Overview of various stimuli responsive nano-carriers for smart drug delivery systems with mode of drug release applications
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-nanotechnology 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, pre-determined 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 . 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 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 ingredients. There are numerous biodegradable and biocompatible polymers with different physicochemical characters are offered to prepare smart nanoparticles, those polymeric nano-carriers 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 , 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 . 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 speciﬁc 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 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 bio-nanotechnology 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 acid-hydrolysis, 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 polymeric 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 non-biodegradable. 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 nanoparticle have been prepared by emulsion polymerization method . Drawbacks in polymerization techniques are evolving noxious factors such as toxic, reactive residues, un-reacted monomers, the risk of a chemical reaction and the formation of unwanted oligomers , and these drawbacks are overcome by using preformed polymers for the polymerization process . 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 nanoemulsion, 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 nanoparticle 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 , evaporation precipitation [36, 37], antisolvent precipitation and electrospray methods .
Also, many approaches have been developed for the drug particle size reduction (increase 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 multi-component particles because of different kinetics . Nanoparticles prepared by spray-drying 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 , 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 technology platform for recognizing the targeted, environment-responsive and, multi-functional with navigated controlled drug delivery system. Polymer in smart drug delivery is a rapid-emerging 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 , diabetes , 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 nano-particulate 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.
The rapid advancement in the above direction has been made with the initiation and development of more advanced alternative nanofabrication techniques to produce structures in various nano-scales level of controlled manners. Drug loaded polymeric nano-systems 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  microfluidic systems [72-76], electrodropping system , microneedle based system [78-81], advanced high pressure homogenization, interfacial emulsion polymerization 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-responsive micelles, colloids, nano hydrogel, core-shell nanoparticles, nano-spheres and core-shell 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 formulation method plays a vital role. Thus, it is extremely beneficial to have synthesis mechanism at hand to approach multi-functional polymeric nanoparticles with exact physiochemical properties for a specific application.
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 responses, 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 numerous 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 nanostructures 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 nanostructures have inherent capacity of the nano-carrier for delivering many kinds of active ingredients, because of good biocompatibility and degradation/resorption properties . 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 . In this self-assembled and core-shell particulate delivery systems, including water-soluble polymeric drug compounds conjugates , 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-responsive controlled release, and delivery of hydrophobic anticancer agents for acidic tumor tissues . Recently Choi DH, et al have optimized electrodropping system to produce a homogeneous biocompatible core shell capsules for angiogenesis in dual delivery system , 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 manipulating 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  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 . Recently, various micro-fluidic systems provide rapid mixing without any stimulator, such as stirring or electric force; have been originated . Among these various systems the flow-focusing , droplet mixers  are widely utilized and it enables micro-mixing within the micro channel . 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 .
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 transdermal 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 circulation via the skin, it provides the therapeutic advantage to clinical levels. The rate-programmed drug delivery systems, the release of drug molecules from the rate controlling membrane system has been pre-programmed at particular rate kinetics. The rate controlling 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 micro-scale 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 nanoparticles 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 hybrid-type and (4): reservoir partition-controlled systems. The recent advance in the smart rate-programmed 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 various applications. For selecting the polymers, need to consider some important key factors for pharmaceutical application such as reduced tensile strength , water vapor permeability rate, biocompatibility, non-toxic , 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 . 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-programmed polymeric membrane. The pre-programmed polymeric membrane can be optimized and achieved by multi-functionalization with block copolymers. The scaffold or membrane 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-programmed rate-controlling membrane; it's based on the molecules, diffusivity, partition co-efficient, 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 , ocular insert [119, 120], some transdermal therapeutic system , polymer matrix, sub-dermal  and subcutaneous implantation [122-125].
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 administration. 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).
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 . This has been targeted with hypoxia-responsive 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 reproducible nature, also remote controlled delivery possible, then the release profile can be pulsatile delivered (means that switched on and off) possible . On the other hand, the various light-responsive polymeric nanoparticles system has been developed for activating antitumor drug release . Also numerous of temperature-sensitive multi-functionalized polymeric and copolymers nanoparticles have been formulated based on thermally-responsive 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.
|Physical stimuli||Osmotic pressure||Controlled through the permeability of water|
Controlled through a gradient of osmotic pressure
|Hydrodynamic pressure||Generate hydrodynamic pressure gradient|
Forces the drug to release through the orifice
|Vapor pressure||Pumping system contains vaporizable fluid|
Creates vapor pressure, vaporizes at body temperature
|A mechanical force||Equipped with a mechanically activated pump|
First-pass elimination and pressure-sensitive delivery
|Magnetics||Electromagnetism-triggering vibration mechanism|
Magnetically activated, vibrate by an electromagnetic field
|Sonophoresis||Utilizes ultrasonic energy to activate the delivery|||
|Iontophoresis||Electrical current to activate and diffuse the charged drug|||
|Hydration||Utilized swellable polymer matrix|
Activated by hydration-induced swelling delivery
Electrically erodible matrix for delivery
|Chemical stimuli||pH||Deliver the drug in the intestinal tract not in the stomach|
Deliver the drug in the ulcer stomach by floating delivery
|Salt concentration||Prepared by ionizable drug with ion-exchange resin|
Controlling the delivery of an ionic or an ionisable drug
|Hydrolysis||Hydrolysis-induced degradation of polymer chains Hydrolysis activate the release of drug molecules|||
|Biochemical stimuli||Enzyme||Polymer chains fabricated with biopolymers|
Deliver the drug by enzymatic hydrolysis of polymers
Feedback-regulated delivery concept has been applied
|Environmental stimuli||Temperature||Depends on the transition temperature|
Shifting the hydrophilic/hydrophobic balance
|Light||Polymers undergo isothermal phase transitions by photon|
Reversible phase separations through photo-irradiation
|Hypoxia||Hydrophobically modified imidazole derivative was conjugated to the carboxymethyl dextran, it can release the hydrophobic agents under hypoxic conditions|||
|Dual-stimuli||Two different responses||Based on the polymer architecture|
Micelles are reported pH and thermo-responsive
|Multi-stimuli||More than two responses||Functionalization of pyrene-quaternized segments form a light-responsive shell and the unquaternized segments form a temperature/pH-responsive core|||
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 nano-particulate 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 nano-particulate 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 multi-functionalized 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 .
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 biocompatible, 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 polymeric 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.
|Dual-stimuli||pH & Thermo||P(NIPAAm-co-DMAAm-co-UA) nanoparticles|
PNIPAAm and PAA hollow nanogels
|pH & redox||PEG-SS-PDEA polymersomes|
Poly(b-amino ester)s-PEG micelles
|pH & magnetic||Fe3O4 nanocarrier with peptide mimic polymers|
DOX-tethered Fe3O4 conjugates nanoparticles
|T & redox||EO-PAA-PNIPAAm polymersomes|| |
|Double pH||PPC-Hyd-DOX-DA nanoparticles|
Poly-b-amino ester ketal nanoparticles
|pH & diols||PEG-b-dendritic cholic acid telodendrimers nano-carriers containing boronic acid|||
|T & magnetic||Pluronic with Fe3O4 nanoparticles|||
|T & enzyme||DNA-capped MSNs|||
|Multi- stimuli||T/pH/redox||PNIPAAm-SS-P(THP-protected HEMA) micelles|||
|T/pH/magnetic||P(NIPAAm-co-MAA) coated magnetic MSNs|||
|Fe(II) loaded PMAA crosslinked by N,N-methylene-bisacrylamide and N,N-bis(acryloyl)- cystamine|||
|Vesicles based on hosteguest complex formation between C4AS and MVC12|||
|Cucurbit(8)uril micelles, methylviologene-functionalize PNIPAAm and naphthalene-terminated PDMAEMA|||
|Light/pH/T||Pyrene-functionalized poly (dimethylaminoethyl methacrylate)|
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 self-regulating 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, enzyme-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, 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 . 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 de-swell 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 bio-erodible 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 , and some polymers require high pH to degrade.
The bio-responsive controlled drug delivery system, glucose-triggered insulin delivery has developed , 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 . Again in the development of self-regulating insulin delivery has achieved by enzymatically controlled implantable glucose-dependent insulin delivery systems . 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 co-polymeric 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 , 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 . Moreover, the molecular imprinting technology has a huge possibility for producing acceptable dosage forms in the feedback-regulated 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  and scaffolds  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. Nowadays the site targeted drug delivery systems involve deep investigation as they are very eager to overcome the modern medical application . A well-designed multi-functionalized 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 bio-pharmaceutics because of the effectiveness in controlled drug release. The traditional formulations 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, distribution, disintegration over time throughout the biological system, which provides the importance 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 . 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.
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 inflammations. 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 . 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 . Also the amine functionalized 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.
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, non-immunogenic 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].
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 necessary for medicine and healthcare development. In the material science field provides biodegradable, biocompatible, environment-responsive, and highly effective novel polymeric system for targeted delivery. Nanotechnology provides bottom-up and top-down nanofabrication 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.
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 mono-or 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 bio-molecule ratio should controlled by calculating the number of conjugate sites presents in the nanoparticles with different applications, 2) due to the environment and electrostatic interactions the alignment of functionalization has been varying, so the non specific attachment should be avoided in the performed nanoparticles, 3) depends on the applications requirements the nanoparticles bio-molecule distance should be maintained, 4) control the conjugation 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 . Also polymer nanoparticles are broadly used in several therapeutic applications, mostly cancer targeting and therapeutics. And we provide some examples of various nanoparticles with different functionalization and different therapeutic uses based on the target, shown in Table 3. Therefore, the multi-functionalized nanoparticle over comes from the drawbacks of conventional therapy. In the latest study provided that more than 26 nanoparticle based therapeutic system have been approved for clinical treatment and several nanoparticles are under consideration . 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.
|Human serum albumin||Amino/acid group||Doxorubicin||Antineoplastic|||
|Trimyristin||Sterically stabilized||Paclitaxel||Ovarian, lung, breast cancer|||
|PLLA-b-PEG||Folate targeted||Doxorubicin||Solid tumors|||
|PEG-PE||Lipid conjugated||Paclitaxel||Various cancers|||
|PEG||Lipid conjugated||Tamoxifen||Lung carcinoma|||
|Polymer-lipid hybrid||Lipid conjugated||Doxorubicin||Solid cancer|||
|PCL-b-trimethylene carbonate-PEG||Serum protein||Ellipticin||Anticancer|||
|PAMAM dendrimers||Folic acid||ethotrexate||Epithelial cancer|||
|PEG||Albumin bound||Doxorubicin||Various cancers|||
|Poly(DEAP-Lys)-b-PEG -b-PLLA||Poly(lysine)||Doxorubicin||pH sensitive tumor|||
|PLGA-b-PEG-COOH||PSMA||Anti cancer||Prostate- cancer|||
|PEG or PE particles||Transferrin||Oligonucleotide||Brain- gene|||
|PLLA-PEG||Biotin||Anti cancer||Cancer therapy|||
|Polystyrol||Sc-TNF||Anti cancer||Cancer therapy|||
|PLA||Aptamer||Anti cancer||Prostate cancer|||
|PE||RGD peptides||siRNA||Vasculature cancer|||
|mPEG/PLGA||Peptidomimetics||Anti cancer||Brain cells cancer|||
|PLGA||MP lipid A||Anti cancer||Dentritic cells|||
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 bio-medical 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 . 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 . For the hydrophobic drug the phage display technique has been used for the functionalization , and the bioavailability have enhanced by post-polymerization. Additionally, the post-polymerization with copolymer produces efficient targeting in the extracellular compartment of the biological system [297-300]. With the nanoparticles the polymers like PEG establishes for prolonged systemic circulation [301, 302]. For the stimuli responsive targeted drug delivery has been achieved by the functionalization of suitable materials (light or magnetic or thermal or ionic responsive material). Particularly, the magnetic induction systems have been used with functionalized magnetic nanoparticles for cell or tissue specific targeted delivery. For targeting brain delivery system the nanoparticles has been functionalized for specific or nonspecific binding mechanisms . The fabrication and functionalization science has merged with software oriented technology for the development of controlled and targeted nanoparticle loaded micro-device system . 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.
