TME‐Responsive Polyprodrug Micelles for Multistage Delivery of Doxorubicin with Improved Cancer Therapeutic Efficacy in Rodents

It is of great significance to develop multifunctional biomaterials to effectively deliver anticancer drug to tumor cells for cancer therapy. Here, inspired by the specific tumor microenvironment (TME) cues, a unique multistage pH/redox-responsive polyprodrug composed of amphiphilic pH-sensitive diblock copolymer poly(ethylene glycol) methyl ether-b-poly(β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) is designed and developed. This polyprodrug can self-assemble into micelles (DOX-ss@PMs) at low concentration with high serum stability, indicating that DOX-ss@PMs have prolonged circulation time. The dual pH/redox-responsiveness of the multistage platform is thoroughly evaluated. In vitro results demonstrate that DOX-ss@PMs can highly accumulate at tumor site, followed by responding to the acidity for disassembly and effectively penetrating into the tumor cells. DOX is released from the platform due to the cleavage of disulfide bonds induced by high glutathione (GSH) concentration, thereby inducing the apoptosis of tumor cells. In vivo studies further reveal that multistage DOX-ss@PMs can more efficiently inhibit the growth of tumors and improve the survival of tumor-bearing mice in comparison to the free drug and control. These results imply that multistage delivery system might be a potential and effective strategy for drug delivery and DOX-ss@PMs could be a promising nanomedicine for cancer chemotherapy.