title: CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer.
abstract: 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.
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Dong-Yu
authors.initials: DY
authors.lastname: Gao
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ts-Ting
authors.initials: TsT
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Sung
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ya Chi
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: yunching@mx.nthu.edu.tw.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019718:Receptors, CXCR4 / Q000378:metabolism*; D000077157:Sorafenib; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D008055:Lipids; D010671:Phenylurea Compounds; D019718:Receptors, CXCR4; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D009536:Niacinamide; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000077157:Sorafenib
keywords: Angiogenesis; CXCR4; Drug resistance; HCC; Nanoparticle; PLGA; Sorafenib; Tumor microenvironment