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A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

Authors Han LQ, Wang TQ, Wu JL, Yin XL, Fang H, Zhang N

Received 4 August 2016

Accepted for publication 11 October 2016

Published 11 November 2016 Volume 2016:11 Pages 6003—6022

DOI https://doi.org/10.2147/IJN.S118727

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Linlin Sun


Leiqiang Han, Tianqi Wang, Jingliang Wu, Xiaolan Yin, Hao Fang, Na Zhang

School of Pharmaceutical Science, Shandong University, Ji’nan, Shandong, People’s Republic of China

Abstract: Small molecule-based nanodrugs with nanoparticles (NPs) that are mainly composed of small molecules, have been considered as a promising candidate for a next-generation nanodrug, owing to their unique properties. Vorinostat (SAHA) is a canonical US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma. However, the lack of efficacy against solid tumors hinders its progress in clinical use. Herein, a novel nanodrug of SAHA was developed based on disulfide-linked prodrug SAHA-S-S-VE. SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms, which were validated by molecular dynamics simulations. Under reduced conditions, the redox-responsive behavior of SAHA-S-S-VE was investigated, and the HDAC inhibition results verified the efficient release of free SAHA. With a biocompatible d-a-tocopheryl polyethylene glycol succinate (TPGS) functionalization, the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration of 4.5 µM and outstanding stability in vitro with drug-loading capacity of 24%. In vitro biological assessment indicated that SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2. Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in the tumor region and inhibit the tumor growth effectively. This approach, which turned SAHA into a self-assembled redox-responsive nanodrug, provided a new channel for the use of HDAC inhibitor in solid tumor therapy.

Keywords: SAHA, HDAC, small molecule, nanoparticles, self-assemble, disulfide bond

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