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 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. Nanotechnology manipulates the multiple properties including the size and other physical characteristics 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, intramuscular, 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 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, patient-friendly 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 hypodermic needles . 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 . 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 . Iontophoresis and electroporation use electric fields to alter the skin structure and/or provide additional driving force for drug penetration through the skin . 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].
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, polysaccharide 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 biocompatibility, 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 transdermal 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.
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 successfully 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 reasonably 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, functionalization, 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 combination 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.
This work was supported by the R&D Program for Society of the National Research Foundation(NRF) funded by the Ministry of Science, ICT & Future Planning (2013M3C8A3078806 and 2013M3C1A8A01072922).
Allemann E, Gurny R, Doelker E. Drug-Loaded Nanoparticles: Preparation Methods and Drug Targeting Issues. European Journal of Pharmaceutics and Biopharmaceutics 1993;39(5) 173-191.
Kawashima Y. Nanoparticulate Systems for Improved Drug Delivery. Advanced Drug Delivery Reviews 2001;47(1) 1-2.
Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable Polymeric Nanoparticles as Drug Delivery Devices. Journal of Controlled Release 2001;70(1-2) 1-20.
Panyam J, Labhasetwar V. Biodegradable Nanoparticle from Drug and Gene Delivery to Cells and Tissue. Advanced Drug Delivery Reviews 2003;55(3) 329-347.
Brigger I, Dubernet C, Couvreur P. Nanoparticles in Cancer Therapy and Diagnosis. Advanced Drug Delivery Reviews 2002;54(5) 631-651.
Cui Z, Mumper RJ. Plasmid DNA-Entrapped Nanoparticles Engineered from Microemulsion Precursors: In Vitro and In Vivo Evaluation. Bioconjugate Chemistry 2002;13(6) 1319-1327.
Cohen H, Levy RJ, Gao J, Fishbein I, Kousaev V, Sosnowski S, Slomkowski S, Golomb G. Sustained Delivery and Expression of DNA Encapsulated in Polymeric Nanoparticles. Gene Therapy 2000;(22) 71896-1905.
Cao X, Lai S, Lee LJ. Design of a Self-Regulated Drug Delivery Device. Biomedical Micro devices 2001;3(2)109-118.
Kasagana VN, Karumuri SS, Thirumal. M. Recent Advances in Smart Drug Delivery Systems. International Journal of Pharmacy and Biotechnology 2011;1(3) 201-207.
Kreuter, J. Nanoparticles and Nanocapsules-New Dosage Forms in the Nanometer Range. Pharmaceutica Acta Helvetiae 1978;53(2) 33-39.
Kreuter J. Nanoparticles. In: Swarbrick J, Boylan JC. (ed.) Encyclopedia of Pharmaceutical Technology. Marcel Dekker Inc: New York, NY, 1994. p165-190.
Birrenbach G, Speiser PP. Polymerized Micelles and their use as Adjuvants in Immunology. Journal of Pharmaceutical Sciences 1976;65(12) 1763-1766.
Fresta M, Cavallaro G, Giammona G, Wehrli E, Puglisi G. Preparation and Characterization of Polyethyl-2-Cyanoacrylate Nanocapsules containing Antiepileptic Drugs. Biomaterials 1996;17(8) 751-758.
Vauthier-Holtzscherer C, Benabbou S, Spenlehauer G, Veillard M, Couvreur P. Methodology for the Preparation of Ultra-Dispersed Polymer Systems. STP Pharma Sciences 1991;1 109-116.
Al Khouri Fallouh N, Roblot-Treupel L, Fessi H, Devissaguet JP, Puisieux F. Development of a New Process for the Manufacture of Polyisobutylcyanoacrylate Nanocapsules. International Journal of Pharmaceutics 1986;28(2-3) 125-132.
Rollot JM, Couvreur P, Roblot-Treubel L, Puisieux F. Physicochemical and Morphological Characterization of Polyisobutyl Cyanoacrylate Nanocapsules. Journal of Pharmaceutical Sciences 1986;75(4) 361-364.
Legrand P, Barratt G, Mosqueira V, Fessi H, Devissaguet JP. Polymeric Nanocapsules as Drug Delivery Systems. A review. STP Pharma Sciences 1999;9(5) 411-418.
Barratt GM. Therapeutic Applications of Colloidal Drug Carriers. Pharmaceutical Science and Technology Today 2000;3(5) 163-171.
Fresta M, Cavallaro G, Giammona G, Wehrli E, Puglisi G. Preparation and Characterization of Polyethyl-2-Cyanoacrylate Nanocapsules containing Antiepileptic Drugs. Biomaterials 1996;17(8) 751-758.
Schroeder U, Sommerfeld P, Ulrich S, Sabel BA. Nanoparticle Technology for Delivery of Drugs across the Blood-Brain Barrier. Journal of Pharmaceutical Sciences 1998;87(11) 1305-1307
Hans ML. Lowman AM. Biodegradable Nanoparticles for Drug Delivery and Targeting. Current Opinion in Solid State and Materials Science 2002;6(4) 319-327.
Arshady R. Preparation of Biodegradable Microspheres and Microcapsules: 2. Polylactides and Related Polyesters. Journal of Controlled Release 1991;17(1) 1-22.
Bodmeier R, Chen H, Tyle P, Jarosz P. Spontaneous Formation of Drug-containing Acrylic Nanoparticles. Journal of Microencapsulation 1991;8(2) 161-170.
Niwa T, Takeuchi H, Hino T, Kunou N, Kawashima Y. Preparations of Biodegradable Nanospheres of Water-Soluble and Insoluble Drugs with D,L-Lactide/Glycolide Copolymer by a Novel Spontaneous Emulsification Solvent Diffusion Method, and the Drug Release Behaviour. Journal of Controlled Release 1993;25(1-2) 89-98.
Leroux J-C, Allemann E, Doelker E, Gurny R. New Approach for the Preparation of Nanoparticles by an Emulsification-Diffusion Method. European Journal of Pharmaceutics and Biopharmaceutics 1995;41(3) 14-18.
Quintanar-Guerrero D, Fessi H, Allemann E, Doelker E. Influence of Stabilizing Agents and Preparative Variables on the Formation of Poly(D,L-Lactic Acid) Nanoparticles by an Emulsification-Diffusion Technique. International Journal of Pharmaceutics 1996;143(2) 133-141.
Kawashima Y, Niwa T, Handa T, Takeuchi H, Iwamoto T, Itoh K. Preparation Of Controlled-Release Microspheres of Ibuprofen with Acrylic Polymers by a Novel Quasi-Emulsion Solvent Diffusion Method. Journal of Pharmaceutical Sciences 1989;78(7) 68-72.
Kawashima Y, Iwamoto T, Niwa T, Takeuchi H, Hino T. Size Control of Ibuprofen Microspheres with an Acrylic Polymer by Changing the pH In an Aqueous Dispersion Medium and its Mechanism. Chemical and Pharmaceutical Bulletin 1993;41(1) 191-195.
Quintanar-Guerrero D, Allemann E, Doelker E, Fessi H. Preparation and Characterization of Nanocapsules from Preformed Polymers by a New Process based on Emulsification-Diffusion Technique. Pharmaceutical Research 1998;15(7) 1056-1062.
Allemann E, Doelker E, Gurny R. Drug Loaded Poly(lactic acid) Nanoparticles Produced by a Reversible Salting-out Process: Purification of an Injectable Dosage Form. European Journal of Pharmaceutics and Biopharmaceutics 1993;39 13-18.
Allemann E, Gurny R, Doelker E. Preparation of Aqueous Polymeric Nanodispersions by a Reversible Salting-Out Process: Influence of Process Parameters on Particle Size. International Journal of Pharmaceutics 1992;87(1-3) 247-253.
Rodrigues Jr JM, Fessi H, Bories C, Puisieux F, Devissaguet JP. Primaquine-Loaded Poly(Lactide) Nanoparticles: Physicochemical Study and Acute Tolerance in Mice. International Journal of Pharmaceutics 1995;126(1-2) 253-60.
Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule Formation by Interfacial Polymer Deposition Following Solvent Displacement. International Journal of Pharmaceutics 1989;55(1) R1-R4
Peltonen L, Koistinen P, Karjalainen M, Hakkinen A, Hirvonen J. The Effect of Cosolvents on the Formulation of Nanoparticles from Low-Molecular-Weight Poly(L)Lactide. AAPS PharmSciTech 2002;3(4) E32.
Niwa T, Takeuchi H, Hino T, Nohara M, Kawashima Y. Biodegradable Submicron Carriers for Peptide Drugs: Preparation of Dl-Lactide/Glycolide Copolymer (PLGA) Nanospheres with Nafarelin Acetate by a Novel Emulsion-Phase Separation Method in an Oil System. International Journal of Pharmaceutics 1995;121(1) 45-54.
Chen X, Young TJ, Sarkari M, Williams RO 3rd, Johnston KP. Preparation of Cyclosporine a Nanoparticle by Evaporative Precipitation into Aqueous Solution. International Journal of Pharmaceutics 2002;242(1-2) 3-14.
Sarkari M, Brown J, Chen X, Swinnea S, Williams RO 3rd, Johnston KP. Enhanced Drug Dissolution using Evaporative Precipitation into Aqueous Solution. International Journal of Pharmaceutics 2002;243(1-2) 17-31.
Gomez A, Bingham D, de Juan L, Tang K. Production of Protein Nanoparticles by Electrospray Drying. Journal of Aerosol Science 1998;29(5-6) 561-574.
Liversidge GG, Cundy KC. Particle Size Reduction for Improvement of Oral Bioavailability of Hydrophobic Drugs: I. Absolute Oral Bioavailability of Nanocrystalline Danazol in Beagle Dogs. International Journal of Pharmaceutics 1995;125(1) 91-97.
