Hydrogen sulfide-activatable prodrug-backboned block copolymer micelles for delivery of chemotherapeutics

Amphiphilic block copolymer prodrugs, which can self-assemble into stable core-shell micelles, have been widely used for anticancer drug delivery. However, a major challenge is to design drug-conjugating linkers stable in blood but selectively cleavable inside tumor cells for drug release. Hydrogen sulfide (H 2 S) is an important gaseous signaling molecule involved in tumor formation, development, and metastasis and is highly upregulated in multiple cancer types. Accordingly, we designed an H 2 S-sensitive azide-based linker and used it to conjugate paclitaxel (PTX) to a prodrug copolymer (PEG-PAMPTX). The amphiphilic PEG-PAMPTX self-assembled into micelles with a diameter of about 30 nm, stable under normal physiological conditions for long blood circulation. Once in tumors, the intratumoral H 2 S selectively reduced the azide group into an amino group, triggering self-cyclization to release PTX rapidly. As a result, the micelles showed remarkably enhanced antitumor activity compared to Taxol in a triple-negative breast cancer orthotopic model. A novel hydrogen sulfide-activatable block copolymer prodrug with high tumor specificity was developed for cancer chemotherapy.