Oxidation and temperature dual responsive polymers based on phenylboronic acid and N-isopropylacrylamide motifs

Abstract

Oxidation stress has been becoming an important target for the development of smart nanomedicines, triggering research interest in oxidation responsive polymers. Herein, we report a new type of temperature/oxidation dual responsive copolymer. They were synthesized by the sequential atom transfer radical copolymerization (ATRP) of N-isopropylacrylamide (NIPAM, M1) and a phenylboronic pinacol ester-containing acrylate (M2) and dialysis against water to remove the pinacol protecting groups. The copolymers with a small amount of phenylboronic acid units (<7%) were soluble in cold neutral phosphate buffer but showed lower critical solution temperatures in the range of 12–31 °C. The thermally induced phase transition profiles depended on both the composition and concentration of the polymers. The cloud points of the copolymers were shifted to higher temperatures upon H₂O₂ induced oxidation of the phenylboronic acid and the subsequent 1,6-elimination. Using PEG-Cl as the macroinitiator to initiate ATRP of M1 and M2, three block copolymers composed of a PEG block and a temperature/oxidation dual responsive segment were prepared after dialysis in water. These block copolymers had a similar ratio of NIPAM to phenylboronic acid units but different molecular weights. We have studied their thermal self-assembly and H₂O₂ triggered decomposition by laser light scattering, ¹H NMR, and transmission electron microscopy. Upon a fast heating protocol, these block copolymers formed stable micelle-like nanoparticles (at 37 °C) that were capable of encapsulating doxorubicin (DOX) and showed H₂O₂ triggered release. The naked nanoparticles were cytocompatible, however the DOX-loaded ones exhibited concentration dependent cytotoxicity, in particular to cancer cells.