Preclinical evaluation of MC1R targeting theranostic pair [ 155 Tb]Tb-crown-αMSH and [ 161 Tb]Tb-crown-αMSH.

Autor: Wharton L; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada; Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada., McNeil SW; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada., Zhang C; Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada., Engudar G; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada., Van de Voorde M; Belgian Nuclear Research Centre, Boeretang 200, 2400 Mol, Belgium., Zeisler J; Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada., Koniar H; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada; Department of Physics and Astronomy, University of British Columbia, Vancouver, BC V6T 1Z1, Canada., Sekar S; Centre for Comparative Medicine, University of British Columbia, 4145 Wesbrook Mall, Vancouver, BC V6T 1W5, Canada., Yuan Z; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada., Schaffer P; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada; Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada., Radchenko V; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada., Ooms M; Belgian Nuclear Research Centre, Boeretang 200, 2400 Mol, Belgium., Kunz P; Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Accelerator Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada., Bénard F; Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada., Yang H; Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada; Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada. Electronic address: hyang@triumf.ca.
Jazyk: angličtina
Zdroj: Nuclear medicine and biology [Nucl Med Biol] 2024 Sep-Oct; Vol. 136-137, pp. 108925. Date of Electronic Publication: 2024 May 16.
DOI: 10.1016/j.nucmedbio.2024.108925
Abstrakt: Background: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium ( 149 Tb, 152 Tb, 155 Tb, 161 Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving 155 Tb- and 161 Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma.
Methods: 155 Tb was produced via proton induced spallation of Ta targets using the isotope separation and acceleration facility at TRIUMF with isotope separation on-line (ISAC/ISOL). The radiolabeling characteristics of crown-αMSH with 155 Tb and/or 161 Tb were evaluated by concentration-dependence radiolabeling studies, and radio-HPLC stability studies. LogD 7.4 measurements were obtained for [ 161 Tb]Tb-crown-αMSH. Competitive binding assays were undertaken to determine the inhibition constant for [ nat Tb]Tb-crown-αMSH in B16-F10 cells. Pre-clinical biodistribution and SPECT/CT imaging studies of 155 Tb and 161 Tb labeled crown-αMSH were undertaken in male C57Bl/6 J mice bearing B16-F10 melanoma tumors to evaluate tumor specific uptake and imaging potential for each radionuclide.
Results: Quantitative radiolabeling of crown-αMSH with [ 155 Tb]Tb 3+ and [ 161 Tb]Tb 3+ was demonstrated under mild conditions (RT, 10 min) and low chelator concentrations; achieving high molar activities (23-29 MBq/nmol). Radio-HPLC studies showed [ 161 Tb]Tb-crown-αMSH maintains excellent radiochemical purity in human serum, while gradual metabolic degradation is observed in mouse serum. Competitive binding assays showed the high affinity of [ nat Tb]Tb-crown-αMSH toward MC1R. Two different methods for preparation of the [ 155 Tb]Tb-crown-αMSH radiotracer were investigated and the impacts on the biodistribution profile in tumor bearing mice is compared. Preclinical in vivo studies of 155 Tb- and 161 Tb- labeled crown-αMSH were performed in parallel, in mice bearing B16-F10 tumors; where the biodistribution results showed similar tumor specific uptake (6.06-7.44 %IA/g at 2 h pi) and very low uptake in nontarget organs. These results were further corroborated through a series of single-photon emission computed tomography (SPECT) studies, with [ 155 Tb]Tb-crown-αMSH and [ 161 Tb]Tb-crown-αMSH showing comparable uptake profiles and excellent image contrast.
Conclusions: Collectively, our studies highlight the promising characteristics of [ 155 Tb]Tb-crown-αMSH and [ 161 Tb]Tb-crown-αMSH as theranostic pair for nuclear imaging ( 155 Tb) and radionuclide therapy ( 161 Tb).
Competing Interests: Declaration of competing interest LW, CZ, ZY, FB, PS, and HY have pending patent rights for the crown chelator.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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