Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity
| العنوان: | Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity |
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| المؤلفون: | Christoph A. Umbricht, Martina Benešová, Roger Schibli, Konstantin Zhernosekov, Cristina Müller, Francesca Borgna, Luisa M. Deberle, Manuel Büchler |
| المصدر: | Theranostics Theranostics, 10 (4) |
| بيانات النشر: | Ivyspring International Publisher, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Glutamate Carboxypeptidase II, Male, Medicine (miscellaneous), Ibuprofen, Lutetium, Pharmacology, Ligands, urologic and male genital diseases, 030218 nuclear medicine & medical imaging, Mice, 0302 clinical medicine, Radioligand, Tissue Distribution, prostate cancer, PSMA ligands, Lu-177, albumin-binder, ibuprofen, Internalization, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), media_common, chemistry.chemical_classification, Chemistry, In vitro toxicology, 3. Good health, Amino acid, Prostatic Neoplasms, Castration-Resistant, 030220 oncology & carcinogenesis, Antigens, Surface, Female, Serum Globulins, Research Paper, Biodistribution, Single Photon Emission Computed Tomography Computed Tomography, Injections, Subcutaneous, media_common.quotation_subject, Mice, Nude, Serum Albumin, Human, 03 medical and health sciences, Pharmacokinetics, Albumins, Cell Line, Tumor, Animals, Humans, Cyclooxygenase Inhibitors, Radioisotopes, Albumin, 177Lu, Xenograft Model Antitumor Assays, In vitro, Radiopharmaceuticals, Carrier Proteins |
| الوصف: | Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. Methods: Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the 177Lu-labeled PSMA ligands were tested in vitro using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. Results: The PSMA ligands were obtained in moderate yields at high purity (>99%). 177Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. In vitro assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. 177Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. Conclusion: The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. 177Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation. ISSN:1838-7640 |
| وصف الملف: | application/application/pdf |
| تدمد: | 1838-7640 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f65b458ab4a6b534f188752b68260f7 https://doi.org/10.7150/thno.40482 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4f65b458ab4a6b534f188752b68260f7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18387640 |
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