Jacobs C, Kayser O, Muller RH. Nanosuspensions as a New Approach for the Formulation for the Poorly Soluble Drug Tarazepide. International Journal of Pharmaceutics 2000;196(2) 161-164.
Merisko-Liversidge E, Sarpotdar P, Bruno J, Hajj S, Wei L, Peltier N, Rake J, Shaw JM, Pugh S, Polin L, Jones J, Corbett T, Cooper E, Liversidge GG. Formulation and Antitumor Activity Evaluation of Nanocrystalline Suspensions of Poorly Soluble Anticancer Drugs. Pharmaceutical Research 1996;13(2) 272-278.
Jacobs C, Kayser O, Muller RH. Production and Characterisation of Mucoadhesive Nanosuspensions for the Formulation of Bupravaquone. International Journal of Pharmaceutics 2001;214(1-2) 3-7.
Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: A Formulation Approach for Poorly-Water-Soluble Compounds. European Journal of Pharmaceutical Sciences 2003;18(2) 113-120.
Muller CR, Schaffazick SR, Pohlmann AR, de Lucca Freitas L, Pesce da Silveira N, Dalla Costa T, Guterres SS. Spray-Dried Diclofenac-Loaded Poly(E-Caprolactone) Nanocapsules and Nanospheres. Preparation and Physicochemical Characterization. Pharmazie 2001;56(11) 864-867.
Vergote GJ, Vervaet C, Van Driessche I, Hoste S, De Smedt S, Demeester J, Jain RA, Ruddy S, Remon JP. An Oral Controlled Release Matrix Pellet Formulation Containing Nanocrystalline Ketoprofen. International Journal of Pharmaceutics 2001;219(1-2) 81-87.
Bodmeier R, Wang H, Dixon DJ, Mawson S, Johnston KP. Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide. Pharmaceutical Research 1995;12(8) 1211-1217.
Reverchon E. Supercritical Antisolvent Precipitation of Micro-and Nano-Particles. Journal of Supercritical Fluids 1999;15(1) 1-21.
Reverchon E. Della Porta G. Production of Antibiotic Micro-and Nano-Particles by Supercritical Antisolvent Precipitation. Powder Technology 1999;106 23-29.
Reverchon E, Marco De I, Della Porta G. Rifampicin Micoparticles Production by Supercritical Antisolvent Precipitation. International Journal of Pharmaceutics 2002;243(1-2) 83-91.
Rogers TL, Johnston KP, Williams RO 3rd. Solution-based Particle Formation of Pharmaceutical Powders by Supercritical or Compressed Fluid Co2 and Cryogenic Spray-Freezing Technologies. Drug Development and Industrial Pharmacy 2001;27(10) 1003-1015.
Tom JW, Debenedetti PG. Particle Formation with Supercritical Fluids-A Review. Journal of Aerosol Science 1991;22(5) 555-584.
Tu LS, Dehghani F, Forster NR. Micronisation and Microencapsulation of Pharmaceuticals using a Carbon Dioxide Antisolvent. Powder Technology 2002;126(2) 134-149
Broadhead J, Rouan SKE, Rhodes CT. The Spray Drying of Pharmaceuticals. Drug Development and Industrial Pharmacy 1992;18(11-12) 1169-1206.
Giunchedi P, Conte U. Spray-Drying as a Preparation Method of Microparticulate Drug Delivery System: An Overview. STP Pharma Sciences 1995;5 276-290.
Nielsen F. Spray Drying Pharmaceuticals. Manufacturing Chemist 1982;57 38-41.
Esposito E, Cervellati F, Menegatti E, Nastruzzi C, Cortesi R. Spray Dried Eudragit Microparticles as Encapsulation Devices for Vitamin C. International Journal of Pharmaceutics 2002;242(1-2) 329-334.
Bodmeier, R. and Chen, H. Preparation of Biodegradable Poly(+)Lactide Microparticles using a Spray-Drying Technique. Journal of Pharmacy and Pharmacology 1988;40(11) 754-757.
Wang FJ, Wang CH. Sustained Release of Etanidazole from Spray Dried Microspheres Prepared by Non-Halogenated Solvents. Journal of Controlled Release 2002;81(3) 263-280.
Pignatello R, Vandelli MA, Giunchedi P, Puglisi G. Properties of Tolmetin-Loaded Eudragit RL100 and Eudragit RS100 Microparticles Prepared by Different Techniques. STP Pharma Sciences 1997;7 148-157.
Magenheim B, Benita S. Nanoparticle Characterization: A Comprehensive Physicochemical Approach. STP Pharma Sciences 1991;1 221-241.
Muller RH, Jacobs C, Kayser O. Nanosuspensions as Particulate Drug Formulations in Therapy Rationale for Development and what can we expect for the Future. Advanced Drug Delivery Reviews 2001;47(1) 3-19.
Palakodaty S, York P. Phase Behavioural Effects on Particle Formation Processes using Supercritical Fluids. Pharmaceutical Research 1999;16(7) 976-985.
Kong DF, Goldschmidt-Clermont PJ. Tiny Solutions for Giant Cardiac Problems. Trends in Cardiovascular Medicine 2005;15(6)207-11.
Khafagy el S, Morishita M, Onuki Y, Takayama K. Current Challenges in Non-Invasive Insulin Delivery Systems: A Comparative Review. Advanced Drug Delivery Reviews 2007;59(15) 1521-46.
Ferrari M. Cancer Nanotechnology: Opportunities and Challenges. Nature Reviews. Cancer 2005;5(3) 161-71.
Duncan R. Polymer Conjugates as Anticancer Nanomedicines. Nature Reviews. Cancer 2006; 6(9) 688-701.
Nasir A. Nanodermatology: A Bright Glimpse just Beyond the Horizon-Part I. Skin Therapy Letter 2010;15(8) 1-4.
Gupta S, Bansal R, Gupta S, Jindal N, Jindal A. Nanocarriers and Nanoparticles for Skin Care and Dermatological Treatments. Indian Dermatology Online Journal 2013;4(4) 267-272.
Silva GA. Neuroscience Nanotechnology: Progress, Opportunities and Challenges. Nature Reviews. Neuroscience 2006;7(1) 65-74.
Pardridge WM, Blood-Brain Barrier Delivery. Drug Discovery Today 2007;12(1-2) 54-61.
Nuxoll E. BioMEMS in Drug Delivery. Advanced Drug Delivery Reviews 2013;65(11-12) 1611-25.
Wang Y, Byrne JD., Napier ME, DeSimone JM. Engineering Nanomedicines using Stimuli-Responsive Biomaterials. Advanced Drug Delivery Reviews 2012;64(11) 1021-1030.
Shim TS, Kim S, Yang S, Elaborate Design Strategies Toward Novel Microcarriers for Controlled Encapsulation and Release. Particle and Particle Systems Characterization 2013;30(1) 9-45.
Christopher GF, Anna SL. Microﬂuidic Methods for Generating Continuous Droplet Streams. Journal of Physics D: Applied Physics 2007;40(19) R319-R336.
Dendukuri D, Doyle PS. The Synthesis and Assembly of Polymeric Microparticles using Microﬂuidics. Advanced Materials 2009;21(41) 4071-4086.
Valencia PM, Farokhzad OC, Karnik R, Langer R. Microfluidic Technologies for Accelerating the Clinical Translation of Nanoparticles. Nature Nanotechnology 2012;7(10) 623-9.
Choi DH, Subbiah R, Kim IH, Han DK, Park K. Dual Growth Factor Delivery using Biocompatible Core-Shell Microcapsules for Angiogenesis. Small 2013;9(20) 3468-76.
Luttge R, Berenschot E, De Boer M, Altpeter D, Vrouwe E, Van den Berg A, Elwenspoek M. Integrated Lithographic Molding for Microneedle-Based Devices. Journal of Microelectromechanical Systems 2007;6(4) 872-884.
Park J, Allen M, Prausnitz M, Biodegradable Polymer Microneedles: Fabrication, Mechanics and Transdermal Drug Delivery, Journal of Controlled Release 2005;104(1) 51-66.
Wendorf JR, Ghartey-Tagoe EB, Williams SC, Enioutina E, Singh P, Cleary GW, Transdermal Delivery of Macromolecules using Solid-State Biodegradable Microstructures. Pharmaceutical Research 2011;28(1) 22-30.
Raphael AP, Prow TW, Crichton ML, Chen X, Fernando GJP, Kendall MAF, Targeted Needle-Free Vaccinations in Skin Using Multilayered, Densely-Packed Dissolving Microprojection Arrays. Small 2010;6(16) 1785-1793.
Kronenberg HM. Developmental Regulation of the Growth Plate. Nature 2003;423(6937) 332-336.
Karsenty G. The Complexities of Skeletal Biology. Nature 2003;423(6937) 316-318.
Zhuang J, Wu H, Yang Y, Cao YC. Controlling Colloidal Superparticle Growth through Solvophobic Interactions. Angewandte Chemie 2008;47(12) 2208-2212.
Manoharan VN, Elsesser MT, Pine DJ. Dense Packing and Symmetry in Small Clusters of Microspheres. Science 2003;301(5632) 483-487.
Brannon-Peppas L. Recent Advances on the use of Biodegradable Microparticles Andnanoparticles in Controlled Drug Delivery. International Journal of Pharmaceutics 1995;116(1) 1-9.
Marimuthu M, Bennet D, Kim S. Self-assembled Nanoparticles OF PLGA-Conjugated Glucosamine as a Sustained Transdermal Drug Delivery Vehicle. Polymer Journal 2013;45 202-209
Kopecek J, Kopeckova P, Minko T, Lu ZR, Peterson CM. Water Soluble Polymers in Tumor Targeted Delivery. Journal of Controlled Release 2001;74(1-3) 147-158.
Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Development of the Polymer Micelle Carrier System for Doxorubicin. Journal of Controlled Release 2001;74(1-3) 295-302,
Tian Y, Bromberg L, Lin SN, Alan Hatton T, Tam KC. Complexation and Release of Doxorubicin from its Complexes with Pluronic P85-b-Poly(Acrylic Acid) Block Copolymers. Journal of Controlled Release 2007;121(3) 137-145.
Cao T, Munk P, Ramireddy C, Tuzar Z, Webber SE. Fluorescence Studies of Amphiphilic Poly(Methacrylic Acid)-Block-Polystyrene-Block-Poly(Methacrylic Acid) Micelles. Macromolecules 1991;24(23) 6300-6305.
Zhang L, Yu K, Eisenberg A. Ion-Induced Morphological Changes in "Crew-Cut" Aggregates of Amphiphilic Block Copolymers. Science 1996;272(5269) 1777-1779.
Discher DE, Eisenberg A. Polymer Vesicles. Science 2002;2979(5583) 967-973.
