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 (H2S) 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 H2S-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 H2S 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.