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

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

Supplementary materials

Figure S1 Pharmacophore model and structures of FDA-approved HDAC inhibitors.

Abbreviations: FDA, US Food and Drug Administration; HDAC, histone deacetylase; ZBG, zinc binding group.

Figure S2 Molecular dynamics simulations of the self-assembly of SAHA-S-S-VE molecules (initial status).

Figure S3 Molecular dynamics simulations of the self-assembly of SAHA-S-S-VE molecules (final status).

Figure S4 Spectra of SAHA-S-S-VE, SAHA, and VECOOH (d-α-tocopherol succinate) in methanol. According to the UV/Vis spectra, SAHA-S-S-VE and VECOOH, both had absorption at 288 nm, while SAHA had no absorption. This can be attributed to the d-α-tocopherol group of SAHA-S-S-VE and VECOOH. Then 288 nm was chosen as the wavelength to detect the remaining SAHA-S-S-VE, without the interference of SAHA or its derivatives. In addition, compared to the UV/Vis absorption of free SAHA at 240 nm and free VECOOH at 288 nm, the SAHA-S-S-VE conjugate possessed both UV/Vis absorptions of SAHA and VECOOH. The UV/Vis results further confirmed the successful conjugation between SAHA and VECOOH.

Abbreviation: UV/vis, ultraviolet-visible.

Figure S5 SAHA-S-S-VE in RP-HPLC chromatograms was detected by UV absorption using 288 nm as the monitored wavelength. (A) SAHA-S-S-VE; (B) mixture of SAHA-S-S-VE and its reduced product; (C) totally reduced product of SAHA-S-S-VE.

Abbreviations: HPLC, high performance liquid chromatography; RP, reverse phase; UV, ultraviolet; min, minutes.

Scheme S1 Synthesis of SAHA-O-VE. Reagents: (a) CDI, CH₂Cl₂; (b) CDI, THF.

Abbreviations: CDI, N,N′-carbonyldiimidazole; THF, tetrahydrofuran.

Acknowledgments

This work was supported by National Natural Science Foundation of China (81573368). The authors are very grateful to Dr Livesey David Olerile (School of Pharmaceutical Science, Shandong University) for the English language editing.

Disclosure

The authors report no conflicts of interest in this work.