Lee CM, Tanaka T, Murai T, Kondo M, Kimura J, Su W, Kitagawa T, Ito T, Matsuda H, Miyasaka M. Novel Chondroitin Sulfate-Binding Cationic Liposomes Loaded with Cisplatin Efficiently Suppress the Local Growth and Liver Metastasis of Tumor Cells In Vivo. Cancer Research 2002;62(15) 4282-4288.
Gabizon AA. Selective Tumor Localization and Improved Therapeutic Index of Anthracyclines Encapsulated in Long-Circulating Liposomes. Cancer Research 1992;52(4) 891-896.
Cleland JL, Lim A, Barron L, Duenas ET, Powell MF. Development of a Single-Shot Subunit Vaccine for HIV-1: Part 4. Optimizing Microencapsulation and Pulsatile Release of MN rgp120 from Biodegradable Microspheres. Journal of Controlled Release 1997;47(2) 135-150.
Rilling P, Walter T, Pommershein R, Vogt W. Encapsulation of Cytochrome C by Multilayer Microcapsules. A Model for Improved Enzyme Immobilization. Journal of Membrane Science 1997;129(2) 283-287.
Fonseca T, Relogio P, Martinho JMG, Farinha JPS. Preparation and Surface Characterization of Polymer Nanoparticles Designed for Incorporation into Hybrid Materials. Langmuir 2007;23(10) 5727-5734.
Sajjadi S. Population Balance Modeling of Particle Size Distribution in Monomer-Starved Semibatch Emulsion Polymerization. AIChE Journal 2009;55(12) 3191-3205.
Hui Wang, Garry L, Rempel. pH-Responsive Polymer Core-Shell Nanospheres for Drug Delivery. Journal of Polymer Science, Part A: Polymer Chemistry 2013;51(20) 4440-4450
Valencia PM, Farokhzad OC, Karnik R, Langer R. Microfluidic Technologies for Accelerating the Clinical Translation of Nanoparticles. Nature Nanotechnology 2012;7(10) 623-9.
DeMello AJ. Control and Detection of Chemical Reactions in Microfluidic Systems. Nature 2006;442(7101) 394-402.
Capretto L, Cheng W, Hill M, Zhang X. Micromixing within Microfluidic Devices. Topics in Current Chemistry 2011;304 27-68.
Rhee M, Valencia PM, Rodriguez MI, Langer R, Farokhzad OC, Karnik R. Synthesis of Size-Tunable Polymeric Nanoparticles Enabled by 3D Hydrodynamic Flow Focusing in Single-Layer Microchannels. Advanced Materials 2011;23(12) H79–H83.
Liu K, Wang H, Chen KJ, Guo F, Lin WY, Chen YC, Phung DL, Tseng HR, Shen CK. A Digital Microfluidic Droplet Generator Produces Self-Assembled Supramolecular Nanoparticles for Targeted Cell Imaging. Nanotechnology 2010;21(44) 445603.
Valencia PM, Basto PA, Zhang L, Rhee M, Langer R, Farokhzad OC, Karnik R. Single-Step Assembly of Homogenous Lipid-Polymeric and Lipid-Quantum Dot Nanoparticles Enabled by Microfluidic Rapid Mixing. ACS Nano 2010;4(3) 1671-1679.
Jahn A, Reiner JE, Vreeland WN, DeVoe DL, Locascio LE, Gaitan M. Preparation of Nanoparticles by Continuous-Flow Microfluidics. Journal of Nanoparticle Research 2008;10(6) 925-934.
Bennet D, Kim S. A Transdermal Delivery System to Enhance Quercetin Nanoparticle Permeability, Journal of Biomaterials Science. Polymer Edition 2013;24(2) 185-209.
Bennet D, Marimuthu M, Kim S, An J. Dual Drug-Loaded Nanoparticles on Self-Integrated Scaffold for Controlled Delivery. International Journal of Nanomedicine 2012;2012(7) 3399-419.
Srinivasa PC, Ramesh MN, Tharanathan RN. Effect of Plasticizers and Fatty Acids on Mechanical and Permeability Characteristics of Chitosan Films. Food Hydrocolloids 2007;21(7) 1113-22.
Zhang ML, Gong XH, Zhao YD, Zhang NM. Properties and Biocompatibility of Chitosan Films Modified by Blending with PEG. Biomaterials 2002;23(13) 2641-8
Badet C, Furiga A, Thebaud N. Effect of Xylitol on an In Vitro Model of Oral Biofilm. Oral Health & Preventive Dentistry 2008;6(4) 337-41.
Chandy T, Mooradian DL, Rao GH. Chitosan/Polyethylene Glycol-Alginate Microcapsules for Oral Delivery of Hirudin. Journal of Applied Polymer Science 1998;70(11) 2143-2153.
Rajangam T, Paik HJ, An SSA. Development of Fibrinogen Microspheres as a Biodegradable Carrier for Tissue Engineering. BioChip Journal 2011;5(2) 175-183.
Bromberg LE, Ron ES. Temperature-Responsive Gels and Thermogelling Polymer Matrices for Protein and Peptide Delivery. Advanced Drug Delivery Reviews 1998;31(3)197-221.
Jain GK, Sharma AK, Agrawal SS. Transdermal Controlled Administration of Verapamil-Enhancement of Skin Permeability. International Journal of Pharmaceutics 1996;130(2) 169-177.
Ding H, Triggle CR. Endothelial Cell Dysfunction and the Vascular Complications Associated with Type 2 Diabetes: Assessing the Health of the Endothelium. Vascular Health and Risk Management 2005;1(1) 55-71.
Chien YW. Novel Drug Delivery Systems: 2nd ed, Revised and Expanded; Marcel Dekker, Inc.: New York, 1992.
Chien YW. Rate-Control Drug Delivery Systems: Controlled Release vs. Sustained Release. Medical Progress Through Technology 1989;15(1-2) 21-46.
Robinson JR. Sustained and Controlled Release Drug Delivery Systems; Marcel Dekker, Inc.: New York, 1978.
Hsieh DST. Subcutaneous Controlled Delivery of Estradiol by Compudose Implants: In Vitro and In Vivo Evaluations. Drug Development and Industrial Pharmacy 1987;13(15) 2651-2666.
Segal SJ. The Development of NORPLANT Implants. Studies in Family Planning 1983;14(6-7) 159-163.
Diaz S, Pavez M, Miranda P, Robertson DN, Sivin I, Croxatto HB. A ﬁve-Year Clinical Trial of Levonorgestrel Silastic Implants (Norplant 2). Contraception 1982;25(5) 447-456.
Weiner E, Victor A, Johansson ED. Plasma Levels of D-Norgestrel after Oral Administration. Contraception 1976;14(5) 563-570.
Croxatto HB, Diaz S, Miranda P, Elamsson K, Johansson ED. Plasma Levels of Levonorgestrel in Women during Longterm use of Norplant. Contraception 1981;23(2) 197-209.
Chien YW. Microsealed Drug Delivery Systems: Theoretical Aspects and Biomedical Assessments. In Recent Advances in Drug Delivery Systems; Anderson, JM, Kim, SW. Ed. Plenum Press: New York; 1984. p367-387.
Sunil K, Anil K, Vaibhav G, Kuldeep M, Pankaj R. Oral Extended Release Drug Delivery System A Promising Approach. Asian Pharma Press. Asian Journal of Research in Pharmaceutical Sciences 2012;2(3) 101-106.
Chien YW. Novel Drug Delivery Systems: Fundamental, Developmental Concepts and Biomedical Assessments; Marcel Dekker, Inc.: New York, 1982.
Haznar-Garbacz D, Garbacz G, Eisenacher F, Klein S, Weitschies W. A Novel Liquefied Gas based Oral Controlled Release Drug Delivery System for Liquid Drug Formulations. European journal of Pharmaceutics and Biopharmaceutics 2012;81(2) 334-8.
Rajesh A, Jaimin P, Sangeeta A. A Novel Approach: Pulsatile Drug Delivery System. International Research Journal of Pharm 2012;3(9) 43-49
Hsieh, DST, Langer R. Zero-order Drug Delivery Systems with Magnetic Control. In Controlled Release Delivery Systems; Roseman TJ, Mansdorf SZ. Ed. Marcel Dekker, Inc.: New York, 1983.
Tyle P, Agrawala P. Drug Delivery by Phonophoresis. Pharmaceutical Research 1989;6(5) 355-361.
Dhote V, Bhatnagar P, Mishra PK, Mahajan SC, Mishra DK. Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System. Scientia pharmaceutica 2012;80(1) 1-28.
Okahata Y, Hachiya S, Ariga K, Seki T. The Electrical Breakdown and Permeability Control of a Bilayer-Corked Capsule Membrane in an External Electric Field. Journal of the American Chemical Society 1986;108(11) 2863-2869.
Kwon IC, Bae YH, Kim SW. Electrically Erodible Polymer Gel for Controlled Release of Drugs. Nature 1991;354(6350) 291-293.
Foss AC, Goto T, Morishita M, Peppas NA. Development of Acrylic-based Copolymers for Oral Insulin Delivery. European Journal of Pharmaceutics and Biopharmaceutics 2004;57(2) 163-169.
Ramachandran S, Shaheedha SM, Thirumurugan G, Dhanaraju MD. Floating Controlled Drug Delivery System of Famotidine Loaded Hollow Microspheres (Microballoons) in the Stomach. Current Drug Delivery 2010;7(1) 93-7.
Chu LY, Yamaguchi T, Nakao S. A Molecular-Recognition Microcapsule for Environmental Stimuli-Responsive Controlled Release. Advanced Materials 2002;14(5) 386-389.
Heller J. Biodegradable Polymers in Controlled Drug Delivery. Critical Reviews in Therapeutic Drug Carrier Systems 1984;1(1) 39-90.
Morimoto Y, Fujimoto S. Albumin Microspheres as Drug Carriers. Critical Reviews in Therapeutic Drug Carrier Systems 1985;2(1) 19-63.
Veronese FM, Schiavon O, Pasut G, Mendichi R, Andersson L, Tsirk A, Ford J, Wu G, Kneller S, Davies J, Duncan R. PEG-Doxorubicin Conjugates: Inﬂuence of Polymer Structure on Drug Release, In Vitro Cytotoxicity, Biodistribution, and Antitumor Activity. Bioconjugate Chemistry 2005;16(4) 775-784.
You L-C, Lu F-Z, Li Z-C, Zhang W, Li F-M, Glucose-Sensitive Aggregates Formed by Poly(Ethylene Oxide)-Block-Poly(2-Glucosyloxyethyl Acrylate) with Concanavalin A in Dilute Aqueous Medium. Macromolecules 2003;36(1) 1-4.
Prausnitz MR, Langer R. Transdermal Drug Delivery. Nature biotechnology 2008;26(11) 1261-8.
Kaneko Y, Nakamura S, Sakai K, Kikuchi A, Aoyagi T, Sakurai Y, Okano T. Synthesis and Swelling-Deswelling Kinetics of Poly(n-Isopropylacrylamide) Hydrogels Grafted with LCST Modulated Polymers. Journal of Biomaterials Science. Polymer Edition 1999;10(11) 1079-1091.
