北京大学刘志博研究小组发现，通过放射性药物在肿瘤局部释放原药可用于癌症治疗。相关论文于2024年7月15日在线发表在《科学通报》杂志上。

研究人员提出了一种使用放射性药物激活前药的策略。该策略利用放射性药物的高肿瘤靶向能力，实现化疗药物的靶向释放。[¹⁸F]FDG（2-[¹⁸F]-氟-2-脱氧-D-葡萄糖）是临床上广泛使用的放射性药物之一，可以触发Pt(Ⅳ)复合物在肿瘤中控制性释放轴向配体，这可能是通过由¹⁸F放射性核素衰变导致的水辐解产生的水合电子介导的。其应用提供了在活细胞和带瘤小鼠中控制性释放荧光探针和前药的能力。

值得注意的是，研究人员设计了一种OxaliPt(Ⅳ)链接子，用于构建[¹⁸F]FDG激活的抗体-药物偶联物（Pt-ADC）。顺序注射Pt-ADC和[¹⁸F]FDG可以有效地在肿瘤中释放毒素，并显著抑制肿瘤生长。放射疗法作为前药激活的扰动工具正在蓬勃发展，研究人员发现[¹⁸F]FDG能够去保护各种放射治疗可去除的保护基团（RPG）。这些研究结果表明，肿瘤选择性放射性药物可能作为触发器，用于开发具有增强肿瘤选择性的创新前药激活策略。

据悉，化疗是癌症的一线治疗方法，但其系统性毒性可能非常严重。肿瘤选择性前药激活提供了减少系统性毒性的有希望的机会。

附：英文原文

Title: Locally unlocks prodrugs by radiopharmaceutical in tumor for cancer therapy

Author: Zhibo Liu a b c d

Issue&Volume: 2024/07/15

Abstract: 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. [18F]FDG (2-[18F]-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 18F. 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 [18F]FDG-activated antibody-drug conjugate (Pt-ADC). Sequential injection of Pt-ADC and [18F]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 [18F]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.

DOI: 10.1016/j.scib.2024.07.010

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927324004870