posted on 2024-02-23, 18:03authored byJinchao Zhao, Wenbin Dai, Linxing Zhan, Lei Lei, Qiao Jin, Jianwei Wang, Zhe Tang
Combination
therapy with the synergistic effect is an
effective
way in cancer chemotherapy. Herein, an antiangiogenic sorafenib (SOR)
and hypoxia-activated prodrug tirapazamine (TPZ)-coencapsulated liposome
(LipTPZ/SOR) is prepared for chemotherapy of hepatocellular
carcinoma (HCC). SOR is a multi-target tyrosine kinase inhibitor that
can inhibit tumor cell proliferation and angiogenesis. The antiangiogenesis
effect of SOR can reduce oxygen supply and aggravate tumor hypoxia,
which is able to activate hypoxia-sensitive prodrug TPZ, exhibiting
the synergistic antitumor effect. LipTPZ/SOR at different
molar ratios of TPZ and SOR can significantly inhibit the proliferation
of hepatocellular carcinoma cells. The mole ratio of TPZ and SOR was
optimized to 2:1, which exhibited the best synergetic antitumor effect.
The synergistic antitumor mechanism of SOR and TPZ was also investigated
in vivo. After treated with SOR, the number of vessels was decreased,
and the degree of hypoxia was aggravated in tumor tissues. What is
more, in the presence of SOR, TPZ could be activated to inhibit tumor
growth. The combination of TPZ and SOR exhibited an excellent synergistic
antitumor effect. This research not only provides an innovative strategy
to aggravate tumor hypoxia to promote TPZ activation but also paints
a blueprint about a new nanochemotherapy regimen for the synergistic
chemotherapy of HCC, which has excellent biosafety and bright clinical
application prospects.