Biodegradable Interlayer-Crosslinked Polymer Micelles with Reduction Sensitivity for Non-Small Cell Lung Cancer Therapy.

: To achieve higher therapeutic efficiency with catabatic side effects, desirable nanocarriers should be designed to retain the loaded drug tightly during the systemic circulation, but release the drug rapidly and efficiently upon endocytosis by tumor cells. Herein, we synthesized a novel folate conjugated poly(ethylene glycol)-poly(L-glutamic acid)-poly(L-phenylalanine) (folate-PEG-PLG(HS)-PPhe) copolymer to achieve a desired controlled delivery of doxorubicin (DOX). The copolymer could self-assemble into interlayer-crosslinked micelles with reduction sensitivity, and DOX was successfully loaded into the interior of copolymer. The interlayer-crosslinked disulfide bond at the intermediate region of between PEG and poly(L-phenylalanine) led to significant improvement of the system stability through the introduction of an additional mechanism of carrier/carrier interaction. The crosslinked interlayer could be cleaved at the desired target site under tumor-relevant reductive conditions and DOX were rapidly released from the DOX loaded folate-PEG-PLG (HS)-PPhe micelles (DOX-fPGPM), and significantly lowered the drug leakage without glutathione (GSH). Importantly, the DOX-fPGPM exhibited significantly higher antitumor efficiency both in vitro and in vivo in comparison with free DOX, and Doxil (commercial doxorubicin-loaded liposomes). Biodistribution studies showed that DOX more effectively accumulated in tumor tissue after iv injection of DOXfPGPM. The DOX-fPGPM designed in this work potentially resolved the dilemma between systemic stability and rapid intracellular drug release, and would provide a promising nanomedicine platform for cancer therapy.