temperature, that leads to inactivate the active
ingredients. In order to avoid the problems researchers utilized an on/off cycle to maintain a
low temperature. Other examples of general methods to prepare the drug polymer nanopar
ticle are described in the Figure 1. The biodegradable polymeric nanoparticles are commonly
prepared by five different techniques such as emulsification-solvent evaporation, solvent
displacement, salting-out, emulsification-solvent diffusion and double emulsion solvent
evaporation. The synthesizing methods include salting-out method [1, 30, 31]; it is based on
the separation of a water miscible solvent from aqueous solution through the salting out effect,
solvent displacement method [1, 32-34], phase separation method [35], evaporation precipi
tation [36, 37], antisolvent precipitation and electrospray methods [38].
Figure 1. General methods of preparation of polymeric nanoparticles and their principle involved in the mechanisms

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Also, many approaches have been developed for the drug particle size reduction (in
crease in the surface) to the nanometer size range. For size-reduction, high pressure
homogenization or wet bead milling is frequently used technique to produce reduced size
nanoparticle [39-43]. Among these the high-pressure homogenization has been shown to be
effective methods to produce size reduction particle. Moreover, its need sophisticated
equipment to resist increasing pressures and temperature. Then, in order to obtain dried
polymeric nanoparticle formulations researchers used various drying techniques such as
atmospheric freeze drying, spray freeze drying, vacuum freeze drying, and lyophilisation.
The uniformity of spray-dried nanoparticle is better than a freeze-dried nanoparticle.
Moreover the lyophilisation and spray-drying are used to prepare the nanoparticle [44, 45],
these nanoparticles easily tends to aggregates. Also the polymeric nanoparticles have also
been synthesized by supercritical fluid techniques [46-52]. This method can get a dry
product without any solution, also no need additional drying stages, but the supercritical
fluid can swell some of the polymers and act as a softener, extender, and lubricant, which
lead to aggregation. Moreover, this method is not easy to get the mono-dispersed multicomponent particles because of different kinetics [52]. Nanoparticles prepared by spraydrying technique are one-step based on the conversion of a droplet to a dry particle by
evaporation [53-55]. These one-step techniques have been revealed that the nanoparticle
could be prepared without any problems [56-58], and the drug content in the particles is
almost high [59], but produce an amorphous residual structure. In all above technique
induce some unwanted noxious factors, as well as the organic solvents used in the
preparations are increasing the risk of pharmaceutical application, also the increased
processing time leads to microbial contamination [60, 61, 62]. Understanding the all risk
factors, recently the modern instrument provides a promising and viable platform for the
preparation polymeric nanoparticles.
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
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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.
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

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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].
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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

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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

4.2.1. 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
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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).
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

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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.
Based on
Stimulus
Osmotic pressure
Generate hydrodynamic pressure gradient

Forces the drug to release through the orifice
[127]
[128]
[129]
Equipped with a mechanically activated pump

First-pass elimination and pressure-sensitive delivery
Electromagnetism-triggering vibration mechanism
Magnetically activated, vibrate by an electromagnetic field
[130]
[131]
Sonophoresis
Utilizes ultrasonic energy to activate the delivery
[132]
Iontophoresis
Electrical current to activate and diffuse the charged drug
[133]
Utilized swellable polymer matrix
[128]
Activated by hydration-induced swelling delivery
[126]
Electric-sensitive capsule
[134]
Electrically erodible matrix for delivery
[135]
Deliver the drug in the intestinal tract not in the stomach
[136]
Deliver the drug in the ulcer stomach by floating delivery
[137]
Prepared by ionizable drug with ion-exchange resin
[128]
Controlling the delivery of an ionic or an ionisable drug
[138]
Electricity
pH
Salt concentration
Hydrolysis
Enzyme
Biochemical
Temperature
Environmental
stimuli
[126]
Creates vapor pressure, vaporizes at body temperature
force
Hydration
stimuli
Ref.
Pumping system contains vaporizable fluid
A mechanical
Magnetics
Biochemical
Controlled through a gradient of osmotic pressure
pressure
Physical stimuli
stimuli
Controlled through the permeability of water
Hydrodynamic
Vapor pressure
Chemical
Mode
Light
Hydrolysis-induced degradation of polymer chains Hydrolysis activate

