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J Drug Target. 2018 Jun - Jul;26(5-6):448-457. doi: 10.1080/1061186X.2017.1419355. Epub 2017 Dec 27.

Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs.

Xu J1,2,3, Sun J1,2,3, Wang P1,2, Ma X1,2, Li S1,2,3.

Author information

1
a Center for Pharmacogenetics , University of Pittsburgh , Pittsburgh , PA , USA.
2
b Department of Pharmaceutical Sciences , School of Pharmacy, University of Pittsburgh , Pittsburgh , PA , USA.
3
c University of Pittsburgh Cancer Institute , Pittsburgh , PA , USA.

Abstract

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 tumours 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-b-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 tumour 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 tumour cells than free DOX and DOX loaded in a pharmacologically '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.

KEYWORDS:

Vorinostat; co-delivery; doxorubicin; prodrug micelles

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