Stimuli-Responsive Polymers

One of the most important fields of interest in respect of stimuli-responsive hydro-gels is modeling and simulation of their deswelling behavior. The problem mentioned above plays an important role regarding diffusion of fluid from hydrogel to media, what is very useful in biomedical applications, such as controlled drug delivery systems, biomaterials or biosensors. In this study, the pH-and temperature responsive poly(N-isopropylacrylamide-co-acrylic acid) interpenetrating polymer network (poly(NIPAAm-co-AAc) IPN) hydrogel was synthesized by free radical solution polymerization method. In order to improve the deswelling rate of the conventional poly(NIPAAm-co-AAc) hydrogels, their IPN structure was synthesized by using poly(NIPAAm-co-AAc) microgels. The chemical structure and surface morphology of poly(NIPAAm-co-AAc) IPN hydrogels were characterized by FT-IR and SEM analysis techniques. The synthesized poly(NIPAAm-co-AAc) IPN hydrogel has high swelling capacity (112 g water/g dry polymer at 20 °C and pH 7) and exhibited fast and multivariable deswelling behaviors dependent on pH and temperature. The pH-and temperature-dependent mechanical property of IPN hydrogel was investigated. It was found that the compressive strength of the IPN hydrogels was changed inversely proportional to the swelling capacity. To develop the model for deswelling behaviors of IPN hydrogel, artificial neural network (ANN) model and least squares support vector machine model techniques were used. The predictions from the ANN model showed very good correlation with observed data. The results indicated that the ANN model could accurately predict complex deswelling behavior of pH-and temperature-responsive IPN hydrogels.

Background: Silicon and its oxides are widely used in biomaterials research, tissue engineering and drug delivery. These materials are highly biocompatible, easily surface-functionalized, degrade into non-toxic silicic acid and can be processed into various forms such as micro- and nanoparticles, monoliths, membranes and micromachined structures.  The large surface area of porous forms of silicon and silica (up to 1200 m2g-1) permits high drug loadings. Discussion: The degradation kinetics of silicon and silica based materials can be tailored by coating or grafting with polymers.  Incorporation of polymers also improves control over drug release kinetics. The use of stimuli-responsive polymers has enabled environmental stimuli triggered drug release.  At the same time, silicon micro-fabrication techniques have facilitated the development of sophisticated implantable drug delivery micro-devices. This paper reviews the synthesis, novel properties and biomedical applications of silicon-polymer hybrid materials with particular emphasis on drug delivery. Conclusion: The biocompatible and bioresorptive properties of mesoporous silica and porous silicon make these materials attractive candidates for use in biomedical applications. The combination of polymers with silicon-based materials has generated a large range of novel hybrid materials tailored to applications in localized and systemic drug delivery.

In the past few years, an increasing number of stimuli responsive thin polymer films and intelligent hydrogels have been reported in the literature for various biomedical applications, including drug delivery, tissue engineering and wound healing. The thermo-sensitive approach can be advantageous for some specific applications as it does not require organic solvents, co-polymerization agents, or an externally applied trigger for gelation. The conformation as well as change in physical properties of polymer brushes and polymer hydrogel can be influenced by the environmental stimuli, such as solvent composition, temperature, pH and electric fields. This review focuses on the recent advances of these stimuli responsive molecular thin film and stimuli responsive polymeric gels with unique properties and utilities. We also discuss some conflicting behaviors shown by polymer grafted membrane and polymer gel surfaces, synthesized by using same monomers. Major properties of stimuli responsive thin polymer films, and on their potential application in the field of nano-optics, ultrasensitive spectroscopies and other biomedical applications including drug delivery are also outlined.

New temperature-responsive hydrogels containing various composition of N-acryloyl morpholine (AM) and N-isopropyl acrylamide (NIPAM) were prepared by free-radical solution poly- merization using poly(ethyleneglycol) diacrylate (PEGDA) as the chemical crosslinker. The gels were responsive to changes in external temperature, and exhibited the volume phase transition phenomenon. The gels swelled extensively in water at 23◦C, with water-uptake of more than 90% at swelling equilibrium. The influ- ence of molecular heterogeneity of the gels in terms of co-monomer and crosslinker composition on the swelling capacity and equilib- rium water uptake was evaluated. The dye adsorption capacity of the gels at room temperature was studied using Congo red as a model dye. The gels displayed significant adsorption capacity of the dye, and the adsorption capacity was found to be dependent on the hydrophilic character of the gel. The characteristic adsorption parameters were determined using the Langmuir isotherm model. The value of equilibrium binding constant was below 1 which indi- cated favorable adsorption of dye by the hydrogels. The dye release behavior was studied below and above the volume phase transition temperature of the gels. The dye release from the gels was about 95% at temperatures above the volume phase transition temper- ature of the gels. These gels can be used as reversible sorbents in the efficient removal of Congo red from waste water.

