Pendant HDAC Inhibitor SAHA Derivatized Polymer as a Novel Prodrug Micellar Carrier for Anticancer Drugs

摘要

Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumors as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and Doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed. POEG-b-PSAHA prodrug polymer was able to form spherical micelles with a diameter around 60 nm, and well retained the pharmacological activity of SAHA in either inhibiting the proliferation of tumor cells or inducing histone acetylation. DOX formulated in POEG-b-PSAHA-based micelles showed a sustained release profile. DOX-loaded POEG-b-PSAHA exhibited more potent cytotoxicity towards tumor cells than free DOX and “inert” nanocarrier, POEG-b-POM. Consistently,DOX/POEG-b-PSAHA formulation resulted in an improved therapeutic effect in vivo compared to free DOX, Doxil, or DOX formulated in POEG-b-POM micelles. These results suggest that SAHA-based prodrug micelles may serve as a dual functional carrier for combination strategies in epigenetic-oriented anticancer therapy