Antitumor effect of liposomal histone deacetylase inhibitor-lipid conjugates in vitro.
Antitumor effect of liposomal histone deacetylase inhibitor-lipid conjugates in vitro.
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DOI：
10.1248/cpb.59.1386
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发表时间：
2011-11
影响因子：
1.7
通讯作者：
Y. Hattori;Y. Nagaoka;Manami Kubo;H. Yamasaku;Y. Ishii;Hiroko Okita;Hiroki Nakano;S. Uesato;Y. Maitani
中科院分区：
文献类型：
--
作者：
Y. Hattori;Y. Nagaoka;Manami Kubo;H. Yamasaku;Y. Ishii;Hiroko Okita;Hiroki Nakano;S. Uesato;Y. Maitani
组蛋白去乙酰化酶抑制剂（HDACI）亚eroylanilide羟肟酸（SAHA）被美国食品和药物管理局（FDA）批准用于治疗皮肤T细胞淋巴瘤，是一种很有前景的治疗多种癌症的新策略。在这项研究中，我们假设HDACI的脂质体制剂可能有效地将HDACI输送到肿瘤中。为了将HDACI有效地结合到脂质体膜中，我们合成了六种HDACI-脂质偶联物，其中聚乙二醇（2000）(PEG(2000))-脂质或胆固醇（Chol）通过可切割的连接物，如酯、尿素和二硫键，与强效羟肟酸HDACI、SAHA或K-182连接。采用二硬脂酰磷脂酰胆碱（dsc）和HDACI-Chol偶联物或dsc、Chol和hdaci - peg -脂偶联物制备脂质体hdaci -脂偶联物，并对人宫颈肿瘤HeLa和小鼠结肠肿瘤结肠26细胞进行细胞毒性评价。在脂质体中，脂质体olyl - peg (2000)-SAHA通过氨基甲酸酯连接物与SAHA和olyl - peg（2000）偶联，通过组蛋白H3的超乙酰化和诱导caspase 3/7活性显示出更高的细胞毒性。这些结果表明脂质体hdac -脂质偶联物可能是一种潜在的癌症治疗工具。
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.