Abstract
Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [223Ra]RaCl2is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [223Ra]Ra2+localizes. To specifically direct [223Ra]Ra2+to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [223Ra]Ra2+for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [223Ra]Ra2+was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [223Ra]Ra2+under these conditions. [223Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [223Ra]RaCl2, signifying that [223Ra][Ra(macropa)] remains intactin vivo. Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for223Ra, complexing >95% of Ra2+in solution. Furthermore, [223Ra][Ra(macropa-β-alanine)] was rapidly cleared from mice and showed low223Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stabilityin vivofor this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with223Ra and its subsequent stabilityin vivoestablishes for the first time the possibility of delivering [223Ra]Ra2+to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.
| Original language | English |
|---|---|
| Pages (from-to) | 3733-3742 |
| Number of pages | 10 |
| Journal | Chemical Science |
| Volume | 12 |
| Issue number | 10 |
| DOIs | |
| State | Published - Mar 14 2021 |
Funding
In vivo experiments were conducted following a laboratory protocol approved by IACUC animal welfare of Washington University (DCM), conforming to the recommendations published in Animal Welfare Act and Animal Welfare Regulations (the “Blue Book”) by the USDA animal care. Research reported in this publication was supported by the National Cancer Institute and National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Numbers ZIA BC 011800 (FEE), NCI R01CA229893 (DLJT), R01CA201035 (DLJT), R01CA240711 (DLJT), R21EB027282 (JJW), and R01EB029259 (JJW). This research was also supported by a Cottrell Research Scholar Award from the Research Corporation for Science Advancement to JJW. This research made use of the NMR facility at Cornell University, which is supported, in part, by the National Science Foundation under Award CHE-1531632. Isotopes were provided in part through the Department of Energy Isotope Program. We thank the support of the WUSTL EH&S team.