New multi-stimuli responsive cationic copolymers based on N-acryloyl-N0-ethyl piperazine (AcrNEP) and N-isopro- pylacrylamide (NIPAM) were prepared by thermal free-radical solution polymerization in dioxane at 75 􏰀C. The chemical com- position of the copolymers was determined by 1H NMR spec- troscopy and was found that the copolymers were slightly rich in NIPAM content than that of AcrNEP. The reactivity of the two monomers for the copolymerization reaction was eval- uated by the extended Kelen-Tu€do€s method. The distribution of monomer sequence in the copolymer chain was estimated using the terminal copolymerization model. The maximum tendency to alternation (􏰁 70%) was at 60 mol % of AcrNEP in the monomer feed. The copolymers were readily soluble in water at room temperature at all compositions and exhibited well-defined lower critical solution temperature (LCST) phe- nomenon. The influence of various stimuli such as pH, temper- ature, simple inorganic salts, and surfactants on the LCST of the copolymers was studied in detail. Simple inorganic salts such as sodium chloride, sodium bromide, and sodium sulfate showed a salting-out effect while sodium iodide showed a salt- ing-in effect. The salting-out coefficient of the salts were calcu- lated using the Sestchenow method, and the salting trend followed the order SO422 > Cl2 > Br2 > I2. The divalent salt was more effective in lowering the LCST than the monovalent salts. The cationic surfactant hexadecyl trimethylammonium bromide at concentrations above the critical micelle concentration caused a gradual increase in the LCST of the copolymer solu- tions. The intrinsic viscosity and light scattering behavior of the copolymers in water and in sodium chloride solutions were studied in detail.

The convergence of wearable sensors and personalized medicine enhance the ability to sense and control the drug composition and dosage, as well as location and timing of administration. To date, numerous stimuli-triggered smart drug-delivery systems have been developed to detect changes in light, pH, temperature, biomolecules, electric field, magnetic field, ultrasound and mechanical forces. This review examines the major advances within the last 5 years for the three most common light-responsive drug delivery-on-demand strategies: photochemical, photoisomerization and photothermal. Examples are highlighted to illustrate progress of each strategy in drug delivery applications, and key limitations are identified to motivate future research to advance this important field.

Thermal desolvation of poly(N-isopropylacrylamide) (PNIPAM) in the pres-ence of a low concentration of gold nanoparticles incorporates the nano-particles resulting in suspended aggregates. By covalently incorporating <1% acenaphthylene into the polymerization feed this copolymer is enabled to be used as a model to study the segmental mobility of the PNIPAM backbone in response to gold nanoparticles both below and above the desolvation temperature, showing that there is a physical conformational rearrange-ment of the soluble polymer at ultralow nanoparticle loadings, indicating low affinity interactions with the nanoparticles. Thermal desolvation is capable of extracting >99.9% of the nanoparticles from their solutions and hence demonstrates that poly(N-isopropylacrylamide) can act as an excellent scrubbing system to remove metallic nanomaterial pollutants from solution.

In this study, we investigate the thermotropic effects of diblock copolymer poly(N-isopropylacrylamide)-block-poly(acrylic acid) (PNIPAM-b-PAA) on fully hydra-ted 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayers and its ability to alter the membranes' organization , fluidity and phase behavior. The composition of the diblock copolymer and the nature of dispersion medium (pH and ionic strength) were also examined. For these purposes, pure DPPC lipid and polymer–lipid mixed systems, hydrated in three different dispersion media (i.e., HPLC-grade water, phosphate buffer saline and hydrochloric acid solution of pH 4.5), were investigated by differential scanning calorimetry. Two compositions of PNIPAM-b-PAA with different molar ratio of the polymeric blocks were used. PNIPAM-b-PAA presents great scientific interest due to the combination of the special characteristics of its homopolymer components; it is dual responsive both in temperature and in pH changes. The incorporation of the PNIPAM-b-PAA into the DPPC bilay-ers causes particularly significant perturbations in their thermotropic behavior, slightly different in each dispersion medium. The results indicated the ordering of the polymer guest near the polar head group surface probably by its PAA block and, on the other hand, the penetration of the PNIPAM block into the hydrophobic bilayer core, causing membrane disruption in a temperature-depended manner. We can conclude that the lipid–polymer interactions seem to be affected by the pH and the ionic strength of the hydration medium, as well as the polymer content incorporated in the DPPC bilayer. These studies could be a roadmap in order to rationally design and develop chimeric liposomes.

