Biocompatible Thermoresponsive Polymers with Pendent Oligo(ethylene glycol) Chains and Cyclic Ortho Ester Groups

Two acrylate monomers with six-member cyclic ortho ester groups, i.e., 2-(1,3-dioxan-2-yloxy)ethyl acrylate (DEA) and 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), were synthesized. These two monomers were copolymerized with an oligo(ethylene glycol) acrylate (OEGA) under atom transfer radical polymerization conditions to afford two series of thermoresponsive copolymers, poly(DEA-co-OEGA)s and poly(DMDEA-co-OEGA)s. All the copolymers were soluble in water to form transparent solutions at low temperature, however, some of them exhibited association behaviors below the cloud point (CP) as evidenced by (HNMR)-H-1, dynamic light scattering (DLS) and fluorescence method. The aggregation tendency of the copolymers depends on their composition as well as the structure of the ortho ester units. With a similar composition, poly(DMDEA-co-OEGA) showed a stronger aggregation tendency than poly(DEA-co-OEGA). In addition, increasing molar content of the ortho ester units in a copolymer promoted its aggregation in water. Thermally induced phase transitions of these copolymers were studied by various methods including turbidimetry, temperature-dependent (HNMR)-H-1, DLS, and microscopy. The results indicate that CP of the copolymers increased with increasing the content of OEGA units, but the changing behaviors of CP were rather different for two types of copolymers, which can be ascribed to the difference in hydrophobicity of the ortho ester units. Little hysteresis was observed for the copolymers with more OEGA units while those with more alto ester units showed significant hysteresis probably due to the hydrophobic character of the ortho ester. The formation of coacervate droplets above CP reveals that the copolymers underwent a liquid liquid phase separation upon heating. pH-dependent hydrolyses of the copolymers were studied by turbidimetry and H-1 NMR methods. The hydrolysis rate depends greatly on pH and the hydrophilic/hydrophobic balance of the copolymers: lower pH and more hydrophilic character resulted in a faster hydrolysis rate. Finally, this type of acid-labile thermoresponsive copolymers and the acid-catalyzed hydrolysis products have low cytotoxicity.