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28 October 2019 to 1 November 2019
Vienna International Centre
Europe/Vienna timezone
Announcement and Call for Papers

The synthesis and cytotoxicity of 64Cu/NOTA-terpyridine platinum conjugate, as a novel theranostic agent

29 Oct 2019, 23:44
15m
Vienna International Centre

Vienna International Centre

Wagramerstrasse 5, 1400 Vienna

Speaker

Mr Meysam Khosravifarsani (Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada)

Description

Objective: Currently, theranostics for both imaging and concomitant chemoradiotherapy is widely used in the treatment of cancerous patients. In this regard, defining the optimal timing between Pt-drugs injection and radiation delivery to the patients is an important issue. Recent advances in the field of nuclear medicine can potentially solve this problem by selective delivery of Pt-based compounds labeled with a positron/Auger-emitting radionuclide to cancer cells. In this study, we designed and validated for the first time a 64Cu-NOTA terpyridine platinum conjugate as a novel Pt-based positron/Auger emitting agent targeting G-quadruplexes DNA structure. This project is aimed to demonstrate that such theranostic agent could give rise to a synergistic effect with a greater selectivity toward cancer cells.

Methodology: The in-vitro cytotoxic and synergistic effects of the conjugate were assessed by Presto-blue assay. The cellular uptake, internalization and efflux of 64Cu-NOTA terpyridine platinum conjugate was measured for colorectal cancer cell (HCT116) as well as a normal fibroblast cell line (GM05757) at 24, 48 and 72 h after initial incubation time.

Results and Discussion: natCu-conjugate showed 3.4, 1.7 and 2.3 times higher cytotoxicity against HCT116 cells relative to GM05757 fibroblast normal cells. However, natCu-conjugate exhibited 9.6, 11.5, 14.1 folds lower cytotoxic effects on HCT116 cells than cisplatin at 24, 48 and 72 h, respectively. The internalization of 64Cu-conjugate in HCT116 cells increased from 15 min (0.04±0.021%) to 24h (18.7±2.8%) and followed by a plateau at 48h (18.6±1.5%), post-administration. The percentages of internalization were significantly higher in HCT116 cancer cells as compared to GM05757 normal cells at 24h, 48h and 72h post-administration (Pvalue<0.001), which is associated with higher cytotoxicity of the conjugate toward HCT116 cells. More importantly, the efflux profile of HCT116 cells showed that considerable amount of 64Cu-conjugate was retained throughout the time course from 15 min (100±7 %) to 72h (48±6%). Additionally, there was a little percentage of the conjugate (<1%) internalized at 4 °C and all time points, indicating that passive uptake of the compound is not primarily responsible for internalization. A synergistic (radiosensitizing) effect was measured for the 64Cu-conjugate (5 and 8MBq) at low concentrations (<100µM). Conversely, cell viability (%) started to increase steadily exhibiting an infra-additive (radio-protective) effect at highest concentration (500µM) on the HCT116 cells.

Conclusion: These results support the potential use of 64Cu-labeled terpyridine platinum conjugate as a novel theranostic agent to diagnose and treat cancers.

Primary authors

Mr Meysam Khosravifarsani (Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada) Dr Samia Ait-mohand (Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada) Prof. Léon Sanche (Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada) Prof. Brigitte Guérin (Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada, 2Sherbrooke Molecular Imaging Center (CIMS) of the CRCHUS, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada)

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