Abstract
Currently, the chemotherapy drugs-loaded thermosensitive liposomes have not shown an over standard of clinical effects compared to preclinical trials. In addition to the limiting factors of clinical trial design and heating device, abnormal angiogenesis in desmoplastic tumor is a key factor for unexpected clinical efficacy. Malformed tumor vasculature may result in reduced vascular transport and the heterogeneous distribution of thermosensitive liposomes in tumor. Here, we report an anti-angiogenesis strategy through hypoxia-inducible factors (HIF)-1α-vascular endothelial growth factor (VEGF) axis based on icaritin and coix seed oil dual loaded multicomponent thermosensitive lipid complexes (IC-ML). IC-ML could downregulate the HIF-1α expression in HepG2 cells with a synergetic antitumor effect. In addition, HepG2 + LX-2 cells co-cultured 3D tumor spheres administered IC-ML showed the strongest penetration and inhibition of growth. Accordingly, IC-ML displayed improved tumor penetration and superior synergistic antitumor efficacy with HIF-1α-VEGF downregulation in vivo under mild hyperthermia. The improvement of antitumor efficacy of IC-ML comes from the anti-angiogenesis strategy and comprehensive tumor microenvironment remodeling, including depletion of cancer-associated fibroblasts as well as inhibition of M2-type tumor associated macrophage infiltration in desmoplastic tumor. This study proposes a novel multicomponent synergistic antitumor strategy to improve the therapeutic potential of thermosensitive lipid complexes for hepatocellular carcinoma.
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