title: 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.
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Leiqiang
authors.initials: L
authors.lastname: Han
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Jingliang
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yin
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004220:Disulfides / Q000737:chemistry; D005260:Female; D005978:Glutathione / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051379:Mice; D056004:Molecular Dynamics Simulation; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011355:Prodrugs; D011092:Polyethylene Glycols; D000077337:Vorinostat; D005982:Glutathione Transferase; D006655:Histone Deacetylases; D005978:Glutathione
keywords: HDAC; SAHA; disulfide bond; nanoparticles; self-assemble; small molecule