Ding Guanwen, Liu Shengnan, Yang Xiangshan, Lv Hongying, Jia Mengchao, Li Juan, Zhang Rui
NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Chang Chun, 130021, China.
China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China.
J Nanobiotechnology. 2024 Dec 19;22(1):774. doi: 10.1186/s12951-024-03057-4.
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.
Therefore, to overcome these obstacles multifunctional core-shell BMS@PtAu nanoparticles (NPs) are prepared using nanoprecipitation followed by electrostatic assembly. PtAu clusters are released from BMS@PtAu NPs to alleviate tumor hypoxia by catalyzing the decomposition of endogenous HO to generate O 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@PtAu 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.
In conclusion, the therapeutic outcome supports the high-efficiency of radiotherapy based on BMS@PtAu NPs in hypoxic tumors expressing PD-L1.
由于存在多种障碍，包括缺氧肿瘤的放射抗性、高剂量X射线对邻近健康组织的损伤以及肿瘤细胞内PD-L1介导的DNA损伤修复，癌症放射治疗（RT）的临床成功率仍然有限。
因此，为克服这些障碍，采用纳米沉淀法结合静电组装制备了多功能核壳型BMS@PtAu纳米颗粒（NPs）。PtAu簇从BMS@PtAu NPs中释放出来，通过催化内源性H₂O₂分解产生O₂以及增强肿瘤部位的X射线沉积来缓解肿瘤缺氧，从而降低所需的X射线剂量。释放出的BMS-202分子同时阻断肿瘤细胞表面和内部的PD-L1，激活效应T细胞并抑制DNA损伤修复。因此，基于BMS@PtAu NPs的放射治疗可增强癌细胞中钙网蛋白的表达、促使高迁移率族蛋白B1（HMGB1）从细胞核转位至细胞质、产生活性氧（ROS）、导致DNA断裂并诱导癌细胞在体外凋亡。在体内1 Gy X射线照射三个周期后，肿瘤抑制率达到92.5%。
总之，治疗结果支持基于BMS@PtAu NPs的放射治疗对表达PD-L1的缺氧肿瘤具有高效性。
