CXCR 4-Targeted Lipid-Coated PLGA Nanoparticles Deliver Sorafenib and Overcome

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-coglycolic 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. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 1 CXCR4-Targeted Lipid-Coated PLGA Nanoparticles Deliver Sorafenib and Overcome Acquired Drug Resistance in Liver Cancer Dong-Yu Gaoa, Ts-Ting Lina, Yun-Chieh Sunga, Ya Chi Liua, Wen-Hsuan Chiangb, Chih-Chun Changa, Jia-Yu Liua, Yunching Chena,* aInstitute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan; bDepartment of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan * Corresponding author: Yunching Chen, PhD, Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC; telephone: 886-3-571-5131 ext. 35503; email: yunching@mx.nthu.edu.tw M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT