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Mono- and multimeric PSMA-targeting small molecule-thorium-227 conjugates for optimized efficacy and biodistribution in preclinical models

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Titel: Mono- and multimeric PSMA-targeting small molecule-thorium-227 conjugates for optimized efficacy and biodistribution in preclinical models
Autoren: Niels Böhnke, Bård Indrevoll, Stefanie Hammer, Alex Papple, Alexander Kristian, Hans Briem, Arif Celik, Dominik Mumberg, Alan Cuthbertson, Sabine Zitzmann-Kolbe
Quelle: Eur J Nucl Med Mol Imaging
Verlagsinformationen: Springer Science and Business Media LLC, 2023.
Publikationsjahr: 2023
Schlagwörter: Cell Line, Tumor [MeSH], Glutamate Carboxypeptidase II/metabolism [MeSH], Swine [MeSH], Macaca fascicularis/metabolism [MeSH], Chelating Agents/chemistry [MeSH], Humans [MeSH], Thorium [MeSH], Small molecule conjugates, Prostate specific membrane antigen, Prostatic Neoplasms/metabolism [MeSH], Radiopharmaceuticals [MeSH], Antigens, Surface/metabolism [MeSH], Prostatic Neoplasms/diagnostic imaging [MeSH], Animals [MeSH], Original Article, Mice [MeSH], Male [MeSH], Thorium-227, Tissue Distribution [MeSH], Swine, Miniature/metabolism [MeSH], Prostate cancer, Targeted alpha therapy, Male, Glutamate Carboxypeptidase II, Swine, Thorium, Prostatic Neoplasms, 3. Good health, Mice, Macaca fascicularis, Cell Line, Tumor, Antigens, Surface, Humans, Animals, Swine, Miniature, Tissue Distribution, Radiopharmaceuticals, Chelating Agents
Beschreibung: Purpose PSMA (prostate-specific membrane antigen) is highly expressed on prostate cancer (PrCa) cells and extensively used as a homing target for PrCa treatment. Most prominently, PSMA-targeting conjugate PSMA-617, carrying a DOTA chelator and labeled with therapeutic radionuclides like beta-emitting lutetium-177 or alpha-emitting actinium-225, has shown clinical activity in PrCa patients. We sought to develop PSMA-targeting small molecule (SMOL) conjugates that show high uptake in PSMA-expressing tumors and fast clearance, and can easily be labeled with the alpha emitter thorium-227 (half-life 18.7 days). Methods A novel linker motif with improved competition against 3H-PSMA-617 on PSMA-expressing LNCaP cells was identified. A 2,3-hydroxypyridinone chelator modified with carboxyl groups (carboxy-HOPO) with increased hydrophilicity and robust labeling with thorium-227 was developed and allowed the synthesis of mono-, di-, tri-, and tetrameric conjugates. The resulting monomeric and multimeric PSMA SMOL-TTCs (targeted thorium conjugate) were evaluated for cellular binding, internalization, and antiproliferative activity. The in vivo antitumor efficacy of the PSMA SMOL-TTCs was determined in ST1273 and KUCaP-1 PrCa models in mice, and their biodistribution was assessed in cynomolgus monkeys, minipigs, and mice. Results The monomeric and multimeric PSMA SMOL conjugates were readily labeled with thorium-227 at room temperature and possessed high stability and good binding, internalization, and antiproliferative activity in vitro. In vivo, the monomeric, dimeric, and trimeric PSMA SMOL-TTCs showed fast clearance, potent antitumor efficacy, and high uptake and retention in prostate tumors in mice. No major uptake or retention in other organs was observed beyond kidneys. Low uptake of free thorium-227 into bone confirmed high complex stability in vivo. Salivary gland uptake remained inconclusive as mini pigs were devalidated as a relevant model and imaging controls failed in cynomolgus monkeys. Conclusion Monomeric and multimeric PSMA SMOL-TTCs show high tumor uptake and fast clearance in preclinical models and warrant further therapeutic exploration.
Publikationsart: Article
Other literature type
Sprache: English
ISSN: 1619-7089
1619-7070
DOI: 10.1007/s00259-023-06474-z
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/37882848
https://repository.publisso.de/resource/frl:6492274
Rights: CC BY
Dokumentencode: edsair.doi.dedup.....cd4761bf7c1c74298e48979ddbb1ce10
Datenbank: OpenAIRE
Beschreibung
Abstract:Purpose PSMA (prostate-specific membrane antigen) is highly expressed on prostate cancer (PrCa) cells and extensively used as a homing target for PrCa treatment. Most prominently, PSMA-targeting conjugate PSMA-617, carrying a DOTA chelator and labeled with therapeutic radionuclides like beta-emitting lutetium-177 or alpha-emitting actinium-225, has shown clinical activity in PrCa patients. We sought to develop PSMA-targeting small molecule (SMOL) conjugates that show high uptake in PSMA-expressing tumors and fast clearance, and can easily be labeled with the alpha emitter thorium-227 (half-life 18.7 days). Methods A novel linker motif with improved competition against 3H-PSMA-617 on PSMA-expressing LNCaP cells was identified. A 2,3-hydroxypyridinone chelator modified with carboxyl groups (carboxy-HOPO) with increased hydrophilicity and robust labeling with thorium-227 was developed and allowed the synthesis of mono-, di-, tri-, and tetrameric conjugates. The resulting monomeric and multimeric PSMA SMOL-TTCs (targeted thorium conjugate) were evaluated for cellular binding, internalization, and antiproliferative activity. The in vivo antitumor efficacy of the PSMA SMOL-TTCs was determined in ST1273 and KUCaP-1 PrCa models in mice, and their biodistribution was assessed in cynomolgus monkeys, minipigs, and mice. Results The monomeric and multimeric PSMA SMOL conjugates were readily labeled with thorium-227 at room temperature and possessed high stability and good binding, internalization, and antiproliferative activity in vitro. In vivo, the monomeric, dimeric, and trimeric PSMA SMOL-TTCs showed fast clearance, potent antitumor efficacy, and high uptake and retention in prostate tumors in mice. No major uptake or retention in other organs was observed beyond kidneys. Low uptake of free thorium-227 into bone confirmed high complex stability in vivo. Salivary gland uptake remained inconclusive as mini pigs were devalidated as a relevant model and imaging controls failed in cynomolgus monkeys. Conclusion Monomeric and multimeric PSMA SMOL-TTCs show high tumor uptake and fast clearance in preclinical models and warrant further therapeutic exploration.
ISSN:16197089
16197070
DOI:10.1007/s00259-023-06474-z