索拉菲尼，一種多重酪胺酸酶抑制劑，是臨床上用以治療具高度血管化的肝癌組織(HCC)之抗血管新生療法用藥；近年來其不僅表現臨床療效不佳，還造成嚴重的肝癌復發情形。索拉菲尼治療將誘導腫瘤組織的缺氧情況進而活化「第四型半胱氨酸─X─半胱氨酸受器」(CXC4)與其配體「基質細胞衍生因子─1α 」(SDF-1α)之結合，引導肝癌組織朝向促腫瘤發展之微環境，使之對抗血管新生療法產生抗藥性(Resistance)。此研究中，我們研發出一種具標靶CXCR4且攜載索拉菲尼之脂質包覆PLGA奈米粒子；奈米粒子表面以CXCR4 拮抗劑─AMD3100進行修飾，透過全身循環方式將索拉菲尼輸送至肝癌組織內並提高肝癌組織對索拉菲尼的敏感性。此研究於in vitro 與 in vivo 實驗結果皆呈現標靶CXCR4之奈米粒子能有效率地將索拉菲尼輸送至肝癌細胞以及人類臍靜脈內皮細胞(HUVECs)並達到顯著地細胞毒殺以及抗血管新生效果。於動物實驗結果，儘管 SDF-1α 的表現量會受到具標靶CXCR4且同時攜載索拉菲尼之奈米粒子治療而造成組織缺氧之情形提高，修飾 AMD3100於奈米粒子的表面上能夠阻斷 SDF-1α與CXCR4 鍵結，進而導致腫瘤相關巨噬細胞(TAMs)的浸潤情況減少、抗血管新生效果提升、抑制腫瘤生長以及延長具有原位肝癌模型小鼠之總存活期(Overall survival)，相較於控制組之結果。總結，本研究結果顯示出具有高度臨床潛力的多功能奈米粒子不僅能透過標靶方式輸送抗血管新生藥物至肝癌組織中，還改善腫瘤微環境以及克服肝癌組織對索拉菲尼的抗藥性，進而達到最有效的肝癌治療方法。

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 (SDF-1α) 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 SDF-1α upon the persistent hypoxia induced by sorafenib-loaded CXCR4-targeted NPs, AMD3100 attached to the NPs can block CXCR4/SDF-1α, 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 to 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.

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