Delivery of siRNA Using CXCR4-targeted Nanoparticles Modulates Tumor Microenvironment and Achieves a Potent Antitumor Response in Liver Cancer.
Antiangiogenic therapy has recently emerged as a highly promising therapeutic strategy for treating hepatocellular carcinoma (HCC). However, the only clinically approved systemic antiangiogenic agent for advanced HCC is sorafenib, which exerts considerable toxicity. Moreover, acquired resistance to antiangiogenic therapy often develops and restricts the therapeutic efficacy of this treatment. Hence, in this study, we develop a CXCR4-targeted lipid-based nanoparticle (NP) formulation to specifically deliver vascular endothelial growth factor (VEGF) siRNA as an antiangiogenic substance into HCC. AMD3100, a CXCR4 antagonist, is added into NPs to serve as both a targeting moiety and a sensitizer to antiangiogenic therapy. We demonstrate that AMD-modified NPs (AMD-NPs) can efficiently deliver VEGF siRNAs into HCC and downregulate VEGF expression in vitro and in vivo. Despite the upregulation of the SDF1α/CXCR4 axis upon the induction of hypoxia after antiangiogenic therapy, CXCR4 inhibition by AMD-NPs in combination with either conventional sorafenib treatment or VEGF siRNA prevents the infiltration of tumor-associated macrophages. These dual treatments also induce synergistic antiangiogenic effects and suppress local and distant tumor growth in HCC. In conclusion, the tumor-targeted multifunctional AMD-NPs that co-deliver VEGF siRNA and AMD3100 provide an effective approach for overcoming tumor evasion of antiangiogenic therapy, leading to delayed tumor progression in HCC.
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Jia-Yu
JY
Liu
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Tsaiyu
T
Chiang
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Chun-Hung
CH
Liu
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Guann-Gen
GG
Chern
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Ts-Ting
TT
Lin
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Dong-Yu
DY
Gao
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address: yunching@mx.nthu.edu.tw.
Yunching
Y
Chen
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000628:therapy*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D018450:Disease Progression; D015316:Genetic Therapy; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000628:therapy*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020533:Angiogenesis Inhibitors; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; C088327:plerixafor