the release of drug molecules
[139]
Polymer chains fabricated with biopolymers
[140]
Deliver the drug by enzymatic hydrolysis of polymers
[141]
Enzymatic-activated, biodegradation
[142]
Feedback-regulated delivery concept has been applied
[143]
Depends on the transition temperature
[144]
Shifting the hydrophilic/hydrophobic balance
[145]
Polymers undergo isothermal phase transitions by photon
[146]
Reversible phase separations through photo-irradiation
[147]
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Based on
Stimulus
Mode
Ref.
Hydrophobically modified imidazole derivative was conjugated to the

Hypoxia
carboxymethyl dextran, it can release the hydrophobic agents under [148]

hypoxic conditions
Dual-stimuli
Multi-stimuli
Two different
Based on the polymer architecture
[149]
responses
Micelles are reported pH and thermo-responsive
[150]
More than two

responses
Functionalization of pyrene-quaternized segments form a lightresponsive shell and the unquaternized segments form a
temperature/pH-responsive core
[151]
[152]
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.

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4.2.2. Dual and multi-stimuli responsive smart delivery system

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 disulde 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
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site targeting, site-specic, 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
pH & Thermo
pH & redox
Nanoparticles
P(NIPAAm-co-DMAAm-co-UA) nanoparticles
[176]
P(NIPAAm-co-AA)-b-PCL nanoparticles
[177]
PLA-g-P(NIPAAm-co-MAA) nanoparticles
[178]
P(NIPAAm-co-DMAAm)-b-PCL/PLA micelles
[179]
PNIPAAm and PAA hollow nanogels
[180]
PEG-SS-PDEA polymersomes
[181]
DS-g-PEG/cRGD nanoparticles
[182]
Poly(b-amino ester)s-PEG micelles
[183]
PMAA-based nanogels
[184]
mPEG-PAsp(MEA)-PAsp(DIP) micelles
[185]
Fe3O4 nanocarrier with peptide mimic polymers

Dual-stimuli
DOX-tethered Fe3O4 conjugates nanoparticles

pH & magnetic
mPEG-b-PMAA-b-PGMA-Fe3O4 nanoparticles
Fe3O4-capped MSNs
MCM-TAA-Fe3O4-capped MSNs
T & redox
Double pH
pH & diols
Multi- stimuli
Ref.
EO-PAA-PNIPAAm polymersomes
[186]
[187]
[188]
[189]
[190]
[191]
PPC-Hyd-DOX-DA nanoparticles
[192]
Poly-b-amino ester ketal nanoparticles
[193]
PEG-b-dendritic cholic acid telodendrimers nano-carriers containing

boronic acid
[194]
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]
pH/redox/
Fe(II) loaded PMAA crosslinked by N,N-methylene-bisacrylamide
magnetic
and N,N-bis(acryloyl)- cystamine
T/redox/guest
Vesicles based on hosteguest complex formation between C4AS
molecule
and MVC12
T/pH/guest
Cucurbit(8)uril micelles, methylviologene-functionalize PNIPAAm
molecule
and naphthalene-terminated PDMAEMA
Light/pH/T
Pyrene-functionalized poly (dimethylaminoethyl methacrylate)
[199]
[200]
[201]
Table 2. Overview of dual and multi-stimuli responsive materials for nano-carriers of various smart drug delivery
systems

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4.3. Feedback-regulated drug delivery

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,
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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.

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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 specic compounds on the cell surface, and
this can be appropriate for further developing and targeting the delivery system to specic
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
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.
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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 its 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.
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

http://dx.doi.org/10.5772/58422
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.
Figure 6. Schematic diagrams represent the site-targeting specificity particulate drug delivery systems
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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.
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-specic 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
its 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 specic 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 specic 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,

http://dx.doi.org/10.5772/58422
safety of the drugs, and when it should be reached. Described all above application strategies
have a significant interest in targeting drugs into specic regions [257, 258].
5. Bioengineered materials: Ideal and recent advances for drug delivery

systems
5.1. Nano-engines of drug delivery systems
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
smart drug delivery system
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6. Polymeric nanoparticles functionalization and considerations for smart