Nakayama M, Okano T, Miyazaki T, Kohori F, Sakai K, Yokoyama M. Molecular Design of Biodegradable Polymeric Micelles for Temperature-Responsive Drug Release, Journal of Controlled Release 2006;115(1) 46-56.
Irie M. Stimuli-Responsive Poly(N-Isopropylacrylamide). Photo and Chemical-Induced Phase Transitions. Advances in Polymer Science 1993;110 49-65.
Suzuki A, Tanaka T. Phase Transition in Polymer Gels Induced by Visible Light. Nature 1990;346 345-347.
Thambi T, Deepagan VG, Yoon HY, Han HS, Kim SH, Son S, Jo DG, Ahn CH, Suh YD, Kim K, Kwon IC, Lee DS, Park JH. Hypoxia-Responsive Polymeric Nanoparticles for Tumor-Targeted Drug Delivery. Biomaterials 2014;35(5) 1735-43.
Schmaljohann D. Thermo-and pH-Responsive Polymers in Drug Delivery. Advanced Drug Delivery Reviews 2006;58(15)1655-70.
Wei H, Zhang XZ, Cheng H, Chen WQ, Cheng SX, Zhuo RX. Self-Assembled Thermo-and pH Responsive Micelles of Poly(10-Undecenoic Acid-B-N-Isopropylacrylamide) for Drug Delivery. Journal of Controlled Release 2006;116(3) 266-74.
Medeiros SF, Santos AM, Fessi H, Elaissari A. Stimuli-Responsive Magnetic Particles for Biomedical Applications. International Journal of Pharmaceutics 2011;403(1-2) 139-61.
Cheng R, Meng F, Deng C, Klok HA, Zhong Z. Dual and Multi-Stimuli Responsive Polymeric Nanoparticles for Programmed Site-Specific Drug Delivery. Biomaterials 2013;34(14) 3647-57.
Torchilin V. Tumor Delivery of Macromolecular Drugs based on the EPR Effect. Advanced Drug Delivery Reviews 2011;63(3) 131-5.
Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J, Campbell T, De Witt D, Figa M, Figueiredo M, Horhota A, Low S, McDonnell K, Peeke E, Retnarajan B, Sabnis A, Schnipper E, Song JJ, Song YH, Summa J, Tompsett D, Troiano G, Van Geen Hoven T, Wright J, LoRusso P, Kantoff PW, Bander NH, Sweeney C, Farokhzad OC, Langer R, Zale S. Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile. Science Translational Medicine 2012;4(128) 128ra139.
Gong J, Chen MW, Zheng Y, Wang SP, Wang YT. Polymeric Micelles Drug Delivery System in Oncology. Journal of Controlled Release 2012;159(3) 312-23.
Deng C, Jiang YJ, Cheng R, Meng FH, Zhong ZY. Biodegradable Polymeric Micelles for Targeted and Controlled Anticancer Drug Delivery: Promises, Progress and Prospects. Nano Today 2012;7(5) 467-80.
Meng FH, Cheng R, Deng C, Zhong ZY. Intracellular Drug Release Nanosystems. Materials Today 2012;15(10) 436-42.
Ganta S, Devalapally H, Shahiwala A, Amiji M. A Review of Stimuli-Responsive Nanocarriers for Drug and Gene Delivery. Journal of Controlled Release 2008;126(3) 187-204.
Meng FH, Zhong ZY, Feijen J. Stimuli-Responsive Polymersomes for Programmed Drug Delivery. Biomacromolecules 2009;10(2) 197-209.
Rapoport N. Physical Stimuli-Responsive Polymeric Micelles for Anti-Cancer Drug Delivery. Progress in Polymer Science 2007;32(8-9) 962-90.
Chen W, Meng FH, Li F, Ji SJ, Zhong ZY. pH-Responsive Biodegradable Micelles based on Acid-Labile Polycarbonate Hydrophobe: Synthesis and Triggered Drug Release. Biomacromolecules 2009;10(7) 1727-35.
Du JZ, Tang YQ, Lewis AL, Armes SP. pH-Sensitive Vesicles based on a Biocompatible Zwitterionic Diblock Copolymer. Journal of the American Chemical Society 2005;127(51) 17982-3.
Saito G, Swanson JA, Lee KD. Drug Delivery Strategy Utilizing Conjugation via Reversible Disulﬁde Linkages: Role and Site of Cellular Reducing Activities. Advanced Drug Delivery Reviews 2003;55(2) 199-215.
Meng FH, Hennink WE, Zhong ZY. Reduction-Sensitive Polymers and Bio-Conjugates for Biomedical Applications. Biomaterials 2009;30(12) 2180-98.
Cheng R, Feng F, Meng FH, Deng C, Feijen J, Zhong ZY. Glutathione-Responsive Nano-Vehicles as a Promising Platform for Targeted Intracellular Drug and Gene Delivery. Journal of Controlled Release 2011;152(1) 2-12.
Kuppusamy P, Li H, Ilangovan G, Cardounel AJ, Zweier JL, Yamada K, Krishna MC, Mitchell JB. Noninvasive Imaging of Tumor Redox Status and its Modiﬁcation by Tissue Glutathione Levels. Cancer Research 2002;62(1) 307-12.
Chan A, Orme RP, Fricker RA, Roach P. Remote and Local Control of Stimuli Responsive Materials for Therapeutic Applications. Advanced Drug Delivery Reviews 2013;65(4) 497-514.
Alvarez-Lorenzo C, Bromberg L, Concheiro A. Light-Sensitive Intelligent Drug Delivery Systems. Photochemistry and Photobiology 2009;85(4) 848-60.
Chilkoti A, Dreher MR, Meyer DE, Raucher D. Targeted Drug Delivery by Thermally Responsive Polymers. Advanced Drug Delivery Reviews 2002;54(5) 613-30.
Wei H, Cheng SX, Zhang XZ, Zhuo RX. Thermo-Sensitive Polymeric Micelles based on Poly(N-Isopropylacrylamide) as Drug Carriers. Progress in Polymer Science 2009;34(9) 893-910.
Arruebo M, Fernandez-Pacheco R, Ibarra MR, Santamaria J. Magnetic Nano-Particles for Drug Delivery. Nano Today 2007;2(3) 22-32.
Sun C, Lee JSH, Zhang M. Magnetic Nanoparticles in MR Imaging and Drug Delivery. Advanced Drug Delivery Reviews 2008;60(11) 1252-65.
Xu HF, Meng FH, Zhong ZY. Reversibly Crosslinked Temperature-Responsive Nano-Sized Polymersomes: Synthesis and Triggered Drug Release. Journal of Materials Chemistry 2009;19(24) 4183-90.
Cheng R, Meng FH, Ma SB, Xu HF, Liu HY, Jing XB, Zhong Z. Reduction and Temperature Dual-Responsive Crosslinked Polymersomes for Targeted Intracellular Protein Delivery. Journal of Materials Chemistry 2011;21(47) 19013-20.
Dai J, Lin SD, Cheng D, Zou SY, Shuai XT. Interlayer-Crosslinked Micelle with Partially Hydrated Core Showing Reduction and pH Dual Sensitivity for Pin-Pointed Intracellular Drug Release. Angewandte Chemie 2011;50(40):9404-8.
Soppimath KS, Tan DCW, Yang YY. pH-Triggered Thermally Responsive Polymer Core-Shell Nanoparticles for Drug Delivery. Advanced Materials 2005;17(3) 318-23.
Zhang LY, Guo R, Yang M, Jiang XQ, Liu BR. Thermo and pH Dual-Responsive Nanoparticles for Anti-Cancer Drug Delivery. Advanced Materials 2007;19(19) 2988-92
Lo CL, Lin KM, Hsiue GH. Preparation and Characterization of Intelligent Core-Shell Nanoparticles based on Poly(D, L-lactide)-g-Poly(N-Isopropyl-Acryl-Amide-Co-Methacrylic Acid). Journal of Controlled Release 2005;104(3) 477-88.
Li W, Li JF, Gao J, Li BH, Xia Y, Meng YC, Yu Y, Chen H, Dai J, Wang H, Guo Y. The Fine-Tuning of Thermosensitive and Degradable Polymer Micelles for Enhancing Intracellular Uptake and Drug Release in tumors. Biomaterials 2011;32(15) 3832-44.
Xing ZM, Wang CL, Yan J, Zhang L, Li L, Zha LS. Dual stimuli responsive hollow nanogels with IPN structure for temperature controlling drug loading and pH triggering drug release. Soft Matter 2011;7(18) 7992-7.
Zhang JC, Wu LL, Meng FH, Wang ZJ, Deng C, Liu H, Zhong Z. pH and Reduction Dual-Bioresponsive Polymersomes for Efﬁcient Intracellular Protein Delivery. Langmuir 2011;28(4) 2056-65.
Bahadur KCR, Thapa B, Xu P. pH and Redox Dual Responsive Nanoparticle for Nuclear Targeted Drug Delivery. Molecular Pharmaceutics 2012;9(9) 2719-29.
Chen J, Qiu XZ, Ouyang J, Kong JM, Zhong W, Xing MMQ. pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery. Biomacromolecules 2011;12(10) 3601-11.
Pan YJ, Chen YY, Wang DR, Wei C, Guo J, Lu DR, Chu CC, Wang CC. Redox/pH Dual Stimuli-Responsive Biodegradable Nanohydrogels with Varying Responses to Dithiothreitol and Glutathione for Controlled Drug Release. Biomaterials 2012; 33(27) 6570-9.
Shao Y, Huang W, Shi C, Atkinson ST, Luo J. Reversibly Crosslinked Nanocarriers for On-Demand Drug Delivery in Cancer Treatment. Therapeutic delivery 2012;3(12) 1409-27.
Barick KC, Singh S, Jadhav NV, Bahadur D, Pandey BN, Hassan PA. pH-Responsive Peptide Mimic Shell Cross-Linked Magnetic Nanocarriers for Combination Therapy. Advanced Functional Materials 2012;22(23) 4975-4.
Zhao ZH, Huang DT, Yin ZY, Chi XQ, Wang XM, Gao JH. Magnetite Nanoparticles as Smart Carriers to manipulate the Cytotoxicity of Anticancer Drugs: Agnetic Control and pH-Responsive Release. Journal of Materials Chemistry 2012;22(31) 15717-5.
Gan Q, Lu XY, Yuan Y, Qian JC, Zhou HJ, Lu X, Shi J, Liu C. A Magnetic, Reversible pH-Responsive Nanogated Ensemble based on Fe3O4 Nanoparticles-Capped Mesoporous Silica. Biomaterials 2011;32(7) 1932-2.
Gan Q, Lu XY, Dong WJ, Yuan Y, Qian JC, Li YS, Shi J, Liu C. Endosomal pH-Activatable Agnetic Nanoparticle-Capped Mesoporous Silica for Intracellular Controlled Release. Journal of Materials Chemistry 2012;22(31) 15960-8.
