PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties
| Autor: | Jolanta Zaborniak, Wioletta Wojdowska, Piotr F. J. Lipiński, Monika Wyczółkowska, Piotr Garnuszek, Justyna Pijarowska-Kruszyna, Antoni Jaron, Dariusz Pawlak, Urszula Karczmarczyk, Arkadiusz Sikora, Renata Mikolajczak, Michał Maurin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_treatment urologic and male genital diseases 030218 nuclear medicine & medical imaging Targeted therapy lcsh:Chemistry DOTA conjugated PSMA ligand (PSMA-D4) chemistry.chemical_compound Mice 0302 clinical medicine Drug Delivery Systems in vivo studies Radioligand lutetium-177 lcsh:QH301-705.5 Spectroscopy Mice Inbred BALB C in vitro studies Chemistry General Medicine scandium-47 Ligand (biochemistry) prostate cancer Computer Science Applications Biochemistry 030220 oncology & carcinogenesis PC-3 Cells Kallikreins Pharmacophore Biodistribution Mice Nude actinium-225 Article Catalysis Inorganic Chemistry 03 medical and health sciences optical imaging LNCaP medicine PSMA yttrium-90 DOTA Animals Humans Physical and Theoretical Chemistry Molecular Biology Organic Chemistry Prostatic Neoplasms Prostate-Specific Antigen Xenograft Model Antitumor Assays lcsh:Biology (General) lcsh:QD1-999 Radiopharmaceuticals Ex vivo |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 5 'International Journal of Molecular Sciences ', vol: 22, pages: 2731-1-2731-35 (2021) International Journal of Molecular Sciences, Vol 22, Iss 2731, p 2731 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22052731 |
| Popis: | A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity > 97%. The radio complexes were obtained with high yields (> 97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol−1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases. |
| Databáze: | OpenAIRE |
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