application
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

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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.
Nanoparticles
Functionalization
Drug
Use
Refs.
Human serum albumin
Amino/acid group
Doxorubicin
Antineoplastic
[260]
Trimyristin
Sterically stabilized
Paclitaxel
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]
Serum protein
Ellipticin
Anticancer
[266]
PAMAM dendrimers
Folic acid
ethotrexate
Epithelial cancer
[267]
PEG
Albumin bound
Doxorubicin
Various cancers
[268]
Daunomycin
Brain tumor
[269]
PCL-b-trimethylene carbonatePEG
Micelles
Biotin-antibodyconjugated
Ovarian, lung, breast

cancer
[261]
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
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280
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.
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

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

strategies
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
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282
are multiple barriers involve in the anatomical and physiological system to lack the drug
efficiency, including enzymatic degradation in the stomach, absorption across the intestinal
epithelium, hepatic clearance, and accumulation in non-targeted tissues. These barriers also
involve a range of complexities from the tissue to the organelle level along with the time that
mismatch the drug potency in vivo. Collectively, these conditions challenge the active
utilization of potent therapeutic molecules for disease treatment or prevention. Extensive
research has been carried out in the field of drug delivery to overcome these challenges and
thus to contribute a significant role in the overall drug-development process. After the
evolution of nanotechnology and vast increment in knowledge about the human body,
advances have been achieved in the drug delivery field as targeted delivery and sustained/
controlled delivery system. By tuning the kinetic properties of therapeutics, the potentiality
could be secured until it reaching the targeted organ and this factor is considered to be the
most important in the field of pharmacology. Progresses in the nanomaterials development
have been fruitful to fulfil the goals of drug delivery. Pharmacologically, the drug delivery is
better explained based on the routes of drug administrations. Development of alternative drug
delivery methods is crucially important to overcome the challenges experienced throughout
the history of medicine. Scientists have been working on the creation of the smart drug delivery
system and such approaches could provide an easy route of administration, ensuring patient
compliance, decreasing toxicity, improving bioavailability and achieving precise therapeutic
targeting. Creation of smart drug carrier as delivery systems and the discovery of new
pharmacological compounds will potentially advance disease diagnosis and treatment beyond
expectation. A variety of novel drug delivery systems have been developed using various
nanomaterials during the last decade and several of them are already marketed. Nanotech
nology manipulates the multiple properties including the size and other physical characteris
tics and thus achieves both controlled and targeted delivery of drugs. The bio-adaptability and
multi-functional properties of smart delivery system minimize the undesirable properties of
drugs in various routes of administration, including oral, rectal, nasal, ocular, topical route
such as transdermal, and dermal, parenteral route such as intravenous/intravascular, intra
muscular, subcutaneous, intradermal/intracutaneous, intraperitoneal and intrathecal. Figure
9 depicts the tremendous applications of new nanomaterials for the development of various
routes of administration and targeting for therapeutics such as transdermal vaccine delivery,
intranasal vaccine delivery and lung targeted delivery. Nasal mucosa offers numerous benefits
as a target tissue for drug delivery, particularly for brain targeting because drug penetration
through the BBB is favored by lipophilicity.
In particular, the non-invasive intranasal delivery offers large interests in the targeted route
of administration. Nasal delivery helps drugs to bypass the blood-brain barrier and hence acts
as an excellent platform for brain targeting. The intranasal drug delivery several approaches
should be considered, attending, specifically, to the nature of pathological condition (acute or
chronic) and intended effects of drug treatment (local, systemic or at CNS). Local delivery,
nasal vaccines, systemic delivery and CNS delivery through nasal route is the prime route for
drug administration to treat the various diseases. So the nasal vaccination is a promising
alternative to the classic parenteral route because the nasal mucosa possesses abundant nasal
associated lymphoid tissue (NALT), dentritic cells, large surface area, and low proteolytic

