Guangzhou First People's Hospital, and Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, China.
Biomater Sci. 2021 Apr 7;9(7):2508-2518. doi: 10.1039/d0bm01881c. Epub 2021 Jan 18.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Sorafenib (sfb) is widely used in clinics for advanced HCC therapy. However, the therapeutic efficacy of sfb is suboptimal due to its poor water solubility, low bioavailability, and side effects. Here, we employed a clinically safe polymer poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) to prepare a nanoparticle (NP)-based sfb formulation (NP-sfb) and tested its antitumor effect in multiple HCC models. NP-sfb could achieve effective drug loading and remain stable under physiological conditions. NP-sfb could be taken up by HepG2, Hepa1-6, and H22 cells and could efficiently inhibit cell proliferation and/or promote cell apoptosis. In vivo studies indicated that NP-sfb showed significantly improved therapeutic efficacy compared with free-sfb at the same dose or even higher doses. Mechanistic studies demonstrated that NP-sfb not only inhibited tumor proliferation and angiogenesis but also stimulated the tumor microenvironment by reducing the infiltration of immunosuppressive myeloid cells and increasing the ratio of cytotoxic T cells. This study demonstrates that the NP-based formulation is a promising strategy to improve the clinical application of sfb.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因。索拉非尼（sfb）广泛用于晚期 HCC 的临床治疗。然而，由于其水溶性差、生物利用度低和副作用，sfb 的治疗效果并不理想。在这里，我们采用临床安全的聚合物聚乙二醇-聚乳酸（PEG-b-PLA）来制备基于纳米颗粒（NP）的 sfb 制剂（NP-sfb），并在多种 HCC 模型中测试了其抗肿瘤效果。NP-sfb 可以实现有效的药物负载，并在生理条件下保持稳定。NP-sfb 可以被 HepG2、Hepa1-6 和 H22 细胞摄取，并可以有效地抑制细胞增殖和/或促进细胞凋亡。体内研究表明，与相同剂量甚至更高剂量的游离 sfb 相比，NP-sfb 显示出显著改善的治疗效果。机制研究表明，NP-sfb 不仅抑制肿瘤增殖和血管生成，而且通过减少免疫抑制性髓样细胞的浸润和增加细胞毒性 T 细胞的比例来刺激肿瘤微环境。这项研究表明，基于 NP 的制剂是提高 sfb 临床应用的有前途的策略。
