Guo Zhibin, Wang Xuanyu, Han Yi, Shen Siyong, Tian Peng, Hu Yuchen, Ding Zexuan, Fu Qunfeng, Liu Zhibo
Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
China Institute of Atomic Energy, Institute of Nuclear Technology, Beijing 102413, China.
ACS Cent Sci. 2024 Dec 5;10(12):2321-2330. doi: 10.1021/acscentsci.4c01369. eCollection 2024 Dec 25.
Over 90% of cancer patients succumb to metastasis, yet conventional frontline therapy struggles to halt the progression of metastatic tumors. Targeted radionuclide therapy, which delivers radiation precisely to tumor sites, shows promise for treating metastasis. The rational design of a prodrug activation platform using radionuclides would be an ideal approach to synergize chemotherapy with targeted radionuclide therapy, yet it has not been established. Here, we present targeted radionuclide therapy-induced cleavage chemistry that enables the controlled release of oxaliplatin and its axis ligands from oxaliplatin(IV) complexes in living systems. Of note, this strategy demonstrates feasibility over clinically relevant β-emitting radionuclides and exhibits dose dependence. These advantages were taken into account, and a Lutetium-177-activatable platinum(IV) based prodrug system was designed that could achieve localized activation at the tumor site with high efficiency, thereby suppressing subcutaneous and metastatic 4T1 tumors. In summary, our approach highlights the potential of radionuclides as reaction switches, bridging the gap between the radiotherapy-induced reaction and internal radiation. It may provide a new perspective for future combination therapy.
超过90%的癌症患者死于转移，然而传统的一线治疗难以阻止转移性肿瘤的进展。靶向放射性核素疗法能将辐射精准地传递到肿瘤部位，显示出治疗转移的潜力。利用放射性核素合理设计前药激活平台将是使化疗与靶向放射性核素疗法协同增效的理想方法，但尚未确立。在此，我们展示了靶向放射性核素疗法诱导的裂解化学，其能够在生物系统中使奥沙利铂及其轴向配体从奥沙利铂（IV）配合物中可控释放。值得注意的是，该策略在临床相关的β发射放射性核素上证明了可行性，并表现出剂量依赖性。考虑到这些优势，设计了一种基于镥-177可激活的铂（IV）前药系统，该系统能够在肿瘤部位高效实现局部激活，从而抑制皮下和转移性4T1肿瘤。总之，我们的方法突出了放射性核素作为反应开关的潜力，弥合了放射治疗诱导反应与内照射之间的差距。它可能为未来的联合治疗提供新的视角。