http://dx.doi.org/10.5772/58422
Figure 9. Schematic diagrams represent the recent developments of various significance routes of administration and
targeting strategies
enzymes that serve as a primary defense system against pathogens. It can exhibit high drug
concentration, permeation, no first-pass effect and compliance administration without
enzymatic destruction. Moreover, antigens encapsulated nanoparticles ensure enhanced
uptake and controlled release of antigens from the nasal vasculature membrane with strong
immunogenicity and improved systemic therapeutic responses. Also, the bio-nanotechnology
applied to the parenteral administrations techniques such as microneedles, jet-injections,
ultrasound, iontophoresis, and electrophoresis. Theses systems extend painless, patientfriendly alternatives to injections for the delivery of molecule [313-317]. Drug administration
using microneedles for the transdermal delivery routes have been reported elsewhere
[318-320]. Microneedles are arrays of micrometer-sized shallow needles that penetrate only
into the superficial layers of skin, thereby eliminating the pain associated with standard
283
284
hypodermic needles [321]. Microneedles have been made from a variety of materials and in
particular the polymers have been shown to be effective. They have also been produced in
solid and as well as in hollow forms. Solid microneedles are used to render skin permeable,
whereas hollow microneedles actively deliver drugs into the skin at a controlled rate. In
contrast, jet injectors deliver a high-velocity liquid jet stream into the skin, delivering drugs
into various skin layers, depending on the jet parameters [322]. Jet injectors have a long history,
particularly in the delivery of vaccines, insulin, and growth hormone. Ultrasound enhances
skin permeability by cavitation, which temporarily disrupts skin structure [323]. Iontophoresis
and electroporation use electric fields to alter the skin structure and/or provide additional
driving force for drug penetration through the skin [324]. These new routes of administration
of therapeutics with improved responses have been achieved by high drug concentration in
target, permeation, no first-pass effect, high bioavailability and compliance administration
without enzymatic destruction [325, 326].
8. Conclusion
The uses of bio-nanotechnology in therapeutics a number of unexpected inventions have been
done recently on polymer based nanometers, which have great attention in the field of smart
drug delivery applications. The biomaterials including protein based polymers, polysacchar
ide based polymers, natural or synthetic or semi-synthetic polymers, various biomaterials and
combination of polymer have utilized to prepare various kinds of nano-formulations towards
the smart drug delivery applications. Several polymeric nanoparticle-based therapeutic
systems have been established for the treatment of various diseases. Several nanoparticle based
drug delivery systems have been approved in clinical trials, some of them in under pre-clinical
trial levels, this nanoparticle based system can provide the increased half-life, high biocom
patibility, and minimum immunogenicity, site targeting and overcome the membrane barriers.
Also the last era, major and new identifications have been drastically established in the smart
material that alter its own structure and function in response to the environment. This
performance has been used for the fabrication smart drug delivery systems, Smart polymer
matrices release drugs by environment responses this system have been successfully achieved.
In parallel the new method of bottom-up and top-down nanofabrication technologies provided
precisely controlled size and shaped nano-particulate delivery system. Simultaneously,
various advanced significant routes of targeting have developed and successfully achieved to
the site of action. At present, the field of microfluidics for synthesis, micro-needle for trans
dermal and site targeted delivery is still in its infancy. So the pharmaceutical industry has to
bring these products into industry-led investigation and the improvement in this would
possibly to quicken their progress.

