Agarose hydrogels embedded with pH-responsive diblock copolymer micelles for triggered release of substances.

Hybrid agarose hydrogels embedded with pH-responsive diblock copolymers micelles were developed to achieve functional hydrogels capable of stimulus-triggered drug release. Specifically, a well-defined poly(ethylene oxide) (PEO)-based diblock copolymer, PEO-b-poly(2-(N,N-diisopropylamino)ethyl methacrylate) (PEO(113)-b-PDPAEMA(31), where the subscripts represent the degrees of polymerization of two blocks), was synthesized by atom transfer radical polymerization. PDPAEMA is a pH-responsive polymer with a pKa value of 6.3. The PEO(113)-b-PDPAEMA(31) micelles were formed by a solvent-switching method, and their pH-dependent dissociation behavior was investigated by dynamic light scattering and fluorescence spectroscopy. Both studies indicated that the micelles were completely disassembled at pH = 6.40. The biocompatibility of PEO(113)-b-PDPAEMA(31) micelles was demonstrated by in vitro primary cortical neural culture. Hybrid agarose hydrogels were made by cooling 1.0 wt % agarose solutions that contained various amounts of PEO(113)-b-PDPAEMA(31) micelles at either 2 or 4 °C. Rheological measurements showed that the mechanical properties of gels were not significantly adversely affected by the incorporation of diblock copolymer micelles with a concentration as high as 5.0 mg/g. Using Nile Red as a model hydrophobic drug, its incorporation into the core of diblock copolymer micelles was demonstrated. Characterized by fluorescent spectroscopy, the release of Nile Red from the hybrid hydrogel was shown to be controllable by pH due to the responsiveness of the block copolymer micelles. Based on the prominent use of agarose gels as scaffolds for cell transplantation for neural repair, the hybrid hydrogels embedded with stimuli-responsive block copolymer micelles could allow the controlled delivery of hydrophobic neuroprotective agents to improve survival of transplanted cells in tune with signals from the surrounding pathological environment.

Tuning of thermally induced sol-to-gel transitions of moderately concentrated aqueous solutions of doubly thermosensitive hydrophilic diblock copolymers poly(methoxytri(ethylene glycol) acrylate)-b-poly(ethoxydi(ethylene glycol) acrylate-co-acrylic acid).

We report in this article a method to tune the sol-to-gel transitions of moderately concentrated aqueous solutions of doubly thermosensitive hydrophilic diblock copolymers that consist of two blocks exhibiting distinct lower critical solution temperatures (LCSTs) in water. A small amount of weak acid groups is statistically incorporated into the lower LCST block so that its LCST can be tuned by varying solution pH. Well-defined diblock copolymers, poly(methoxytri(ethylene glycol) acrylate)-b-poly(ethoxydi(ethylene glycol) acrylate-co-acrylic acid) (PTEGMA-b-P(DEGEA-co-AA)), were prepared by reversible addition-fragmentation chain transfer polymerization and postpolymerization modification. PTEGMA and PDEGEA are thermosensitive water-soluble polymers with LCSTs of 58 and 9 °C, respectively, in water. A 25 wt % aqueous solution of PTEGMA-b-P(DEGEA-co-AA) with a molar ratio of DEGEA to AA units of 100:5.2 at pH = 3.24 underwent multiple phase transitions upon heating, from a clear, free-flowing liquid (<15 °C) to a clear, free-standing gel (15-46 °C) to a clear, free-flowing hot liquid (47-56 °C), and a cloudy mixture (≥57 °C). With the increase of pH, the sol-to-gel transition temperature (T(sol-gel)) shifted to higher values, while the gel-to-sol transition (T(gel-sol)) and the clouding temperature (T(clouding)) of the sample remained essentially the same. These transitions and the tunability of T(sol-gel) originated from the thermosensitive properties of two blocks of the diblock copolymer and the pH dependence of the LCST of P(DEGEA-co-AA), which were confirmed by dynamic light scattering and differential scanning calorimetry studies. Using the vial inversion test method, we mapped out the C-shaped sol-gel phase diagrams of the diblock copolymer in aqueous buffers in the moderate concentration range at three different pH values (3.24, 5.58, and 5.82, all measured at ~0 °C). While the upper temperature boundaries overlapped, the lower temperature boundary shifted upward and the critical gelation concentration increased with the increase of pH. The AA content in PTEGMA-b-P(DEGEA-co-AA) was found to have a significant effect on the pH dependence of T(sol-gel). For PTEGMA-b-P(DEGEA-co-AA) with a molar ratio of DEGEA to AA units of 100:10, the T(sol-gel) of its 25 wt % aqueous solution increased faster with the increase of pH than that of PTEGMA-b-P(DEGEA-co-AA) with a DEGEA-to-AA molar ratio of 100:5.2.

Rheological properties of aqueous micellar gels of a thermo- and pH-sensitive ABA triblock copolymer.

This article presents a systematic study of the effect of pH on the rheological properties of aqueous micellar gels formed from 10.0 wt % aqueous solutions of a thermo- and pH-sensitive ABA triblock copolymer, poly(ethoxydi(ethylene glycol) acrylate-co-acrylic acid)-b-poly(ethylene oxide)-b-poly(ethoxydi(ethylene glycol) acrylate-co-acrylic acid) (P(DEGEA-co-AA)-b-PEO-b-P(DEGEA-co-AA)). The block copolymer was synthesized by atom transfer radical polymerization of DEGEA and tert-butyl acrylate with a molar ratio of 100:5 from a difunctional PEO macroinitiator and subsequent removal of tert-butyl groups using trifluoroacetic acid. PDEGEA is a thermosensitive water-soluble polymer with a cloud point of 9 °C in water. The thermo-induced sol-gel transition temperature (T(sol-gel)) of the 10.0 wt % aqueous solution of P(DEGEA-co-AA)-b-PEO-b-P(DEGEA-co-AA) can be continuously and reversibly tuned over a wide temperature range by varying the solution pH. The sol-gel transition became broader with the increase of pH, which stemmed from the weaker and broader LCST transition of P(DEGEA-co-AA) blocks at higher pH values. The maximum value of dynamic storage modulus, obtained from heating ramp, and the plateau storage moduli (G(N)), evaluated from frequency sweeps at three normalized temperatures (T/T(sol-gel) = 1.025, 1.032, and 1.039), decreased with the increase of pH from 3.00 to 5.40 with the sharpest drop observed at pH = ∼4.7. The decrease in G(N) reflects the reduction of the number of bridging polymer chains and simultaneously the increase of the numbers of loops and dangling polymer chains. The ionization of carboxylic acid groups at higher pH values introduced charges onto the thermosensitive blocks and made the polymer chains more hydrophilic, facilitating the formation of loops and dangling chains in the gels. The increase in the number of dangling polymer chains with the increase of pH was supported by fluorescence spectroscopy studies, which showed that the critical micelle concentration of P(DEGEA-co-AA)-b-PEO-b-P(DEGEA-co-AA) at a temperature corresponding to T(sol-gel) was higher at a higher pH. The results reported in this article showed that both T(sol-gel) and gel strength can be tuned by varying the solution pH, providing greater design flexibility for potential applications.