Targeted delivery by pH-responsive mPEG-S-PBLG micelles significantly enhances the anti-tumor efficacy of doxorubicin with reduced cardiotoxicity

Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and beta-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.