Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China.
Sci Bull (Beijing). 2024 Sep 15;69(17):2745-2755. doi: 10.1016/j.scib.2024.07.010. Epub 2024 Jul 15.
Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumor-selective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [F]FDG (2-[F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note, an OxaliPt(IV) linker is designed to construct an [F]FDG-activated antibody-drug conjugate (Pt-ADC). Sequential injection of Pt-ADC and [F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation, and we find that [F]FDG is capable of deprotecting various radiotherapy-removable protecting groups (RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.
化疗是癌症的一线治疗方法，但它的全身毒性可能很严重。肿瘤选择性前药激活为降低全身毒性提供了有希望的机会。在这里，我们提出了一种使用放射性药物激活前药的策略。由于放射性药物对肿瘤的高靶向能力，这种策略能够实现化疗药物的靶向释放。[F]FDG（2-[F]-氟-2-脱氧-D-葡萄糖）是临床中最广泛使用的放射性药物之一，它可以触发 Pt(IV) 配合物，以控制肿瘤中轴向配体的释放，这可能是由放射性核素 F 衰变产生的水辐解产生的水化电子介导的。它的应用为活细胞和荷瘤小鼠中荧光探针和前药的控制释放提供了可能。值得注意的是，设计了 OxaliPt(IV) 接头来构建 [F]FDG 激活的抗体药物偶联物（Pt-ADC）。Pt-ADC 和 [F]FDG 的序贯注射能够在肿瘤中有效释放毒素，并显著抑制肿瘤生长。放射治疗作为一种前药激活的扰动工具正在蓬勃发展，我们发现 [F]FDG 能够去除各种放射治疗可去除的保护基团 (RPG)。我们的结果表明，肿瘤选择性放射性药物可以作为一种触发剂，用于开发具有增强肿瘤选择性的创新前药激活策略。
