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Prodrugs

Prodrugs

Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...

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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

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Published on: January 29, 2019

Localized in vivo prodrug activation using radionuclides.

J M Quintana, F Jiang, M Kang

Biorxiv : the Preprint Server for Biology

|August 30, 2024

Summary

Radionuclide Induced Drug Engagement for Release (RAiDER) uses targeted radiation to activate chemotherapy drugs specifically at tumor sites. This novel approach enhances cancer treatment efficacy by maximizing tumor cell death while minimizing toxicity to healthy tissues.

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Area of Science:

Nuclear medicine
Radiopharmaceutical therapy
Cancer treatment

Background:

Targeted radionuclides offer molecular specificity for imaging and therapy.
Hypothesis: Localized radionuclide energy can activate prodrugs at disease sites, avoiding off-target toxicity.

Purpose of the Study:

To test the Radionuclide Induced Drug Engagement for Release (RAiDER) strategy for localized combined radiation and chemotherapy.
To maximize tumor cytotoxicity while minimizing exposure to activated chemotherapy in off-target sites.

Main Methods:

Screened radionuclides for activating a radiation-responsive caged-MMAE prodrug.
Utilized TOPAS-nBio for radiobiology simulations.
Evaluated RAiDER in mouse cancer models with FAPI and PSMA agents, combined with caged-MMAE or caged-exatecan.

Main Results:

RAiDER efficiency varied 250-fold across radionuclides, with 99mTc showing high efficacy.
Activated prodrugs restored microtubule destabilization and increased cytotoxicity up to 600-fold.
RAiDER with 99mTc-FAPI-34 or 177Lu-FAPI-04 significantly delayed tumor growth in mice.

Conclusions:

RAiDER is compatible with multiple nuclear medicine radionuclides.
This strategy shows potential for safer and more effective radiopharmaceutical cancer therapies.
RAiDER broadens radiopharmaceuticals' capability to trigger diverse therapeutic responses for disseminated malignancies.