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Updated: Jun 4, 2025
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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
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Localized In Vivo Prodrug Activation Using Radionuclides
Jeremy M Quintana1, Fangchao Jiang1, Mikyung Kang1
1Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.
Summary
This study introduces Radionuclide-Induced Drug Engagement for Release (RAiDER), a novel method to activate chemotherapy drugs specifically at tumor sites using targeted radiation. RAiDER enhances cancer treatment efficacy by combining radiation and chemotherapy, minimizing side effects from off-target drug activation.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Therapy
- Cancer Treatment
Background:
- Targeted radionuclides offer molecular specificity for imaging and therapy.
- Hypothesis: Local radionuclide energy can activate prodrugs at disease sites, avoiding systemic toxicity.
- Development of Radionuclide-Induced Drug Engagement for Release (RAiDER) strategy.
Purpose of the Study:
- To test the RAiDER strategy for localized delivery of combined radiation and chemotherapy.
- To maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy.
- To evaluate RAiDER's potential in cancer treatment.
Main Methods:
- Screened radionuclides for activating a radiation-responsive caged monomethyl auristatin E (MMAE) prodrug.
- Utilized TOPAS-nBio for radiobiology simulations.
- Evaluated RAiDER in mouse cancer models using FAPI and PSMA agents with caged MMAE or exatecan, combined with biodistribution and clinical dosimetry.
Main Results:
- RAiDER efficiency varied significantly across radionuclides (e.g., 99mTc > 111In > 177Lu).
- Activated MMAE restored microtubule destabilization and increased cytotoxicity up to 2,600-fold.
- RAiDER treatment in mice showed significantly delayed tumor growth compared to monotherapies, with high tumor-specific activated MMAE concentrations.
Conclusions:
- RAiDER is compatible with various nuclear medicine radionuclides and shows potential for improved cancer therapy efficacy and safety.
- The strategy effectively targets prodrug activation to tumors, minimizing off-target toxicity.
- RAiDER broadens radiopharmaceutical capabilities for diverse therapeutic responses in disseminated malignancies.