Xu HF, Meng FH, Zhong ZY. Reversibly Crosslinked Temperature-Responsive Nano-Sized Polymersomes: Synthesis and Triggered Drug Release. Journal of Materials Chemistry 2009;19(24) 4183-90.
Cheng R, Meng FH, Ma SB, Xu HF, Liu HY, Jing XB, Zhong Z. Reduction and Temperature Dual-Responsive Crosslinked Polymersomes for Targeted Intracellular Protein Delivery. Journal of Materials Chemistry 2011;21(47) 19013-20.
Du JZ, Du XJ, Mao CQ, Wang J. Tailor-Made Dual pH-Sensitive Polymer-Doxorubicin Nanoparticles for Efﬁcient Anticancer Drug Delivery. Journal of the American Chemical Society 2011;133(44) 17560-3.
Sankaranarayanan J, Mahmoud EA, Kim G, Morachis JM, Almutairi A. Multi-Response Strategies to Modulate Burst Degradation and Release from Nanoparticles. ACS Nano 2010;4(10) 5930-6.
Li YP, Xiao WW, Xiao K, Berti L, Luo J, Tseng HP, Fung G, Lam KS. Well-Deﬁned, Reversible Boronate Crosslinked Nanocarriers for Targeted Drug Delivery in Response to Acidic pH Values AND Cis-Diols. Angewandte Chemie 2012;124(12) 2918-23.
Liu TY, Hu SH, Liu KH, Shaiu RS, Liu DM, Chen SY. Instantaneous Drug Delivery of Magnetic/Thermally Sensitive Nanospheres by a High-Frequency Magnetic Field. Langmuir 2008;24(23) 13306-11.
Chen C, Geng J, Pu F, Yang XJ, Ren JS, Qu XG. Polyvalent Nucleic Acid/Meso-Porous Silica Nanoparticle Conjugates: Dual Stimuli-Responsive Vehicles for Intracellular Drug Delivery. Angewandte Chemie 2011;123(4) 912-6.
Klaikherd A, Nagamani C, Thayumanavan S. Multi-Stimuli Sensitive Amphiphilic Block Copolymer Assemblies. Journal of American Chemical Society 2009;131(13) 4830-8.
Chang BS, Sha XY, Guo J, Jiao YF, Wang CC, Yang WL. Thermo and pH Dual Responsive, Polymer Shell Coated, Magnetic Mesoporous Silica Nanoparticles for Controlled Drug Release. Journal of Materials Chemistry 2011;21(25) 9239-47.
Bilalis P, Chatzipavlidis A, Tziveleka LA, Boukos N, Kordas G. Nanodesigned Magnetic Polymer Containers for Dual Stimuli Actuated Drug Controlled Release and Magnetic Hyperthermia Mediation. Journal of Materials Chemistry 2012;22(27) 13451-4.
Wang K, Guo DS, Wang X, Liu Y. Multistimuli Responsive Supramolecular Vesicles based on the Recognition of P-Sulfonatocalixarene and its Controllable Release of Doxorubicin. ACS Nano 2011;5(4) 2880-94.
Loh XJ, Jesus del B, Toh PPC, Lee TC, Jiao DZ, Rauwald U, Appel EA, Scherman OA. Triply Triggered Doxorubicin Release from Supramolecular Nanocontainers. Biomacromolecules 2012;13(1) 84-91.
Heller J, Self-regulated drug delivery systems. Medical Device and Diagnostic Industry 1985;7 32-37.
Zhao L, Xiao C, Ding J, He P, Tang Z, Pang X, Zhuang X, Chen X. Facile One-Pot Synthesis of Glucose-Sensitive Nanogel via Thiol-ene Click Chemistry for Self-Regulated Drug Delivery. Acta Biomaterialia 2013;9(5) 6535-43.
Heller J. Chemically Self-Regulated Drug Delivery Systems. Journal of Controlled Release 1988;8(2) 111-125.
Zhou G, Lu Y, Zhang H, Chen Y, Yu Y, Gao J, Sun D, Zhang G, Zou H, Zhong Y. A novel pulsed drug-delivery system: polyelectrolyte layer-by-layer coating of chitosan-alginate microgels. International Journal of Nanomedicine 2013;8 877-87.
Singh BN, Kim KH. Floating Drug Delivery Systems: An Approach to Oral Controlled Drug Delivery via Gastric Retention. Journal of Controlled Release 2000;63(3) 235-59.
Alhaique F, Marchetti M, Riccieri F, Santucci E. A Polymeric Film Responding in Diffusion Properties to Environmental PH Stimuli: A Model for a Self-Regulating Drug Delivery System. The Journal of pharmacy and pharmacology 1981;33(7) 413-6.
Alhaique F, Riccieri FM, Santucci E, Crescezi V, Gamini A. A Possible pH-Controlled Drug Delivery System based on a Derivative of the Polysaccharide Scleroglucan, Journal of Pharmacy and Pharmacology 1984;37(5) 310-313.
Bala K, Vasudevan P. pH-Sensitive Microcapsules for Drug Release, Journal of Pharmaceutical Sciences 1982;71(8) 960-962.
Okahata Y, Ozaki K, Seki T. pH-Sensitive Permeability Control of Polymer Grafted Nylon Capsule Membranes. Journal of the Chemical Society, Chemical Communications 1984;(8) 518-521.
Okahata Y, Seki T, pH-Sensitive Capsule Membranes. Reversible Permeability Control from the Dissociative Bilayer-Coated Capsule Membrane by an Ambient pH Change. Journal of American Chemical Society 1984;106(26) 8065–8070.
Siegel RA, Firestone BA. pH-Dependent Equilibrium Swelling Properties of Hydrophobic Polyelectrolyte Copolymer Gels. Macromolecules 1988;21(11) 3254-3259.
Heller J, Trescony PV. Controlled Drug Release by Polymer Dissolution. II: Enzyme-Mediated Delivery Device. Journal of Pharmaceutical Sciences 1979;68(7) 919-921.
Trehan A, Ali A. Recent Approaches in Insulin Delivery. Drug Development and Industrial Pharmacy 1998;24(7) 589-97.
Jeong SY, Kim SW, Eenink MJD, Feijen J. Self-Regulating Insulin Delivery Systems. I. Synthesis and Characterization of Glycosylated Insulin. Journal of Controlled Release 1984;1(1) 57-66.
Fischel-Ghodsian F, Brown L, Mathiowitz E, Brandenburg D, Langer R. Enzymatically Controlled Drug Delivery. Proceedings of the National Academy of Sciences of the United States of America 1988;85(7) 2403-2406.
Hassan CM, Doyle III FJ, Peppas NA.Dynamic Behavior of Glucose-Responsive Poly(methacrylic acid-g-ethylene glycol) Hydrogels. Macromolecules 1997;30 6166-6173.
Kost J, Horbett TA, Ratner BD, Singh M. Glucose Sensitive Membranes Containing Glucose Oxidase: Activity, Swelling and Permeability Studies. Journal of Biomedical Materials Research 1985;19(9) 1117-1133.
Albin G, Horbett TA,. Ratner BD. Glucose Sensitive Membranes for Controlled Delivery of Insulin: Insulin Transport Studies. Journal of Controlled Release 1985;2 153-164.
Jin X, Zhang X, Wu Z, Teng D, Zhang X, Wang Y, Wang Z, Li C. Amphiphilic Random Glycopolymer Based on Phenylboronic Acid: Synthesis, Characterization, and Potential as Glucose-Sensitive Matrix. Biomacromolecules 2009;10(6) 1337-45.
Ishihara K, Kobayashi M, Shonohara I. Insulin Permeation through Amphiphilic Polymer Membranes having 2-Hydroxyethyl Methacrylate Moiety. Polymer Journal 1984;16 647-651.
Ishihara K, Matsui K. Glucose Responsive Insulin Release from Polymer Capsule. Journal of Polymer Science Part C: Polymer Letters 1986;24(8) 413-417.
Ishihara K. Glucose-Responsive Polymers for Controlled Insulin Release. Proceedings International Symposium Controlled Release Bioact. Mater. 1988;15 168-169.
You JO, Auguste DT. Feedback-Regulated Paclitaxel Delivery based on Poly(N,N-Dimethylaminoethyl Methacrylate-Co-2-Hydroxyethyl Methacrylate) Nanoparticles. Biomaterials 2008;29(12) 1950-7.
Ludvig N, Medveczky G, Rizzolo R, Tang HM, Baptiste SL, Doyle WK, Devinsky O, Carlson C, French JA, Kral JG, Charchaflieh J, Kuzniecky RI. An Implantable Triple-Function Device for Local Drug Delivery, Cerebrospinal Fluid Removal and EEG Recording in the Cranial Subdural/Subarachnoid Space of Primates. Journal of Neuroscience Methods 2012;203(2) 275-83.
Hiratani H, Alvarez-Lorenzo C. The Nature of Backbone Monomers Determines the Performance of Imprinted Soft Contact Lenses as Timolol Drug Delivery Systems. Biomaterials 2004;25(6) 1105-13.
Duffy DJ, Das K, Hsu SL, Penelle J, Rotello VM, Stidham HD. Binding Efficiency and Transport Properties of Molecularly Imprinted Polymer Thin Films. Journal of the American Chemical Society 2002;124(28) 8290-6.
Kumar N. Handbook of Particulate Drug Delivery (Nanotechnology book Series). Valencia, CA, USA: American Scientiﬁc Publishers, 2008, vol. 1.
Yamamoto Y, Tsutsumi Y, Yoshioka Y, Nishibata T, Kobayashi K, Okamoto T, Mukai Y, Shimizu T, Nakagawa S, Nagata S, Mayumi T. Site-Speciﬁc PEGylation of a Lysine-Deficient TNF-Alpha with Full Bioactivity. Nature Biotechnology 2003;21(5) 546-552.
Farokhzad OC, Dimitrakov JD, Karp JM, Khademhosseini A, Freeman MR, Langer R. Drug Delivery Systems in Urology--Getting "Smarter". Urology 2006;68(3) 463-9.
Patel MP, Patel RR, Patel JK. Chitosan Mediated Targeted Drug Delivery System: A Review. Journal of Pharmaceutical Sciences 2010;13(4) 536-57.
Kishida A. A Site-Specific Polymeric Drug Carrier for Renal Disease Treatment. Trends in Pharmacological Sciences 2003;24(12) 611-3.
Liu L, Fishman ML, Kost J, Hicks KB. Pectin-Based Systems for Colon-Specific Drug Delivery via Oral Route. Biomaterials. 2003;24(19) 3333-43.
Shirota K, Kato Y, Suzuki K, Sugiyama Y. Characterization of Novel Kidney-Specific Delivery System using an Alkylglucoside Vector. Journal of Pharmacology and Experimental Therapeutics 2001;299(2) 459-67.
