# Expanding the Therapeutic Potential of the Alpha Emitter Radium-223

> **NIH NIH R21** · CORNELL UNIVERSITY · 2021 · $198,329

## Abstract

PROJECT SUMMARY
 Radium-223 is the only FDA-approved alpha-emitting radionuclide. It is employed for the treatment of
bone metastases in patients with castration-resistant prostate cancer. It is administered in the chemical form of
the simple radium dichloride salt, which enables the unchelated calcium-mimetic radium(II) ion to localize to
rapidly dividing bone metastases. Despite the significant therapeutic potential of this radionuclide, its current
FDA-approved formulation cannot be applied for the treatment of soft-tissue metastases. The goal of this
proposal is to expand the therapeutic potential of this nuclide to soft-tissue metastases by developing bifunctional
chelating agents that can stably retain and deliver radium-223 in vivo. In Aim 1, we will synthesize novel diaza-
18-crown-6 macrocycles and calix[4]arene-based ligands as potential candidates for radium chelation. Our
motivation for exploring these classes of ligands is dictated by literature precedence, which shows that these
ligands are uniquely selective for large ions like radium(II). In Aim 2, we will collaborate with Prof. Babich at Weill
Cornell Medicine to evaluate the radiochemistry of our best ligand candidates with radium-223. The radiolabeling
kinetics and the stabilities of the resulting complexes will be measured. An ideal candidate for radium-223
chelation will rapidly and quantitatively form a complex with the radium(II) ion that is stable in serum over a period
of at least 10 days. Based on these data, we will pursue the synthesis of bifunctional chelating agents in Aim 3.
Using our most effective radium-223 chelating agent, we will synthetically install an amine-reactive
isothiocyanate functional group onto the ligand to allow for its conjugation to soft-tissue tumor-targeting
antibodies. This ligand-antibody conjugate will be radiolabeled with radium-223, and its in vivo biodistribution will
be evaluated in tumor-bearing mice to test the long-term stability of our radiometal construct. Collectively, the
successful execution of these three aims will lead to the discovery of new, bifunctional chelating agents for
radium-223, which will expand the therapeutic use of this radionuclide to patients with soft-tissue metastases.
Thus, this technology has the potential to significantly prolong and improve the lives of cancer patients by
rendering access to the highly promising radium-223 radionuclide.

## Key facts

- **NIH application ID:** 10242812
- **Project number:** 5R21EB027282-03
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Justin J Wilson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $198,329
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242812

## Citation

> US National Institutes of Health, RePORTER application 10242812, Expanding the Therapeutic Potential of the Alpha Emitter Radium-223 (5R21EB027282-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242812. Licensed CC0.

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