Project title: Optimizing chelator compositions for alpha particle-based PRRT in neuroendocrine tumors

Description

What critical problem/question will researchers try to answer?
Our project addresses a major challenge in neuroendocrine tumor (NET) treatment — developing a chelator that can stably retain both parent and daughter radionuclides of alpha emitters, such as lead-212 (Pb-212), actinium-225 (Ac-225), and terbium-149 (Tb-149). A key limitation in targeted alpha-particle therapy (TAT) is the uncontrolled release of radioactive daughter radionuclides from existing chelators, leading to radiation damage in normal tissues, particularly the kidneys and bone marrow. This project seeks to design a next-generation chelator with enhanced stability and retention capacity for both parent and daughter radionuclides, improving the precision, safety, and efficacy of TAT for NETs.

Why is this important?
TAT with alpha emitters including Pb-212 and Ac-225 has shown substantial therapeutic potential due to its ability to deliver potent, short-range radiation directly to cancer cells. However, a significant challenge is the leakage of radioactive daughter products from current chelators, which exposes normal tissues to radiation. This leakage limits the dose of alpha emitters that can be safely administered. Our project aims to develop a chelator that securely retains both parent and daughter radionuclides, enabling higher therapeutic doses with fewer side effects.

What will the researchers do?
We will combine density functional theory (DFT) computational modeling with experimental validation. DFT modeling will predict optimal chelation structures capable of tightly binding parent and daughter radionuclides. Using these predictions, we will synthesize and screen chelators to assess their ability to retain radionuclides under physiological conditions. While we aim to identify the most promising chelator structures for multiple alpha emitters of interest, initial experimental testing will focus on Pb-212, leveraging our team’s established expertise with this isotope. Promising candidates will be evaluated in vitro and in vivo using animal models to measure biodistribution, tumor targeting, and clearance from non-target tissues. This dual approach of computational prediction and experimental validation will accelerate the development of a next-generation chelator that addresses key limitations in TAT for NETs.

How might this improve treatment of neuroendocrine cancer?
A new chelator composition with improved performance for TAT potentially reduces off-target radiation exposure to normal tissues. This could enable the administration of higher therapeutic doses in clinical settings, leading to improved tumor control and treatment efficacy. Patients may experience better clinical outcomes, fewer side effects, and an overall improvement in quality of life.

What is the next step?
Upon successful initial validation with Pb-212, we will evaluate the therapeutic efficacy and comprehensive toxicity profile of Pb-212-labeled chelator-conjugated peptides. Building on this success, we aim to broaden the scope to include other alpha emitters, such as Ac-225 and Tb-149. The ultimate goal is clinical translation, advancing the most promising chelator candidate to human trials for NET patients.

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