Heaton LL, Lopez E, Maini PK, Fricker MD, Jones NS. Advection, Diffusion, and Delivery over a Network. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 2012;86(2 pt 1) 021905-10.
Watkins PK, Walker AB, Verschoor GL. Dynamical Monte Carlomodeling of Organic Solar Cells: The Dependence of Internal Quantum Efﬁciency on Morphology. Nano Letters 2005;5(9) 1814-1818.
Basu S, Gerchman Y, Collins CH, Arnold FH, Weiss R. A Synthetic Multicellular System for Programmed Pattern Formation. Nature 2005;434(7037) 1130-4.
Pierobon M, Akyildiz I. Capacity of a Diffusion-based Molecular Communication System with Channel Memory and Molecular Noise. IEEE Transactions on Information Theory 2013;59(2) 942-954.
Moore M, Enomoto A, Nakano T, Egashira R, Suda T, Kayasuga A, Kojima H, Sakakibara H, Oiwa K. A Design of a Molecular Communication System for Nanomachines using Molecular Motors. Pervasive Computing and Communications Workshops, 2006. PerCom Workshops 2006. Fourth Annual IEEE International Conference 2006; 6 p559.
Haas M, Mooletmar F, Meijer DK, de Zeeuw D. Speciﬁc Drug Delivery to the Kidney. Cardiovascular Drugs and Therapy 2002;16(6) 489-96.
Kitamura M, Fine LG. The Concept of Glomerular Self-Defense. Kidney International 1999;55(5) 1639-71.
Christensen EI, Bim H, Verroust P, Moestrup SK. Membrane Receptors For Endocytosis in the Renal Proximal Tubule. International Review Of Cytology 1998;180 237-84.
Leung S, Bendayan R. Role of P-Glycoprotein in the Renal Transport of Dideoxynucleoside Analog Drugs. Canadian Journal of Physiology and Pharmacology 1999;77(8) 625-30.
van Ginneken CA, Russel FG. Saturable Pharmacokineticsin the Renal Excretion of Drugs. Clinical Pharmacokinetics 1989;16(1) 38-54.
Brenner BM, Hostetter TH, Humes HD. Glomerular Permselectivity: Barrier Function based on Discrimination of Molecular Size and Charge. The American Journal of Physiology 1978;234(6) F455-F460.
Takakura Y, Fujita T, Hashida M, Sezaki H. Disposition Characteristics of Macromolecules in Tumor-Bearing Mice. Pharmaceutical Research 1990;7(4) 339-346.
Kamada H, Tsutsumi Y, Sato-Kamada K, Yamamoto Y, Yoshioka Y, Okamoto T, Nakagawa S, Nagata S, Mayumi T. Synthesis of a Poly(Vinylpyrrolidone-Co-Dimethyl Maleic Anhydride) Co-Polymer and its Application for Renal Drug Targeting. Nature Biotechnology 2003;21(4) 399-404.
Manil L, Davin JC, Duchenne C, Kubiak C, Foidart J, Couvreur P, Mahieu P. Uptake of Nanoparticles by Rat Glomerular Mesangial Cells In Vivo and In Vitro. Pharmaceutical Research 1994;11(8) 1160-5.
Choi CH, Zuckerman JE, Webster P, Davis ME. Targeting Kidney Mesangium by Nanoparticles of Deﬁned Size. Proceedings of the National Academy of Sciences of the United States of America 2011;108(16) 6656-61.
Subbiah R, Ramalingam P, Ramasundaram S, Kim DY, Park K, Ramasamy MK, Choi KJ. N,N,N-Trimethyl Chitosan Nanoparticles for Controlled Intranasal Delivery of HBV Surface Antigen. Carbohydrate Polymers 2012;89(4) 1289-1297.
Brich Z, Ravel S, Kissel T, Fritsch J, Schoffmann A. Preparation and Characterization of a Water Soluble Dextran Immunoconjugate of Doxorubicin and the Monoclonal Antibody. Journal of Controlled Release 1992;19(1-3) 245-258.
Igarashi R, Mizushima Y, Takenaga M, Matsumoto K, Morizawa Y, Yasuda A. A Stable PGE1 Prodrug for Targeting Therapy. Journal of Controlled Release 1992;20(1) 37-46.
Kopecek J. Targetable Polymeric Anticancer Drugs. Temporal Control of Drug Activity. Annals of the New York Academy of Sciences 1991;618 335-344.
Nishikawa M, Ohtsubo Y, Ohno J, Fujita T, Koyama Y, Yamashita F, Hashida M, Sezaki H. Pharmacokinetics of Receptor-Mediated Hepatic Uptake of Glycosylated Albumin in Mice. International Journal of Pharmaceutics 1992;85(1-3) 75-85.
Yamaoka T, Tabata Y, Ikada Y. Fate of water-Soluble Polymers Administered via Different Routes. Journal of pharmaceutical sciences 1995;84(3) 349-354.
Yamaoka T, Tabata Y, Ikada Y. Distribution and Tissue Uptake of Poly (Ethylene Glycol) with Different Molecular Weights after Intravenous Administration to Mice. Journal of Pharmaceutical Sciences 1994;83(4) 601-606.
Wang G, Kuroda K, Enoki T, Grosberg A, Masamune S, Oya T, Takeoka Y, Tanaka T. Gel Catalysts That Switch On and Off. Proceedings of the National Academy of Sciences of the United States of America 2000;97(18) 9861-4.
Alvarez-Lorenzo C, Concheiro A. Molecularly Imprinted Polymers for Drug Delivery. Journal of chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 2004;804(1) 231-45.
Guo Z, Pereira T, Choi O, Wang Y, Hahn HT. Surface Functionalized Alumina Nanoparticle Filled Polymeric Nanocomposites with Enhanced Mechanical Properties. Journal of Materials Chemistry 2006;16(1) 2800-2808.
Dreis S, Rothweiler F, Michaelis M, Cinatl J, Kreuter J, Langer K. Preparation, Characterization and Maintenance of Drug Efficacy of Doxorubicin-Loaded Human Serum Albumin (HSA) Nanoparticles. International Journal of Pharmaceutics 2007;341(1-2) 207-214.
Lee MK, Lim SJ, Kim CK. Preparation, Characterization and In Vitro Cytotoxicity of Paclitaxel-Loaded Sterically Stabilized Solid Lipid Nanoparticles. Biomaterials 2007;28(12) 2137-2146.
Lee ES, Na K, Bae YH. Polymeric Micelle for Tumor pH and Folate-Mediated Targeting. Journal of Controlled Release 2003;91(1-2) 103-113.
Wang J, Mongayt D, Torchilin VP. Polymeric Micelles for Delivery of Poorly Soluble Drugs: Preparation and Anticancer Activity In Vitro of Paclitaxel Incorporated into Mixed Micelles based on Poly(Ethylene Glycol)-Lipid Conjugate and Positively Charged Lipids. Journal of Drug Targeting 2005;13(1-2) 73-80.
Gao Z, Lukyanov A, Singhal A, Torchilin V. Diacyllipid-Polymer Micelles as Nanocarriers for Poorly Soluble Anticancer Drugs. Nano Letters 2002;2(9) 979-982.
Wong HL, Rauth AM, Bendayan R, Wu XY. In Vivo Evaluation of a New Polymer–Lipid Hybrid Nanoparticle (Pln) Formulation of Doxorubicin in a Murine Solid Tumor Model. European Journal of Pharmaceutics and Biopharmaceutics 2007;65(3) 300-308.
Liu J, Zeng F, Allen C. Influence of Serum Protein on Polycarbonate-based Copolymer Micelles as a Delivery System for a Hydrophobic Anti-Cancer Agent. Journal of Controlled Release 2005;103(2) 481-497.
Latallo JF, Candido KA, Cao Z, Nigavekar SS, Majoros IJ, Thomas TP, Balogh LP, Khan MK, Baker J. Nanoparticles Targeting of Anticancer Drug Improves Therapeutic Response in Animal Model of Human Epithelial Cancer. Cancer Research 2005;65(12) 5317-5324.
Wosikowski K, Biedermann E, Rattel B, Breiter N, Jank P, Loser R, Jansen G, Peters GJ. In Vitro and In Vivo Antitumor Activity of Methotrexate Conjugated to Human Serum Albumin in Human Cancer Cells. Clinical Cancer Research 2003;9(5) 1917-1926.
Schnyder A, Krahenbuhl S, Drewe J, Huwyler J. Targeting of Daunomycin using Biotinylated Immunoliposomes: Pharmacokinetics, Tissue Distribution and In Vitro Pharmacological Effects. Journal of Drug Targeting 2005;13(5) 325-335.
Choi SW, Kim JH. Design of Surface Modified Poly (D, L-Lactide-Co-Glycolide) Nanoparticles for Targeted Drug Delivery to Bone. Journal of Controlled Release 2007;122(1) 24-30.
Oh KT, Oh YT, Oh NM, Kim K, Lee DH, Lee ES. A Smart Flower-Like Polymeric Micelle for PH-Triggered Anticancer Drug Release. International Journal Of Pharmaceutics 2009;375(1-2) 163-169.
Cheng J, Teply BA, Sherifi I, Sung J, Luther G, Gu FX, Levy-Nissenbaum E, Radovic-Moreno AF, Langer R, Farokhzad OC. Formulation of Functionalized PLGA-PEG Nanoparticles for In Vivo Targeted Drug Delivery. Biomaterials 2007;28(5) 869-876.
Vinogradov SV, Batrakova EV, Kabanov AV. Nanogels for Oligonucleotide Delivery to the Brain. Bioconjugate Chemistry 2004;15(1) 50-60.
Patil YB, Toti US, Khadir A, Ma L, Panyam J. Single-Step Surface Functionalization of Polymeric Nanoparticles for Targeted Drug Delivery. Biomaterials 2009;30(5) 859-866.
Messerschmidt SKE, Musyanovych A, Altvater M, Scheurich P, Pfizenmaier K, Landfester K, Kontermann RE. Targeted Lipid-Coated Nanoparticles: Delivery of Tumor Necrosis Factor-Functionalized Particles to Tumor Cells. Journal of Controlled Release 2009;137(1) 69-77.
Farokhzad OC, Jon S, Khademhosseini A, Tran TT, LaVan A, Langer R. Nanoparticle-Aptamer Bioconjugates: A New Approach for Targeting Prostate Cancer Cells. Cancer Research 2004;64(21) 7668-7672.
Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, Molema G, Lu PY, Scaria PV, Woodle MC. Cancer siRNA Therapy by Tumor Selective Delivery with Ligand-Targeted Sterically Stabilized Nanoparticle. Nucleic Acids Research 2004;32(19) e149-e150.
Olivier JC. Drug Transport to Brain with Targeted Nanoparticles. NeuroRx 2005;2(1) 108-119.
