Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Biomaterials. 2015 Oct;67:194-203. doi: 10.1016/j.biomaterials.2015.07.035. Epub 2015 Jul 21.
Sorafenib, a multikinase inhibitor, has been used as an anti-angiogenic agent against highly vascular hepatocellular carcinoma (HCC) - yet associated with only moderate therapeutic effect and the high incidence of HCC recurrence. We have shown intratumoral hypoxia induced by sorafenib activated C-X-C receptor type 4 (CXCR4)/stromal-derived factor 1α (SDF1α) axis, resulting in polarization toward a tumor-promoting microenvironment and resistance to anti-angiogenic therapy in HCC. Herein, we formulated sorafenib in CXCR4-targeted lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with a CXCR4 antagonist, AMD3100 to systemically deliver sorafenib into HCC and sensitize HCC to sorafenib treatment. We demonstrated that CXCR4-targeted NPs efficiently delivered sorafenib into HCCs and human umbilical vein endothelial cells (HUVECs) to achieve cytotoxicity and anti-angiogenic effect in vitro and in vivo. Despite the increased expression of SDF1α upon the persistent hypoxia induced by sorafenib-loaded CXCR4-targeted NPs, AMD3100 attached to the NPs can block CXCR4/SDF1α, leading to the reduced infiltration of tumor-associated macrophages, enhanced anti-angiogenic effect, a delay in tumor progression and increased overall survival in the orthotopic HCC model compared with other control groups. In conclusion, our results highlight the clinical potential of CXCR4-targeted NPs for delivering sorafenib and overcoming acquired drug resistance in liver cancer.
索拉非尼是一种多激酶抑制剂，已被用作抗血管生成剂来治疗高度血管化的肝细胞癌（HCC），但疗效仅为中度，且 HCC 复发率较高。我们已经表明，索拉非尼诱导的肿瘤内缺氧激活了 C-X-C 受体型 4（CXCR4）/基质衍生因子 1α（SDF1α）轴，导致向促进肿瘤的微环境极化，并对 HCC 的抗血管生成治疗产生耐药性。在此，我们将索拉非尼包封在 CXCR4 靶向的脂质包覆的聚乳酸-共-羟基乙酸（PLGA）纳米颗粒（NPs）中，并用 CXCR4 拮抗剂 AMD3100 进行修饰，以系统地将索拉非尼递送至 HCC 并使 HCC 对索拉非尼治疗敏感。我们证明，CXCR4 靶向 NPs 可有效地将索拉非尼递送至 HCC 和人脐静脉内皮细胞（HUVEC）中，在体外和体内实现细胞毒性和抗血管生成作用。尽管索拉非尼负载的 CXCR4 靶向 NPs 诱导的持续缺氧会增加 SDF1α 的表达，但附着在 NPs 上的 AMD3100 可阻断 CXCR4/SDF1α，导致肿瘤相关巨噬细胞浸润减少，增强抗血管生成作用，延迟肿瘤进展，并提高荷瘤模型的总生存率，与其他对照组相比。总之，我们的研究结果强调了 CXCR4 靶向 NPs 用于递送索拉非尼和克服肝癌获得性耐药的临床潜力。
