Antitumor Effect of Liposomal Histone Deacetylase Inhibitor-Lipid Conjugates in Vitro

作者：Hattori Yoshiyuki^*; Nagaoka Yasuo; Kubo Manami; Yamasaku Haruka; Ishii Yuta; Okita Hiroko; Nakano Hiroki; Uesato Shinichi; Maitani Yoshie

来源：Chemical & Pharmaceutical Bulletin, 2011, 59(11): 1386-1392.

• histone deacetylase inhibitor
• suberoylanilide hydroxamic acid
• liposome
• cytotoxicity

Histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA), approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma, is a promising new treatment strategy for various cancers. In this study, we hypothesized that a liposomal formulation of HDACI might efficiently deliver HDACI into tumors. To incorporate HDACI efficiently into the liposomal membrane, we synthesized six HDACI-lipid conjugates, in which polyethylene glycol(2000) (PEG(2000))-lipid or cholesterol (Chol) was linked with a potent hydroxamic acid, HDACI, SAHA or K-182, by cleavable linkers, such as ester, carbamide and disulfide bonds. Liposomal HDACI-lipid conjugates were prepared with distearoylphosphatidylcholine (DSPC) and HDACI-Chol conjugate or with DSPC, Chol and HDACI-PEG-lipid conjugates, and their cytotoxicities were evaluated for human cervix tumor HeLa and mouse colon tumor Colon 26 cells. Among the liposomes, liposomal oleyl-PEG(2000)-SAHA conjugated with SAHA and oleyl-PEG(2000) via a carbamate linker showed higher cytotoxicity via hyperacetylation of histone H3 and induction of caspase 3/7 activity. These results suggested that liposomal HDACI-lipid conjugates may be a potential tool for cancer therapy.

• 出版日期2011-11
• 单位河北医科大学