Enzymatic multifunctional biodegradable polymers for pH- and ROS-responsive anticancer drug delivery

Abstract A new family of multifunctional biodegradable block copolymers, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine sebacate-co-2,2'-thiodiethylene sebacate) (PEG-PMT), were synthesized via lipase-catalyzed copolymerization procedures. Amphiphilic PEG-PMT copolymers can be readily transformed into stable micellar nanoparticles through self-assembling processes in aqueous medium. The particle sizes increase dramatically after exposure of the particles to the acidic pH and high reactive oxygen species (ROS) conditions in tumor microenvironments, due to protonation of thioether groups and oxidation of amino groups in the PMT micelle cores, respectively. For example, docetaxel (DTX)-loaded PEG-PM-19 % TS micelles were triggered synergistically by acidic pH and ROS stimuli to release over 85 % of the anti-cancer drug. In particular, DTX/PEG-PMT-19 % TS and DTX/PEG-PMT-48 % TS micelles performed better than commercial Duopafei formulation in prohibiting growth of CT-26 tumors xenografed in vivo (70 % of tumor-inhibiting efficiency). Biosafety analysis revealed that DTX-loaded PEG-PMT nanoparticles possessed minimal toxicity towards normal organs, such as liver and kidney. These experimental data demonstrated that the pH- and ROS-responsive PEG-PMT micelles are promising vectors for both delivery of anti-tumor drugs and their controlled release at tumor intracellular sites.