Comparative Evaluation of Novel 177Lu-Labeled PNA Probes for Affibody-Mediated PNA-Based Pretargeting
| العنوان: | Comparative Evaluation of Novel 177Lu-Labeled PNA Probes for Affibody-Mediated PNA-Based Pretargeting |
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| المؤلفون: | Yongsheng Liu, Kristina Westerlund, Amelie Eriksson Karlström, Vladimir Tolmachev, Anna Orlova, Anzhelika Vorobyeva, Hanna Tano, Maryam Oroujeni, Tianqi Xu, Daniel Vasconcelos |
| المصدر: | Cancers, Vol 13, Iss 500, p 500 (2021) Cancers; Volume 13; Issue 3; Pages: 500 |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Biodistribution, pretargeting, lcsh:RC254-282, 030218 nuclear medicine & medical imaging, Nucleobase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, DOTA, Chelation, PNA, affibody molecules, radionuclide therapy, HER2-expressing xenografts, Pretargeting, Chemistry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, In vitro, Oncology, 030220 oncology & carcinogenesis, Radionuclide therapy, Biophysics, Radiologi och bildbehandling, Radiology, Nuclear Medicine and Medical Imaging |
| الوصف: | Simple Summary Affibody molecules are small, engineered affinity proteins based on a nonimmunoglobulin scaffold. Affibody-based radionuclide imaging probes have demonstrated excellent tumor targeting. However, the renal clearance of affibody molecules is accompanied by high reabsorption and retention of activity in the kidney, which prevents their use for radionuclide therapy. We have previously shown the feasibility of overcoming the high renal uptake using a pretargeting approach for affibody-mediated therapy based on peptide nucleic acid (PNA) hybridization. In this study, we test the hypothesis that shortening the PNA pretargeting probes would further increase the difference between the accumulation of radiometals in tumor xenografts and in kidneys. A series of novel PNA probes has been designed and evaluated in vitro and in vivo. We have found that a variant containing 9 nucleobases enables a two-fold increase of the tumor-to-kidney dose ratio compared with a variant containing 15 nucleobases. This creates preconditions for more efficient therapy of cancer. Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe Z(HER2:342)-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [Lu-177]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affinity correlating with the length of the complementary PNA sequences. All the PNA-based probes were bound specifically to HER2-expressing cells in vitro. In vivo studies demonstrated HER2-specific uptake of all Lu-177-labeled probes in xenografts in a pretargeting setting. The ratio of cumulated radioactivity in the tumor to the radioactivity in kidneys was dependent on the secondary probe's size and decreased with an increased number of nucleobases. The shortest PNA probe, [Lu-177]Lu-HP16, showed the highest tumor-to-kidney ratio. [Lu-177]Lu-HP16 is the most promising secondary probe for affibody-mediated tumor pretargeting. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13b9b0b730c450ce30eece72642a8300 https://www.mdpi.com/2072-6694/13/3/500 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....13b9b0b730c450ce30eece72642a8300 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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