http://dx.doi.org/10.5772/58422
9. Future perspectives
Although there are considerable amount researches have been done in the field of drug
delivery so far. In the polymeric nanoparticle based drug therapy has to be enhanced by
incorporating by the combination therapies, Smart delivery has been achieved successful
ly in the case of cancer, but need to be concentrating more on other pathologies, also
numerous challenges remain. From the material viewpoint, most of the smart delivery
systems mechanism do well in vitro studies but flops the in vivo studies. So the research
has to be re-considering to come up with simple, straightforward, efficient and reasona
bly accurate preparations with broadly applicable strategies, the pharmacologically active
agent targeting to pathological sites, for the development of smart drug delivery systems.
In technology vice the research has to focus into the fusion technologies. Although several
specific specialized technologies have been shown to in polymer synthesis, functionaliza
tion, analysis, in vitro and in vivo study in the field of polymer science, the combinations
of two or more techniques are often more effective than single technologies like a combina
tion of controlled radical polymerization with click chemistry. The fusion technologies can
fulfil the various existing drawbacks of some individual technologies, and this has the high
potentiality, synergistic enhancement in safest nanoparticle based drug delivery. Consider
merging and adopting two or more right technologies for getting a high-throughput
technology by selecting the right combinations is a fruitful area for research that is still
largely unexplored. This new understanding must be incorporated into the future of newer
polymeric based nanoparticle synthesis development and evaluation of smart drug delivery.
Also the next generation of polymeric nanoparticle based delivery systems with drugs like
growth factors, hormones, antibodies, genes, peptides, etc.; should also enhance the
efficiency and minimize the unwanted effects.
Acknowledgements
This work was supported by the R&D Program for Society of the National Research Founda
tion(NRF) funded by the Ministry of Science, ICT & Future Planning (2013M3C8A3078806 and
2013M3C1A8A01072922).
Author details
Devasier Bennet1 and Sanghyo Kim1,2*
*Address all correspondence to: samkim@gachon.ac.kr
1 Department of Bionanotechnology, Gachon University, Bokjeong-Dong, Sujeong-Gu,
Seongnam-Si, Republic of Korea
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286
2 Graduate Gachon Medical Research Institute, Gil Medical Center, Inchon, Republic of Korea
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Chapter 8

Polymer Nanoparticles for Smart Drug Delivery

Application of Nanotechnology in Drug Delivery

Polymer Nanoparticles for Smart Drug Delivery

transformation of nanoparticles, which the particles are well-controlled formulated. This

2. General methods for polymeric nanoparticles preparation

Application of Nanotechnology in Drug Delivery

nanoparticle have been prepared by emulsion polymerization method [20]. Drawbacks in

Polymer Nanoparticles for Smart Drug Delivery

3. Modern methods for preparation of polymeric nanoparticles

Application of Nanotechnology in Drug Delivery

Polymer Nanoparticles for Smart Drug Delivery

Application of Nanotechnology in Drug Delivery

4. Controlled drug delivery systems

Polymer Nanoparticles for Smart Drug Delivery

4.2. Activation-modulated drug delivery

Application of Nanotechnology in Drug Delivery

Polymer Nanoparticles for Smart Drug Delivery

Generate hydrodynamic pressure gradient

Equipped with a mechanically activated pump

Utilizes ultrasonic energy to activate the delivery

Electrical current to activate and diffuse the charged drug

Utilized swellable polymer matrix

Activated by hydration-induced swelling delivery

Electrically erodible matrix for delivery

Deliver the drug in the intestinal tract not in the stomach

Deliver the drug in the ulcer stomach by floating delivery

Prepared by ionizable drug with ion-exchange resin

Controlling the delivery of an ionic or an ionisable drug

Creates vapor pressure, vaporizes at body temperature

Pumping system contains vaporizable fluid

Controlled through a gradient of osmotic pressure

Controlled through the permeability of water

Hydrolysis-induced degradation of polymer chains Hydrolysis activate

Polymer chains fabricated with biopolymers

Deliver the drug by enzymatic hydrolysis of polymers

Feedback-regulated delivery concept has been applied

Depends on the transition temperature

Shifting the hydrophilic/hydrophobic balance

Polymers undergo isothermal phase transitions by photon

Reversible phase separations through photo-irradiation

Application of Nanotechnology in Drug Delivery

Hydrophobically modified imidazole derivative was conjugated to the

carboxymethyl dextran, it can release the hydrophobic agents under [148]

Based on the polymer architecture

Micelles are reported pH and thermo-responsive

More than two

Polymer Nanoparticles for Smart Drug Delivery

4.2.2. Dual and multi-stimuli responsive smart delivery system

Application of Nanotechnology in Drug Delivery

PNIPAAm and PAA hollow nanogels

Poly(b-amino ester)s-PEG micelles

Fe3O4 nanocarrier with peptide mimic polymers

DOX-tethered Fe3O4 conjugates nanoparticles

Poly-b-amino ester ketal nanoparticles

PEG-b-dendritic cholic acid telodendrimers nano-carriers containing

Pluronic with Fe3O4 nanoparticles

PNIPAAm-SS-P(THP-protected HEMA) micelles

P(NIPAAm-co-MAA) coated magnetic MSNs