PT  - JOURNAL ARTICLE
AU  - Khosravifarsani, Meysam
AU  - Ait-mohand, Samia
AU  - Sanche, Léon
AU  - Guérin, Brigitte
TI  - <strong>In-vitro cytotoxic effect of <sup>64</sup>Cu/NOTA-terpyridine platinum conjugate, as a novel theranostic agent</strong><strong/>
DP  - 2019 May 01
TA  - Journal of Nuclear Medicine
PG  - 1615--1615
VI  - 60
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/60/supplement_1/1615.short
4100  - http://jnm.snmjournals.org/content/60/supplement_1/1615.full
SO  - J Nucl Med2019 May 01; 60
AB  - 1615Objectives: Recent advances in the field of nuclear medicine have allowed the development of several metal-based compounds for cancer diagnosis and treatment. There is a considerable enthusiasm to improve the efficacy of radiotherapy protocols through synthesizing new metal-based compounds with lower toxicity for normal tissues. Here, we have synthesized 64Cu-NOTA terpyridine platinum conjugate as a novel bi-metallic agent that is tailored toward quadruplex motifs on DNA. Our objective is to demonstrate that such theranostic agent could give rise to greater selectivity for cancer cells. Methods: The in-vitro cytotoxic effect, cell uptake, internalization and efflux of 64Cu-NOTA terpyridine platinum complex and other control compounds were tested on a colorectal cancer cell (HCT116) as well as a normal fibroblast cell line (GM05757) at 24, 48 and 72 hours after initial incubation time. Results: natCu-labeled NOTA-terpyridine platinum complex showed 3.35, 1.74 and 2.26 times higher cytotoxicity against HCT116 cells as compared to GM05757 normal cells. However, the cytotoxic effects of our complex (IC50 = 298.2 - 481 µM) was much less than cisplatin (IC50 = 23.3 - 41.6 µM). Remarkably, removal of natCu from our complex (NOTA-terpyridine platinum) increased its activity against HCT116 cells from 7.63 (IC50=63±1.08µM) to 13.53 (IC50=24±1.25µM) folds, suggesting considerable influence of charge on cytotoxicity of the complex. The internalization of 64Cu-NOTA terpyridine platinum complex in HCT116 cells increased from 15 min (0.04±0.021%) to 24h (18.7±2.77%) and reached a plateau at 48h (18.6±1.45%), 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), consistent with our data indicating higher cytotoxicity of the complex toward HCT116 cells. More importantly, the efflux profile of HCT116 cells showed that considerable amount of 64Cu-NOTA terpyridine platinum complex was retained throughout the time course from 15 min (100 ± 7.2 %) to 72h (48.13 ± 5.6%). Additionally, there was a little percentage of the complex (<1%) internalized in cold temperature (4°C) at all time points, indicating that passive uptake of the compound is not primarily responsible for internalization. Supplementary studies considering antagonism, synergism or additive effects of combined 64Cu with NOTA-terpyridine platinum complex, using the Combination Index (CI) method, is ongoing. Conclusion: In conclusion, this work supports the potential use of 64Cu-labeled terpyridine platinum conjugate as a novel theranostic agent to diagnose and treat cancers.