Localized In Vivo Prodrug Activation Using Radionuclides

Jeremy M. Quintana, Fangchao Jiang, Mikyung Kang, Victor Valladolid Onecha, Arda Könik, Lei Qin, Victoria E. Rodriguez, Huiyu Hu, Nicholas Borges, Ishaan Khurana, Leou I. Banla, Mariane Le Fur, Peter Caravan, Jan Schuemann, Alejandro Bertolet, Ralph Weissleder, Miles A. Miller, Thomas S.C. Ng
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Abstract

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.

使用放射性核素的局部体内药物前激活
放射性核素用于成像和治疗可以显示高分子特异性与适当的靶向配体在体内。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,同时避免在毒性脱靶部位激活。作为原理证明,我们测试了这种放射性核素诱导的药物结合释放(RAiDER)策略是否可以局部传递放化疗联合,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对辐射激活模型前药的化学激活能力,该模型前药由辐射响应性苯叠氮化物笼子中的微管不稳定单甲基auristatin E (MMAE)组成,我们使用放射生物学计算模拟套件TOPAS-nBio解释了实验结果。采用成纤维细胞活化蛋白抑制剂(FAPI)制剂[99mTc]Tc-FAPI-34和[177Lu]Lu-FAPI-04以及前列腺特异性膜抗原(PSMA)制剂[177Lu]Lu-PSMA-617,联合MMAE或exatecan,在同基因小鼠癌症模型中对RAiDER进行了评估。在小鼠体内的生物分布,结合临床剂量学,估计了患者的放射性药物摄取与使用RAiDER预期的活化前药浓度之间的关系。结果:不同放射性核素(99mTc >;111年在177路比;64铜比;32 p比;68 ga比;223 ra比;18F),在99mTc照射下产生高达320 nM的前药激活/Gy。计算模拟表明,低能电子介导的自由基形成驱动了前药活化。放射性核素激活的笼状MMAE恢复了前药破坏微管稳定的能力,并使其细胞毒性比未激活的前药提高了2600倍。用[99mTc]Tc-FAPI-34和笼化MMAE处理的小鼠在肿瘤中积累的活化MMAE浓度比其他组织高3000倍。RAiDER联合[99mTc]Tc-FAPI-34或[177Lu]Lu-FAPI-04可延缓肿瘤生长,而单药治疗无此作用(P <;0.003)。临床指导剂量测定表明,足够的辐射剂量可以激活治疗意义水平的前药。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治疗的安全性,以治疗癌症。RAiDER因此有望成为治疗播散性恶性肿瘤的有效策略,并扩大了放射性药物引发多种生物和治疗反应的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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