Interfacially Hydrazone Cross-linked Thermosensitive Polymeric Micelles for Acid-Triggered Release of Paclitaxel

Polymeric micelles are widely studied as drug carriers, but their poor in vivo stability and, as a consequence, premature drug release hampers their use for targeted drug delivery. Reversible cross-linking of polymeric micelles to achieve stability in the circulation and triggered de-cross-linking/drug release at their site of action is a highly attractive approach to design effective targeted nanomedicines. In this study, the synthesis and RAFT polymerization of a reactive ketone-containing methacrylamide monomer, 1-(acetonylamino)-2-methyl-2-propen-1-one (AMPO), was investigated. A triblock thermosensitive polymer p(HPMAm)-b-p(AMPO)-b-p(HPMAm-Bz-co-HPMAm-Lac) was synthesized by sequential RAFT polymerization of HPMAm for the permanently hydrophilic block, AMPO for the cross-linkable middle block, and HPMAm-Bz with HPMAm-Lac for the thermosensitive block. The triblock copolymer self-assembled into polymeric micelles with size of 52 nm (PDI of 0.03) by increasing the temperature of an aqueous polymer solution above its critical micelle temperature (3 degrees C). The micelles were subsequently cross linked after addition of adipic acid dihydrazide, which reacts with the ketone groups of p(AMPO) located at the interfacial region of the micelles. The cross-linked micelles displayed substantially increased thermal and hydrolytic stability as compared to non cross-linked micelles. The hydrazone bonds in the cross-links were, however, prone to hydrolysis at mild acidic condition (pH 5.0). A chemotherapeutic drug, paclitaxel, was encapsulated in the polymeric micelles with a high loading capacity (29 wt %). The retention of paclitaxel in the micelles at pH 7.4 was substantially increased by interfacial cross-linking, while the release of the drug was triggered at acidic condition (pH 5.0, pH of late endosomes and lysosomes).