Poly(2-ethyl-2-oxazoline) and acrylic acid were copolymerized in different compositions using gamma rays-induced polymerization and cross-linking to obtain a series of pH-sensitive hydrogels. The preparation parameters that may affect the copolymerization process such as the feed solution composition and irradiation dose were optimized. Swelling characteristics of the obtained polymeric hydrogels were evaluated. The results show the significant effects of the hydrogel composition, soaking time, and pH on the swelling equilibrium. The diffusion parameters obtained at pH 1 and 7 show the possibility of using the prepared hydrogels in the field of colon-specific drug delivery systems. Ibuprofen as a model drug was loaded into (poly(2-ethyl-2-oxazoline)/acrylic acid) copolymer hydrogel to investigate their drug release behavior at different pH values.

In this report, we employ surface-initiated atom transfer radical
polymerization (SI-ATRP) to graft a thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM), of controlled thickness from porous silicon (pSi) films to produce a stimulus-responsive inorganic-organic composite material. The optical properties of this material are studied using interferometric reflectance
spectroscopy (IRS) above and below the lower critical solution temperature (LCST) of the PNIPAM graft polymer with regard to variation of pore sizes and thickness of the pSi layer (using discrete samples and pSi gradients) and also the thickness of the PNIPAM coatings. Our investigations of the composite’s thermal
switching properties show that pore size, pSi layer thickness, and PNIPAM coating thickness critically influence the material’s thermoresponsiveness. This composite material has considerable potential for a range of applications including temperature sensors and feedback controlled drug release. Indeed, we demonstrate that modulation of the temperature around the LCST significantly alters the rate of release of the fluorescent anticancer drug camptothecin from the pSi-PNIPAM composite films.

A versatile drug delivery carrier that responds to external stimuli was synthesized via the emulsion poly-merization process. This simple two-step process was carried out by using Poly (Methyl Methacrylate) as a soft template and a series of monomers, with desired properties, as coating monomers. It is noteworthy that during shell fabrication (2nd step) an inner cavity is created inside the nanocontainers that can be used as a host for small drug molecules. The thermo-, pH-and redox sensitive monomers used in the coating procedure were Dimethyl Amino Ethyl Methacrylate (DMAEMA), Acrylic Acid (AA) and N,N-(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (Disulfide or DS), respectively. It has to be noted that DMAEMA is also pH-sensitive and acts synergistically with AA. The surface of the multi-stimuli nanocontainers was functionalized with magnetite nanoparticles in order to induce an alternating magnetic field (AMF) sensitivity. By using AMF in various strenghts and frequencies, the temperature of the final multi-stimuli nanocontainers (Q-NCs) can be increased in a controlled manner resulting in the Hyperthermia phenomenon. Loading and release studies were carried out using the anthracycline drug, Doxorubicin, aiming at the confirmation of the release mechanism.

The present work reports the synthesis of Amino acid functionalized hydrogel networks (AFHs). N-acryloyl-Lphenylalanine and N'-isopropylacrylamide and were crosslinked by N,N-methylene-bis-acrylamide using redox polymerization technique. The diffusion parameters were calculated by swelling kinetics to understand the diffusion mechanism. Equilibrium swelling experiments have been performed on the AFHs in metal ion solutions. The effect of relevant parameters, such as contact time, initial pH, and initial metal ion concentration were investigated to determine the optimum sorption conditions. Adsorption equilibrium data were better fitted by a Langmuir isotherm. The adsorption capacity of Eu 3+ on the AFHs was 0.89 mM/g. Desorption studies were also performed in acid media and EDTA, to observe whether the gels can be utilized as reusable tool for the metal ion removal. Metal ion sorption studies shows that AFHs can be used for removal of Eu 3+ ions from aqueous solutions. Adsorption data were modeled using the pseudo-second-order. The experimental data were fitted well the pseudo-second-order kinetics.

Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previously shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor coverage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid delivery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration.

ABSTRCT. The pH sensitive hydrogels composed of N-isopropylacrylamide (NIPA) and acryloyl phenylalanine (APA) were prepared by redox polymerization using N,N'-methylenebisacrylamide (MBA) as a crosslinker. Anti-inflammatory and analgesic agent, Keterolac Tromethamine (KT), was loaded successfully into poly(NIPA-co-APA) copolymeric hydrogels by swelling equilibrium method. To understand the nature of drug in the polymeric matrix, the newly synthesized drug loaded poly(NIPAco-APA) copolymeric hydrogels were characterized by using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques. The scanning electron microscopy (SEM) technique result indicates the spherical smooth surface of the hydrogels. The drug (KT) releasing nature of the poly(NIPA-co-APA) hydrogels was studied in pH 1.2 and 7.4. Effects of drug loading, crosslinking agent, pH and the ionic strength of the external medium on swelling of hydrogels were also investigated.