Tuning of Thermally Induced Sol-to-Gel Transitions of Moderately Concentrated Aqueous Solutions of Doubly Thermosensitive Hydrophilic Diblock Copolymers Poly(methoxytri(ethylene glycol) acrylate)-<i>b</i>-poly(ethoxydi(ethylene glycol) acrylate-<i>co</i>-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)-<i>b</i>-poly­(ethoxydi­(ethylene glycol) acrylate-<i>co</i>-acrylic acid) (PTEGMA-<i>b</i>-P­(DEGEA-<i>co</i>-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-<i>b</i>-P­(DEGEA-<i>co</i>-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 (<i>T</i>_sol–gel) shifted to higher values, while the gel-to-sol transition (<i>T</i>_gel–sol) and the clouding temperature (<i>T</i>_clouding) of the sample remained essentially the same. These transitions and the tunability of <i>T</i>_sol–gel originated from the thermosensitive properties of two blocks of the diblock copolymer and the pH dependence of the LCST of P­(DEGEA-<i>co</i>-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-<i>b</i>-P­(DEGEA-<i>co</i>-AA) was found to have a significant effect on the pH dependence of <i>T</i>_sol–gel. For PTEGMA-<i>b</i>-P­(DEGEA-<i>co</i>-AA) with a molar ratio of DEGEA to AA units of 100:10, the <i>T</i>_sol–gel of its 25 wt % aqueous solution increased faster with the increase of pH than that of PTEGMA-<i>b</i>-P­(DEGEA-<i>co</i>-AA) with a DEGEA-to-AA molar ratio of 100:5.2

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-<i>b</i>-poly­(2-(<i>N</i>,<i>N</i>-diisopropylamino)­ethyl methacrylate) (PEO₁₁₃-<i>b</i>-PDPAEMA₃₁, 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 p<i>K</i>_a value of 6.3. The PEO₁₁₃-<i>b</i>-PDPAEMA₃₁ 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 PEO₁₁₃-<i>b</i>-PDPAEMA₃₁ micelles was demonstrated by <i>in vitro</i> primary cortical neural culture. Hybrid agarose hydrogels were made by cooling 1.0 wt % agarose solutions that contained various amounts of PEO₁₁₃-<i>b</i>-PDPAEMA₃₁ 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