Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo.
Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo.
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负载去甲斑蝥素二酸代谢物的叶酸受体靶向脂质体在体外和体内增强对 H22 肝细胞癌的抗肿瘤效力
DOI：
10.2147/ijn.s96862
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发表时间：
2016
影响因子：
8
通讯作者：
Gao JQ
中科院分区：
文献类型：
--
作者：
Liu MC;Liu L;Wang XR;Shuai WP;Hu Y;Han M;Gao JQ
去甲斑蝥素的二酸代谢物（DM-NCTD）在临床上对肝细胞癌（HCC）有效，但因其半衰期短和高剂量时不良反应发生率高而受到限制。基于我们之前的研究，我们开发了一种负载DM-NCTD、叶酸（FA）修饰、聚乙二醇化（DM-NCTD/FA-PEG）的脂质体系统，以增强中等剂量对HCC的靶向作用和抗肿瘤效力。 DM-NCTD/FA-PEG脂质体系统制备的脂质体具有规则的球形形态，平均粒径约为200 nm，包封率>80%。 MTT细胞毒性实验表明，DM-NCTD/FA-PEG脂质体对H22肝癌细胞系的细胞毒性作用明显强于未经FA修饰的PEG脂质体（P<0.01）。我们使用液相色谱-质谱法测定组织和肿瘤中的 DM-NCTD，发现它灵敏、快速且可靠。此外，生物分布研究表明，DM-NCTD脂质体提高了肿瘤靶向效率，其中DM-NCTD/FA-PEG脂质体表现出最高的治疗效率（P<0.01）。同时，结果表明，虽然活性脂质体组DM-NCTD的肿瘤靶向效率明显提高，但对肾脏的风险高于普通脂质体组。体内抗肿瘤活性方面，组织病理学检查显示，DM-NCTD/FA-PEG脂质体对H22荷瘤小鼠肿瘤的抑制作用优于游离DM-NCTD或DM-NCTD/PEG脂质体（P<0.01），并且诱导肿瘤细胞凋亡更显着，对模型小鼠组织和正常小鼠肝组织没有明显毒性。所有这些结果表明，负载 DM-NCTD 的 FA 修饰脂质体可能具有 HCC 靶向治疗的潜在应用。
The diacid metabolite of norcantharidin (DM-NCTD) is clinically effective against hepatocellular carcinoma (HCC), but is limited by its short half-life and high incidence of adverse effects at high doses. We developed a DM-NCTD-loaded, folic acid (FA)-modified, polyethylene glycolated (DM-NCTD/FA-PEG) liposome system to enhance the targeting effect and antitumor potency for HCC at a moderate dose based on our previous study. The DM-NCTD/FA-PEG liposome system produced liposomes with regular spherical morphology, with mean particle size approximately 200 nm, and an encapsulation efficiency >80%. MTT cytotoxicity assays demonstrated that the DM-NCTD/FA-PEG liposomes showed significantly stronger cytotoxicity effects on the H22 hepatoma cell line than did PEG liposomes without the FA modification (P<0.01). We used liquid chromatography–mass spectrometry for determination of DM-NCTD in tissues and tumors, and found it to be sensitive, rapid, and reliable. In addition, the biodistribution study showed that DM-NCTD liposomes improved tumor-targeting efficiency, and DM-NCTD/FA-PEG liposomes exhibited the highest efficiency of the treatments (P<0.01). Meanwhile, the results indicated that although the active liposome group had an apparently increased tumor-targeting efficiency of DM-NCTD, the risk to the kidney was higher than in the normal liposome group. With regard to in vivo antitumor activity, DM-NCTD/FA-PEG liposomes inhibited tumors in H22 tumor-bearing mice better than either free DM-NCTD or DM-NCTD/PEG liposomes (P<0.01), and induced considerably more significant cellular apoptosis in the tumors, with no obvious toxicity to the tissues of model mice or the liver tissue of normal mice, as shown by histopathological examination. All these results demonstrate that DM-NCTD-loaded FA-modified liposomes might have potential application for HCC-targeting therapy.