Polymer Micelles with Hydrazone-Ester Dual Linkers for Tunable Release of Dexamethasone

Abstract

To develop polymer micelles for the tunable release of Dexamethasone (DEX) in tumors. DEX was conjugated to poly(ethylene glycol)-poly(aspartate) block copolymers using hydrazone, ester, or hydrazone-ester dual linkers. Ketonic acids containing 3, 4, and 5 methylene groups were used as spacers to separate the dual linkers. Polymer micelles from the DEX-conjugated polymers were tested for drug release at different pH values and carboxylesterase activity levels. DLS measurements and (1)H-NMR analysis confirmed all DEX-loaded micelles were <100nm with core-shell structure. Single linker micelles appeared unsuitable to release DEX preferentially in acidic tumor tissues. Hydrazone linkages between DEX and polymers were non-degradable at both pH 7.4 and 5.0. Ester linkages stable at pH 5.0 were unstable at pH 7.4. Hydrazone-ester dual linkers suppressed DEX release at pH 7.4 while accelerating drug release at pH 5.0. DEX release decreased at pH 5.0 as the length of ketonic acid increased but was independent of spacer length at pH 7.4. Dual linker micelles were stable in the presence of carboxylesterases, suggesting DEX release was primarily due to pH-dependent hydrolysis. Tunable release of DEX was achieved using pH-sensitive polymer micelles with hydrazone-ester dual linkers.