Overcoming Radioresistance In Tumor Therapy By Core-Shell Nanoparticles Modified With HIF-1 Inhibitor

Radiotherapy has been extensively used to treat cancer patients because it can effectively damage most solid tumors without penetration limits.A hypoxic microenvironment in solid tumors leads to severe radioresistance and expression of hypoxic inducible factor-1(HIF-1),both which result in poor efficacy of radiotherapy alone.Therefore,effective alleviation of tumor hypoxia level and reduction of HIF-1-related gene expression can significantly improve the tumor radiotherapy sensitivity,thus improving the radiotherapy efficacy.Herein,we report the excellent efficacy of radiotherapy achieved by using a new type of yolk-shell Cu2-xSe@PtSe(CSP)nanosensitizer functionalized with the HIF-l? inhibitor acriflavine(ACF).We prepare the CSP nanosensitizer through the interfacial redox reactions between chloroplatinic acid and Cu2-xSe nanoparticles(CS),and then functionalize the nanosensitizer with ACF through their electrostatic interactions.We show that the synthesized CSP nanosensitizer can arrest the cell cycle(i.e.at the gap 2/mitosis(G2/M)phases)of tumor cells to enhance their sensitivity to X-rays by testing the cell cycle,,and decompose endogenous H2O2 into O2 to reduce hypoxia and increase the production of reactive oxygen species(ROS),both which lead to severe damage to DNA double strands and apoptosis of tumor cells.In the end,the tumor growth and proliferation are significantly inhibited.We also show that the ACF on the surface of CSP nanoparticles can effectively reduce the expression of HIF-l?.All these effects lead to low vascular endothelial growth factor(VEGF),low density of microvessels in tumor,decreased cell proliferation,and increased cell apoptosis,which synergistically and drastically enhance the efficacy of radiotherapy.This work provides insights and guidance for developing novel nanosensitizers to enhance the efficacy of radiotherapy.