Hypoxia/Temperature/pH Triple Stimuli–Responsive Block Copolymers: Synthesis, Self‐Assembly, and Controlled Drug Release

Abstract The amphiphilic block copolymer poly(methacrylic acid‐co‐2‐nitroimidazole acrylate)‐b‐poly(2‐(N,N‐dimethylamino)ethyl methacrylate) (P(MAA‐co‐NIMA)‐b‐PDMAEMA) with the hypoxia/temperature/pH triple responsiveness is synthesized by reversible addition‐fragmentation chain transfer polymerization (RAFT), hydrolysis, and 3‐(3‐dimethylaminopropyl)‐1‐ethylcarbodiimide (EDC) reactions, and successfully self‐assembled into micelles. The hypoxia response in vitro is realized, and then the sensitivity of the self‐assembled micelles to the hypoxia condition is studied by controlling the grafting amount of aminated 2‐nitroimidazole. Because 2‐(N,N‐dimethylamino) ethyl methacrylate (DMAEMA) is a typical material sensitive to temperature and pH conditions, the self‐assembled micelles are also responsive to temperature and different acidic/basic conditions. In addition, the cumulative release rate of doxorubicin (DOX) at 42 °C, pH = 6.0, and hypoxic conditions increases significantly, and verifies the synergistic promotion effect of the above stimulations. This intelligent polymer with triple response mechanism improves the controllability and efficiency of drug release, and is expected to be a drug carrier for cancer treatment.