Dual Stimuli-responsive Polymer Research Articles

Design of dual stimuli-responsive gels with physical and chemical properties that vary in response to light and temperature and cell behavior on their surfaces

Cell behaviors are highly sensitive to the surrounding environment. Therefore, in regulating cells, biomaterial substrates should be designed so their properties are similar to the surrounding environments of the cells. For cell regulation, we designed dual stimuli-responsive gels whose physical (elastic modulus) and chemical (hydrophilicity) properties can be changed by varying the UV exposure time and temperature, respectively. A dual stimuli-responsive polymer with photodimerizable groups and temperature-responsive moieties was prepared by copolymerizing 7-methacryloyloxycoumarin (MAC) and methoxyoligoethylene glycol methacrylate (OEGMA). The resulting polymers (P(MAC-co-OEGMA)) had lower critical solution temperatures (LCSTs), which depended on the compositions. A buffer solution containing P(MAC-co-OEGMA) was exposed to ultraviolet light (UV) for gelation, and the elastic modulus increased with increasing exposure time. The cell behavior, including adhesion and spreading, on the surfaces of these gels was investigated. Most of the cells adhered to P(MAC-co-OEGMA) gels with higher elastic moduli, and the cells were spread more effectively at temperatures above the LCST. This was because cell adhesion and spreading were strongly influenced by the physical and chemical properties of the P(MAC-co-OEGMA) gels, which were regulated by varying the UV exposure time and temperature.

Design of Dual Stimuli-Responsive Polymers that Undergo Sol-Gel Phase Transition in Response to Light and Biomolecule and Their Application as Cell Scaffolds

Stimuli-responsive polymers that exhibit sol-gel phase transition in response to environmental changes such as temperature and pH have attracted considerable attention as biomaterials such as injectable polymers and scaffolds for cell culture. Although numerous stimuli-responsive polymers that undergo a sol-gel transition have been reported, the literature contains few accounts of biomolecularly stimuli-responsive polymers that undergo a sol-gel transition in response to a specific biomolecule. In previous works, we designed biomolecule-responsive hydrogels that undergo changes in volume in response to a target biomolecule; the strategy involves using biomolecular complexes as dynamic crosslinks in the gel networks. In the present study, we designed biotin-conjugated four-armed poly(ethylene glycol) (biotinylated Tetra-PEG) as biomolecular stimuli-responsive sol-gel transition polymers that underwent the phase transition from a sol to a gel state in response to avidin as a target biomolecule. Photo-dimerization is the reaction that occurs by photo-irradiation. Photo-responsive polymers are synthesized by the introduction of photo-dimerizable moieties. Focusing on the photo-dimerization of maleimide, we designed maleimide-conjugated Tetra-PEG as photo-responsive sol-gel transition polymers that transform from a sol to a gel state in response to photo-irradiation. In this study, we synthesized novel dual stimuli-responsive polymers exhibiting sol-gel phase transition in response to light and biomolecule by introducing both a photo-dimerizable group and a biological ligand in a poly(ethylene glycol) (PEG) chain. In addition, the dual stimuli-responsive sol-gel phase transition polymers were used as scaffolds for cell culture. A PEG derivative with both a maleimide group as a photo-dimerizable group and a biotin as a biological ligand was synthesized as follows: N-(2-aminoethyl)maleimide was conjugated to the a-biotinyl-w-succinimidyl poly(ethylene glycol) by the coupling reaction to obtain a-biotinyl-w-maleimide-poly(ethylene glycol) (BMP). The resultant BMP was mixed with avidin to form a BMP-avidin complex in a phosphate buffer solution (pH 7.4). An aqueous solution containing the BMP-avidin complex was exposed to UV. The exposure of the aqueous BMP-avidin complex solution to UV induced the phase transition from a sol to a gel state within 10 min. The photo-responsive gelation is attributed to the dimerization of maleimide groups that acted as dynamic crosslinks. Furthermore, the resultant gel changed to a sol state by the addition of free biotin because it resulted in a dissociation of BMP-avidin complexes as crosslinks. Cells were successfully entrapped within the hydrogels formed by the sol-gel phase transition of the PEG derivative, and were recovered by gel dissociation without cytotoxity. Cell behavior within the BMP-avidin complex hydrogel was quite different from that after the dissociation of the hydrogel by the addition of free biotin. The smart functions of BMP provide useful tools for regulating cell behavior.

“Click” functionalization of dual stimuli-responsive polymer nanocapsules for drug delivery systems

“Clickable” and dual stimuli-responsive nanocapsules were developed for facile surface functionalizationviathiol–yne click chemistry and employed as drug nano-carriers.

Synthesis of dual stimuli-responsive polymers through atom transfer radical mechanism in aqueous media

New dual stimuli-responsive (thermo- & pH-) polymers were successfully synthesized through an atom transfer radical mechanism in aqueous media. N-Isopropylacrylamide (NiPAM) ([N]) as a precursor of temperatureresponsive moiety and sulfonamide-modified styrenic monomer and methacrylamide ([S]) were employed for the synthesis of the smart copolymers. The molar ratio of NiPAM to sulfonamide composed of the polymer backbone played an important role in the control of the phase transitional behavior of the formed block polymers. When the composition ratio of [S]/[N] decreases from 1/1 to 1/2, the dual stimuli-responsive phase behavior was clearly observed. Another important factor for the control of the phase morphology was to obtain the reactivity ratios, r1 and r2, of the two monomers. In this study, Cu(I)-catalyzed copolymerization of sulfadimethoxinyl methacrylamide (MASX; M1) and NiPAM (M2) as the precursors of smart materials yielded r1 = 8.046 and r2=1.572, leading to the production of a gradient type of copolymer in aqueous media.

Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization and Triggered Drug Release.

Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles is frequently subjected to low drug loading efficiency (DLE) and loading content (DLC), as well as lower micellar stability and uncontrollable drug release. In this report, we prepare the copolymer prodrugs (PPEMA-co-PCPTM) via reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(piperidin-1-yl)ethyl methacrylate (PEMA) and reduction-responsive CPT monomer (CPTM), which were quantitatively encapsulated into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles. The polymer prodrug-loaded nanoparticles showed high stability for a long time in aqueous solution or blood serum and even maintain similar size after a lyophilization-dissolution cycle. The tumoral pH (∼6.8)-responsive properties of PPEMA segments endow the micellar cores with triggered transition from neutral to positively charged and swellable properties. The PEG-b-PCL nanoparticles loading polymer prodrugs (PPEMA-b-PCPTM) eliminated burst drug release. Simultaneously, CPT drug release can be triggered by reductive agents and solution pH. At pH 6.8, efficient cellular internalization was achieved due to positively charged cores of the nanoparticles. As compared with nanoparticles loading PCPTM, higher cytotoxicity was observed by the nanoparticles loading PPEMA-b-PCPTM at pH 6.8. Further multicellular tumor spheroid (MCTs) penetration and growth suppression studies demonstrated that high-efficiency penetration capability and significant size shrinkage of MCTs were achieved after treatment by PPEMA-b-PCPTM-loaded nanoparticles at pH 6.8. Therefore, the responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the nanoparticles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability.

Dual-Responsive Hydrogels for Direct-Write 3D Printing

Direct-write 3D printing enables the fabrication of three-dimensional objects via the extrusion from a nozzle. Stimuli responsive materials that shear-thin are well-suited as inks for these 3D printing systems. Poly(isopropyl glycidyl ether)-block-poly(ethylene oxide)-block-poly(isopropyl glycidyl ether) ABA triblock copolymers were synthesized using controlled ring-opening polymerization to afford dual stimuli-responsive polymers that respond to both shear forces and temperature. These polymers were demonstrated to form hydrogels in water. The gels were observed to be thermoreversible—driven by the lower critical solution temperature of the poly(isopropyl glycidyl ether) block which helps facilitate loading of the ink into the printer syringe. Rheological studies demonstrated that the gels had a rapid and reversible modulus response to shear stress. Thus, these materials were suitable as inks for direct-write 3D printing, as they were easily extruded during printing and maintained sufficient mechanical integrity which was necessary to support the next printed layer. Printed structures of high aspect ratio pillars and stacked layers were successfully demonstrated. These types of 3D hydrogel structures may ultimately have an impact in the biomedical field for applications such as tissue engineering.

Characterization of temperature and pH-responsive poly-N-isopropylacrylamide-co-polymer nanoparticles for the release of antimicrobials

Chitosan and alginate are both pH-responsive biopolymers extracted from crustacean exoskeletons and brown algae, respectively. Poly-N-isopropylacrylamide (PNIPAAM) is a hydrogel that becomes hydrophobic at a lower-critical solution temperature. This study sought to combine pH- and temperature-responsive polymers via crosslinking, in order to create a dual-stimuli responsive polymer for hydrophobic antimicrobial compounds delivery, improving their antimicrobial effects. Cinnamon bark extract (CBE) was used as a model for hydrophobic antimicrobial. Two co-polymers were synthesized to create two nanoparticles types: chitosan-co-PNIPAAM and alginate-co-PNIPAAM. Nanoparticles were formed from the resulting co-polymers using a self-assembly top-down process followed by glutaraldehyde or calcium chloride crosslinking. These nanoparticles were then used as controlled delivery vehicles for CBE, whose rapid release could be triggered by specific external stimuli. For the same pH and temperature conditions, the chitosan-co-PNIPAAM nanoparticles were significantly more potent bacterial inhibitors against both pathogens and also exhibited a faster CBE release over time as well as slightly higher entrapment efficiency. The alginate-co-PNIPAAM nanoparticles were significantly smaller and exhibited a slow, gradual release over a long time period. Although both nanoparticles were able to effectively inhibit pathogen growth at lower (P < 0.05) concentration than free CBE, the chitosan-co-PNIPAAM nanoparticles were more effective in delivering a natural antimicrobial with controlled release against foodborne pathogens.

Dual stimuli-responsive polymers derived from α-amino acids: Effects of molecular structure, molecular weight and end-group

Four kinds of well defined poly(N-methacryloyl-L-amino acid)s were prepared via reversible addition fragmentation chain transfer polymerization. The effects of molecular structure, molecular weight, and end-group on their responsive properties in water were investigated. We found that the monomer structure is critical for the polymer to exhibit stimuli-responsive properties in water; only polymers derived from aspartic acid showed defined dual thermo- and pH-responsive properties. To study the effects of molecular weight and end group on the lower critical solution temperature behavior of poly(N-methacryloyl-L-β-isopropyl aspartic acid) (PMAIPAC), a series of PMAIPAC homopolymers with controlled molecular weights and narrow polydispersities were prepared and treated with excess radical initiators to give defined end groups. The cloud point of PMAIPAC was found to increase with the increase of solution pH, due to the ionization of carboxylic acid groups, and decrease with the increase of molecular weight. The structure of end groups also affects the cloud point of PMAIPAC particularly for low molecular weight samples at low pH.