He Li, Ma Jiao-Jiao, Wu Yi-Qun, Wang Chen-Guang, Lan Tong, Su Lu, Zhu Lin, Huang Shi-Wen, Deng Kai, Wei Yong-Chang
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Theranostics. 2025 Jun 9;15(14):6768-6788. doi: 10.7150/thno.110573. eCollection 2025.
Immunogenicity activation is vital for radioimmunotherapy, but the short-term oxidative damage caused by precise radiation planning limits this effect. Chemodynamic therapy (CDT) with prolonged generation of hydroxyl radical (•OH) can initiate immunogenicity in combination with X-rays, however, its performance is constrained by tumor insufficient H2O2. Here, we propose to construct β-lapachone-based nanoparticles (β-Lap/Fe NPs) which initiate cascade reactions to generate high levels •OH for an extended period in tumor following X-ray irradiation. β-Lap/Fe NPs, constructed by co-encapsulation of β-Lap and Fe3O4 nanoparticles in reactive oxygen species (ROS) responsive C16-S-mPEG2000 micelles, remain stable under normal conditions but rapid decompose and release β-Lap and Fe2+ when exposed to high level ROS. Upon X-ray irradiation, the upregulation of ROS and NAD (P) H: quinone oxidoreductase-1 (NQO1) in tumor cells accurately triggers β-Lap/Fe NPs to persistently generate high levels H2O2 and •OH for 12 hours, ultimately causing strong immunogenic cell death effects. Moreover, β-Lap/Fe NPs with excellent T2-weighted magnetic resonance imaging provide imaging reference for guiding precise X-ray radiation and predicting •OH generation. β-Lap/Fe NPs mediated radio-chemodynamic-immunotherapy remarkably against primary tumor growth, and further shows effective suppression on untreated distant tumors via the abscopal effect. In a word, this work proposed the simple but powerful strategy for cancer radio-chemodynamic-immunotherapy that combines X-ray and CDT to remote locally and visually actuated long-time production of H2O2 and subsequently persistent generation of •OH for initiating strong antitumor immune responses.
免疫原性激活对放射免疫治疗至关重要,但精确放疗计划引起的短期氧化损伤限制了这种效果。能够长时间生成羟基自由基(•OH)的化学动力疗法(CDT)可与X射线联合引发免疫原性,然而,其性能受到肿瘤内过氧化氢(H2O2)不足的限制。在此,我们提出构建基于β-拉帕醌的纳米颗粒(β-Lap/Fe NPs),其在X射线照射后能在肿瘤中引发级联反应,长时间产生高水平的•OH。β-Lap/Fe NPs是通过将β-拉帕醌和四氧化三铁纳米颗粒共包裹于活性氧(ROS)响应性的C16-S-甲氧基聚乙二醇2000(mPEG2000)胶束中构建而成,在正常条件下保持稳定,但在暴露于高水平ROS时会迅速分解并释放β-拉帕醌和Fe2+。在X射线照射后,肿瘤细胞内ROS和烟酰胺腺嘌呤二核苷酸(磷酸):醌氧化还原酶-1(NQO1)的上调精确触发β-Lap/Fe NPs持续产生高水平的H2O2和•OH达12小时,最终导致强烈的免疫原性细胞死亡效应。此外,具有优异T2加权磁共振成像的β-Lap/Fe NPs为引导精确的X射线放疗和预测•OH生成提供成像参考。β-Lap/Fe NPs介导的放射化学动力免疫疗法显著抑制原发性肿瘤生长,并通过远隔效应进一步有效抑制未治疗的远处肿瘤。总之,这项工作提出了一种简单而有效的癌症放射化学动力免疫治疗策略,即将X射线和CDT相结合,以远程、局部和可视化方式驱动长时间产生H2O2,随后持续生成•OH以引发强烈的抗肿瘤免疫反应。
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