Background: There is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC.
Methods: We constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG₂₀₀₀. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice.
Results: Delivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient.
Conclusion: Our results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.



中文翻译：

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负载盐霉素的小分子纳米前药增强肝细胞癌的抗癌活性

背景：目前晚期肝细胞癌（HCC）尚无有效的治疗方法，化疗对HCC患者的长期生存影响不大，主要是由于HCC对癌症干细胞（CSC）的化疗耐药。
方法：我们构建了一种载有盐霉素（SAL）的小分子纳米级前药（nanoprodrug），用于治疗HCC。SAL 被前药 LA-SN38（亚油酸修饰的 7-乙基-10-羟基喜树碱）包裹，以构建自组装的纳米前药，进一步用 DSPE-PEG ₂₀₀₀进行 PEG 化。我们在体外人类 HCC 细胞系和小鼠体内表征了这种共递送的纳米前药及其抗肿瘤活性。
结果：基于 SAL 和 LA-SN38 的纳米前药的递送有效促进了 HCC 细胞的凋亡，抑制了 HCC 肿瘤球的形成以及 HCC 细胞的运动和侵袭，并降低了 CD133+ HCC-CSC 细胞的比例。在裸鼠中，纳米前药抑制了源自人类细胞系和患者的肿瘤异种移植物的生长。
结论：我们的研究结果表明，基于 SAL 的纳米前药是治疗 HCC 患者的有前景的平台，也是癌症联合治疗的新策略。