Metabolizable alloy clusters assemble nanoinhibitor for enhanced radiotherapy of tumor by hypoxia alleviation and intracellular PD-L1 restraint.

Abstract

Background: Cancer radiotherapy (RT) still has limited clinical success because of the obstacles including radioresistance of hypoxic tumors, high-dose X-ray-induced damage to adjacent healthy tissue, and DNA-damage repair by intracellular PD-L1 in tumor.

Results: Therefore, to overcome these obstacles multifunctional core-shell BMS@Pt₂Au₄ nanoparticles (NPs) are prepared using nanoprecipitation followed by electrostatic assembly. Pt₂Au₄ clusters are released from BMS@Pt₂Au₄ NPs to alleviate tumor hypoxia by catalyzing the decomposition of endogenous H₂O₂ to generate O₂ as well as by enhancing X-ray deposition at the tumor site, which thereby reduce the required X-ray dose. The released BMS-202 molecules simultaneously blockade PD-L1 on and in tumor cells, causing the activation of effector T cells and the inhibition of DNA-damage repair. Consequently, radiotherapy based on BMS@Pt₂Au₄ NPs enhance the expression of calreticulin on cancer cells, transposition of HMGB1 from the nucleus to the cytoplasm, generation of reactive oxygen species (ROS), DNA breakage and apoptosis of cancer cells in vitro. The tumor inhibition rate reached 92.5% under three cycles of 1-Gy X-ray irradiation in vivo.

Conclusion: In conclusion, the therapeutic outcome supports the high-efficiency of radiotherapy based on BMS@Pt₂Au₄ NPs in hypoxic tumors expressing PD-L1.