Localized In Vivo Prodrug Activation Using Radionuclides

作者：Jeremy M. Quintana, Fangchao Jiang, Mikyung Kang, Víctor Valladolid Onecha, Arda Könik, Lei Qin, Victoria Rodriguez, Huiyu Hu, Nicholas Borges, Ishaan Khurana, Leou Ismael Banla, Mariane Le Fur, Peter Caravan, Jan Schuemann, Alejandro Bertolet, Ralph Weissleder, Miles A. Miller, Thomas S.C. Ng · 发表于：Journal of Nuclear Medicine · 年份：2025 · DOI：10.2967/jnumed.124.268559 · 被引用次数：9 · 研究领域：Peptidase Inhibition and Analysis、Radiopharmaceutical Chemistry and Applications、S100 Proteins and Annexins

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 [ 99m Tc]Tc-FAPI-34 and [ 177 Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [ 177 Lu]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 ( 99m Tc > 111 ...