pH-Responsive Amphiphilic Polyether Micelles with Superior Stability for Smart Drug Delivery

Despite widespread interest in the amphiphilic polymeric micelles for drug delivery systems, it is highly desirable to achieve high loading capacity and high efficiency to reduce the side effects of therapeutic agents while maximizing their efficacy. Here, we present a novel hydrophobic epoxide monomer, cydohexyloxy ethyl glycidyl ether (CHGE), containing an acetal group as a pH-responsive cleavable linkage. A series of its homopolymers, poly(cyclohexyloxy ethyl glycidyl ether)s (PCHGEs), and block copolymers, poly(ethylene glycol)-block-poly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-b-PCHGE), were synthesized via anionic ring-opening polymerization in a controlled manner. Subsequently, the self-assembled polymeric micelles of mPEG-b-PCHGE demonstrated high loading capacity, excellent stability in biological media, tunable release efficiency, and high cell viability. Importantly, quantum mechanical calculations performed by considering prolonged hydrolysis of the acetal group in CHGE indicated that the CHGE monomer had higher hydrophobicity than three other functional epoxide monomer analogues developed. Furthermore, the preferential cellular uptake and in vivo therapeutic efficacy confirmed the enhanced stability and the pH-responsive degradation of the amphiphilic block copolymer micelles. This study provides a new platform for the development of versatile smart polymeric drug delivery systems with high loading efficiency and tailorable release profiles.

Automated summary

A novel hydrophobic epoxide monomer with a pH-responsive cleavable linkage was successfully synthesized to form amphiphilic block copolymer micelles, demonstrating high loading capacity, excellent stability, tunable release efficiency, and high cell viability. Quantum mechanical calculations showed the monomer's higher hydrophobicity compared to other analogues, and cellular uptake and in vivo therapeutic efficacy confirmed the enhanced stability and pH-responsive degradation of the micelles. This study provides a new platform for versatile smart polymeric drug delivery systems with high loading efficiency and tailorable release profiles.