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)--p(AMPO)--p(HPMAm-Bz--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 °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).