Abstract
Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223Ra and 224Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra2+. A moderate log KML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind 223Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra2+ ion and contributes to the small, but growing, number of chelator development efforts for 223Ra-based TAT.
| Original language | English |
|---|---|
| Pages (from-to) | 20834-20843 |
| Number of pages | 10 |
| Journal | Inorganic Chemistry |
| Volume | 62 |
| Issue number | 50 |
| DOIs | |
| State | Published - Dec 18 2023 |
Funding
This research was supported by the U.S. Department of Energy (DOE) Isotope Program, managed by the Office of Science for Isotope R&D and Production, and by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory (ORNL). This research used resources of the Advanced Photon Source at beamline 12-BM, a DOE User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. This research also used resources of the Compute and Data Environment for Science (CADES) at ORNL. V.K. thanks the DOE, Office of Science, Biological and Environmental Research, Bioimaging Science Program for support. Drs. Andrew R. Burgoyne and Roy Copping (ORNL) are thanked for discussions of the Th/Ra generator. This work has been authored by UT-Battelle, LLC, under Contract DE-AC05-00OR22725 with the U.S. Department of Energy (DOE). The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S. Government retains a non-exclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. Government purposes. The DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). 228 224 This research was supported by the U.S. Department of Energy (DOE) Isotope Program, managed by the Office of Science for Isotope R&D and Production, and by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory (ORNL). This research used resources of the Advanced Photon Source at beamline 12-BM, a DOE User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. This research also used resources of the Compute and Data Environment for Science (CADES) at ORNL. V.K. thanks the DOE, Office of Science, Biological and Environmental Research, Bioimaging Science Program for support. Drs. Andrew R. Burgoyne and Roy Copping (ORNL) are thanked for discussions of the 228Th/224Ra generator. This work has been authored by UT-Battelle, LLC, under Contract DE-AC05-00OR22725 with the U.S. Department of Energy (DOE). The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S. Government retains a non-exclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. Government purposes. The DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).