Cho CS, Cho KY, Park IK, Kim SH, Sasagawa T, Uchiyama M, Akaike T. Receptor-Mediated Delivery of All Trans-Retinoic Acid to Hepatocyte Using Poly(L-Lactic Acid) Nanoparticles Coated with Galactose-Carrying Polystyrene. Journal of Controlled Release 2001;77(1-2) 7-15.
Elamanchili P, Diwan M, Cao M, Samuel J. Characterization of Poly(D,L-Lactic-Co-Glycolic Acid) based Nanoparticulate System for Enhanced Delivery of Antigens to Dendritic Cells. Vaccine 2004;22(19) 2406-2412.
Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in Medicine: Therapeutic Applications and Developments. Clinical Pharmacology and Therapeutics 2008;83(5) 761-769.
Roux S, Garcia B, Bridot JL, Salome M, Marquette C, Lemelle L, Gillet P, Blum L. Perriat P, Tillement O. Synthesis and Characterization of Dihydrolipoic Acid Capped Gold Nanoparticles and Functionalization by the Electroluminescent Luminal. Langmuir 2005;21(6) 2526-2536.
Zatats M, Katz E, Baron R, Willner I. Reconstitution of Apo Glucose Dehydrogenase on Pyrroloquinoline Quinine-Functionalized Au Nanoparticles Yields an Electrically Contacted Biocatalyst. Journal of the American Chemical Society 2005;127(35) 12400-12406.
Ulman A. Formation and Structure of Self-Assembled Monolayers. Chemical Reviews 1996;96(4) 1533-1554.
Fan H, Chen Z, Brinker CJ, Clawson J, Alam T. Synthesis of Organo-Silane Functionalized Nanocrystal Micelles and their Self-Assembly. Journal of the American Chemical Society 2005;127(40) 13746-13747.
Ramirez E, Jansat S, Philippot K, Lecante P, Gomez M, Masdeu-Bulto AM, Chaudret B. Influence of Organic Ligands on the Stabilization of Palladium Nanoparticles. Journal of Organometallic Chemistry 2004;689(24) 4601-4610.
Woehrle GH, Hutchison JE. Thiol-Functionalized Undecagold Clusters by Ligand Exchange: Synthesis, Mechanism, and Properties. Inorganic Chemistry 2005;44(18) 6149-6158.
Sandi G, Kizilel R, Carrado KA, Fernandez-saavedra R Castagnola N. Effect of the Silica Precursor on the Conductivity of Hectorite-Derived Polymer Nanocomposites. Electrochimica Acta 2005;50(19) 3891-3896.
Huang WY, Han CD. Dispersion Characteristics and Rheology of Organoclay Nanocomposites based on a Segmented Main-Chain Liquid-Crystalline Polymer Having Pendent Pyridyl Group. Macromolecules 2006;39(1) 257-267.
Mammeri F, Le Bourhis E, Rozes L, Sanchez CJ. Mechanical Properties of Hybrid Organic-Inorganic Materials. Journal of Materials Chemistry 2005;15(1) 3787-3811.
Sanchez C, Ribot F. Design of Hybrid Organic-Inorganic Materials Synthesized Via Sol-Gel Chemistry. New Journal of Chemistry 1994;18(1) 1007-1047.
Judeinstein P, Sanchez C. Hybrid Organic-Inorganic Materials: A Land of Multidisciplinarity. Journal of Materials Chemistry 1996;6(1) 511-525.
Zhang X, Simon LC. In Situ Polymerization of Hybrid Polyethylene-Alumina Nanocomposites. Macromolecular Materials and Engineering 2005;290(6) 573-583.
Gao SL, Mader E. Characterization of Interphase Nanoscale Property Variations in Glass Fibre Reinforced Polypropylene and Epoxy Resin Composites. Composites Part A: Applied Science and Manufacturing 2002;33(4) 559-576.
Shenhar R, Norsten TB, Rotello VM. Polymer-Mediated Nanoparticle Assembly: Structural Control and Applications. Advanced Materials 2005;17(6) 657-669.
Rothenfluh DA, Bermudez H, O’neil1 CP, Hubbell JA. Biofunctional Polymer Nanoparticles for Intra-Articular Targeting and Retention in Cartilage. Nature Materials 2008;7(3) 248-254.
Arap W, Kolonin MG, Trepel M, Lahdenranta J, Cardo-vila M, Giordano RJ, Mintz PJ, Ardelt PU, Yao VJ, Vidal CL, Flamm CL, Valtanen H, Weavind LM, Hicks ME, Pollock RE, Botz GH, Bucana CD, Koivunen E, Cahill D, Troncoso P, Baggerly KA, Pentz RD, Do KA, Logothetis CJ, Pasqualini R. Steps Toward Mapping the Human Vasculature by Phage Display. Nature medicine 2002;8(2) 121-127.
Kolonin MG, Sun J, Do KA, Vidal CI, Ji Y, Baggerly KA, Pasqualini R, Arap W. Synchronous Selection of Homing Peptides for Multiple Tissues by In Vivo Phage Display. FASEB Journal 2006;20(7) 979-981.
Smith GP, Petrenko VA. Phage Display. Chemical Reviews 1997;97(2) 391-410.
Rehor A, Hubbell JA, Tirelli N. Oxidation-Sensitive Polymeric Nanoparticles. Langmuir 2005;21(1) 411-417.
Harris JM, Martin NE, Modi M. Pegylation: A Novel Process for Modifying Pharmacokinetics. Clinical Pharmacokinetics 2001;40(7) 539-551.
Orringer DA, Koo YE, Chen T, Kopelman R, Sagher O, Philbert MA. Small Solutions for Big Problems: The Application of Nanoparticles to Brain Tumor Diagnosis and Therapy. Clinical Pharmacology & Therapeutics 2009;85(5) 531-534.
Prescott JH, Lipka S, Baldwin S, Sheppard NF, Maloney JM, Coppeta J, Yomtov B, Staples MA Santini JT. Chronic, Programmed Polypeptide Delivery from an Implanted, Multireservoir Microchip Device. Nature Biotechnology 2006;24(4) 437-438.
Lutz JF. Solution Self-Assembly of Tailor-Made Macromolecular Building Blocks Prepared by Controlled Radical Polymerization Techniques. Polymer International 2006;55 979-993.
Jagur-Grodzinski J. Preparation of Functionalized Polymers using Living and Controlled Polymerizations. Reactive & Functional Polymers 2001;49(1) 1-54.
Matyjaszewski K. Macromolecular Engineering: From Rational Design through Precise Macromolecular Synthesis and Processing to Targeted Macroscopic Material Properties. Progress in Polymer Science 2005;30(8-9) 858-875.
Taton D, Gnanou Y, Matmour R, Angot S, Hou SJ, Francis R, Lepoittevin B, Moinard D, Babin J. Controlled Polymerizations as Tools for the Design of Star-like and Dendrimer-like Polymers. Polymer International 2006;55(10) 1138-1145.
Brauncker WA, Matyjaszewski K. Controlled/Living Radical Polymerization: Features, Developments, and Perspectives. Progress in Polymer Science 2007;32(1) 93-146.
Zhang XW, Lian XM, Liu L, Zhang J, Zhao HY. Synthesis of Comb Copolymers with Pendant Chromophore Groups based on RAFT Polymerization and Click Chemistry and Formation of Electron Donor-Acceptor Supramolecules. Macromolecules 2008;41(21) 7863-7869.
Gondi SR, Vogt AP, Sumerlin BS. Versatile Pathway to Functional Telechelics via RAFT Polymerization and Click Chemistry. Macromolecules 2007;40(3) 474-481.
Gao H, Matyjaszewski K. Synthesis of Molecular Brushes by “Grafting Onto” Method: Combination of ATRP and Click Reactions. Journal of the American Chemical Society 2007;129(20) 6633-6639.
Liu H, Li CH, Liu HW, Liu SY. pH-Responsive Supramolecular Self-Assembly of Well-Defined Zwitterionic ABC Miktoarm Star Terpolymers. Langmuir 2009;25(8) 4724-4734.
Arora A, Hakim I, Baxter J, Rathnasingham R, Srinivasan R, Fletcher DA, Mitragotri S. Needle-Free Delivery of Macromolecules Across the Skin by Nano Liter Volume Pulsed Microjets. Proceedings of the National Academy of Sciences of the United States of America 2007;104(11) 4255-4260.
Bashir SL, Chew AL, Anigbogu A, Dreher F, Maibach HI. Physical and Physiological Effects of Stratum Corneum Tape Stripping. Skin Research Technology 2001;7(1) 40-48.
Doukas AG, Kollias N. Transdermal Drug Delivery with a Pressure Wave. Advanced Drug Delivery Reviews 2004;56(5) 559-579.
Habash RW, Bansal R, Krewski D, Alhafid HT. Thermal Therapy, Part 1: An Introduction to Thermal Therapy. Critical Reviews in Biomedical Engineering 2006;34(6) 459-489.
Karande P, Jain A, Mitragotri S. Discovery of Transdermal Penetration Enhancers by High-Throughput Screening. Nature Biotechnology 2004;22(2) 192-197.
Lee SH, Lee HH, Choi SS. Nanoparticle Popsicle: Transdermal Delivery of Nanoparticles using Polymeric Microneedle array. Korean Journal of Chemical Engineering 2011;28(9) 1913-1917.
Demir YK, Akan Z, Kerimoglu O. Characterization of Polymeric Microneedle Arrays for Transdermal Drug Delivery. 2013;8(10) e77289.
Tuan-Mahmood TM, McCrudden MT, Torrisi BM, McAlister E, Garland MJ, Singh TR, Donnelly RF. Microneedles for Intradermal and Transdermal Drug Delivery. European Journal of Pharmaceutical Sciences 2013;50(5) 623-37.
Prausnitz MR. Microneedles for Transdermal Drug Delivery. Advanced Drug Delivery Reviews 2004;56(5) 581-587.
Mitragotri S. Current Status and Future Prospects of Needle-Free Liquid Jet Injectors. Nature Reviews. Drug Discovery 2006;5(7) 543-548.
Paliwal S, Menon GK, Mitragotri S. Low-Frequency Sonophoresis: Ultrastructural basis for Stratum Corneum Permeability Assessed using Quantum Dots. Journal of Investigative Dermatology 2006;126(5) 1095-1101.
Guy RH, Kalia YN, Delgado-Charro MB, Merino V, Lopez A, Marro D. Iontophoresis: Electrorepulsion and Electroosmosis. Journal of Controlled Release 2000;64(1-3) 129-132.
Al-Qadi S, Grenha A, Remunan-Lopez C. Microspheres Loaded with Polysaccharide Nanoparticles for Pulmonary Delivery: Preparation, Structure and Surface Analysis. Carbohydrate Polymers 2011;86(1) 25-34.
Taranejoo S, Janmaleki M, Raﬁenia M, Kamali M, Mansouri M. Chitosan Microparticles Loaded with Exotoxin A Subunit Antigen for Intranasal Vaccination Against Pseudomonas Aeruginosa: An In Vitro Study. Carbohydrate Polymers 2011;83(4) 1854-1861.