Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof of principle, we tested whether this strategy of radionuclide-induced drug engagement for release (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy. Methods: We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule-destabilizing monomethyl auristatin E (MMAE) caged by a radiation-responsive phenyl azide, and we interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using the fibroblast activation protein inhibitor (FAPI) agents [^99mTc]Tc-FAPI-34 and [¹⁷⁷Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [¹⁷⁷Lu]Lu-PSMA-617, combined with caged MMAE or caged exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. Results: RAiDER efficiency varied by 70-fold across radionuclides (^99mTc > ¹¹¹In > ¹⁷⁷Lu > ⁶⁴Cu > ³²P > ⁶⁸Ga > ²²³Ra > ¹⁸F), yielding up to 320 nM prodrug activation/Gy of exposure from ^99mTc. Computational simulations implicated low-energy electron–mediated free radical formation as driving prodrug activation. Radionuclide-activated caged MMAE restored the prodrug’s ability to destabilize microtubules and increased its cytotoxicity by up to 2,600-fold that of the nonactivated prodrug. Mice treated with [^99mTc]Tc-FAPI-34 and caged MMAE accumulated concentrations of activated MMAE that were up to 3,000 times greater in tumors than in other tissues. RAiDER with [^99mTc]Tc-FAPI-34 or [¹⁷⁷Lu]Lu-FAPI-04 delayed tumor growth, whereas monotherapies did not (P < 0.003). Clinically guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. Conclusion: This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and can potentially improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biologic and therapeutic responses.

用于成像和治疗的放射性核素在适当的靶向配体下可在体内显示出高分子特异性。我们假设分子靶向放射性核素传递的局部能量可以在疾病部位化学激活前药物，同时避免在脱靶毒性部位激活。作为原理证明，我们测试了这种放射性核素诱导的药物参与释放 （RAiDER） 策略是否可以局部提供放疗和化疗联合治疗，以最大限度地提高肿瘤细胞毒性，同时最大限度地减少脱靶暴露于活化化疗。方法：我们筛选了放射性核素化学激活模型辐射激活前药的能力，该药物由由辐射响应性苯基叠氮化物笼住的微管不稳定的单甲基 auristatin E （MMAE） 组成，我们使用放射生物学计算模拟套件 TOPAS-nBio 解释实验结果。使用成纤维细胞活化蛋白抑制剂 （FAPI） 药物 [^99mTc]Tc-FAPI-34 和 [¹⁷⁷Lu]Lu-FAPI-04 和前列腺特异性膜抗原 （PSMA） 药物 [¹⁷⁷Lu]Lu-PSMA-617 在癌症同基因小鼠模型中评估 RAiDER，结合笼中 MMAE 或笼中 exatecan。小鼠体内的生物分布与临床剂量测定相结合，使用 RAiDER 估计患者放射性药物摄取与活化前药预期浓度之间的关系。结果：放射性核素的 RAiDER 效率变化了 70 倍（^99mTc > ¹¹¹In > ¹⁷⁷Lu > ⁶⁴Cu > ³²P > ⁶⁸Ga > ²²³Ra > ¹⁸F），从 ^99mTc 产生高达 320 nM 前药活化/Gy 的暴露。 计算模拟表明低能电子介导的自由基形成是驱动前药激活的因素。放射性核素激活的笼状 MMAE 恢复了前药破坏微管稳定性的能力，并将其细胞毒性提高了高达 2,600 倍于未活化的前药。用 [^99mTc]Tc-FAPI-34 和笼中 MMAE 治疗的小鼠在肿瘤中积累的活化 MMAE 浓度比其他组织高 3,000 倍。RAiDER 与 [^99mTc]Tc-FAPI-34 或 [¹⁷⁷Lu]Lu-FAPI-04 延迟了肿瘤生长，而单一疗法则没有 （P < 0.003）。临床指导剂量测定表明，可以提供足够的辐射剂量来激活具有治疗意义的前药水平。结论：这项概念验证研究表明，RAiDER 与核医学中常用的多种放射性核素兼容，并有可能提高放射性药物疗法的安全治疗癌症的疗效。因此，RAiDER 有望成为治疗播散性恶性肿瘤的有效策略，并拓宽放射性药物触发各种生物和治疗反应的能力。