Sensitizing sorafenib to hepatocellular carcinoma with dual-targeted and pH-responsive nanodrugs via overcoming the hypoxia tumor microenvironment

Schematic illustration of the tumor-vascular and pH-responsive nano system co-loaded with SFN/BFL to sensitize SFN via overcoming the hypoxia tumor microenvironment. • Bufalin (BFL) could improve the sensitivity of Sorafenib (SFN) to HCC by overcoming the hypoxia tumor microenvir onment. • A pH sensitive tumor-vascular dual-targeted nanoplatform S/B@FA/cRGD-LB-ZIF-8 was developed, which could enhance the uptake of SFN and BFL by Huh-7 and HUVEC cells. • S/B@FA/cRGD-LB-ZIF-8 could synergistically inhibit angiogenesis and enhance the anti-proliferative effect on tumor cells for anti-HCC. Sorafenib (SFN), a primary targeted therapy for advanced hepatocellular carcinoma (HCC), has long been a first-line systemic agent exerting anti-angiogenic and anti-proliferative effects. However, long-term treatment of SFN could exacerbate tumor tissue hypoxia to activate the HIF-1α/VEGF, consequently reducing SFN’s anti-angiogenic and anti-proliferative effects, thereby promoting tumor deterioration. Enhancing the sensitivity of HCC cells to SFN could be achieved by inhibiting HIF-1α expression. The combination of Bufalin (BFL) and SFN can reduce the expression of HIF-1α/VEGF, enhancing the therapeutic sensitivity of SFN for stronger anti-HCC effects. Here, we designed a tumor/vascular dual-targeted nanoplatform S/B@FA/cRGD-LB-ZIF-8 to enhance drug accumulation in tumor sites by targeted delivery of SFN and BFL to blood vessels and tumor sites. The accumulated drug in tumor sites could improve the hypoxia microenvironment, increase the response sensitivity of SFN, enhance its cytotoxicity, and effectively kill tumor cells. Moreover, targeting tumor blood vessels with BFL and SFN could inhibit VEGF secretion and VEGFR expression to suppress tumor angiogenesis, further inhibiting the growth of tumors. Through comprehensive evaluation of the targeting ability of this drug delivery system in vivo and in vitro , the study showed that S/B@FA/cRGD-LB-ZIF-8 improved the sensitivity of SFN by depressing HIF-1α not only to enhance the tumor cell proliferation but also to potently inhibit angiogenesis, providing a new approach to address SFN insensitivity and enhance its anti-HCC activity.