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Design, Synthesis, and Cytotoxicity Assessment of [⁶⁴Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker.

ABSTRACT: Maximum benefits of chemoradiation therapy with platinum-based compounds are expected if the radiation and the drug are localized simultaneously in cancer cells. To optimize this concomitant effect, we developed the novel chemoradiotherapeutic agent [⁶⁴Cu]Cu-NOTA-C3-TP by conjugating, via a short flexible alkyl chain spacer (C3), a terpyridine platinum (TP) moiety to a NOTA chelator complexed with copper-64 (⁶⁴Cu). The decay of ⁶⁴Cu produces numerous low-energy electrons, enabling the ⁶⁴Cu-conjugate to deliver radiation energy close to TP, which intercalates into G-quadruplex DNA. Accordingly, the in vitro internalization kinetic and the cytotoxic activity of [⁶⁴Cu]Cu-NOTA-C3-TP and its derivatives were investigated with colorectal cancer (HCT116) and normal human fibroblast (GM05757) cells. Radiolabeling by ⁶⁴Cu results in a >55,000-fold increase of cytotoxic potential relative to [^NatCu]Cu-NOTA-C3-TP at 72 h post administration, indicating a large additive effect between ⁶⁴Cu and the TP drug. The internalization and nucleus accumulation of [⁶⁴Cu]Cu-NOTA-C3-TP in the HCT116 cells were, respectively, 3.1 and 6.0 times higher than that for GM05757 normal human fibroblasts, which is supportive of the higher efficiency of the [⁶⁴Cu]Cu-NOTA-C3-TP for HCT116 cancer cells. This work presents the first proof-of-concept study showing the potential use of the [⁶⁴Cu]Cu-NOTA-C3-TP conjugate as a targeted chemoradiotherapeutic agent to treat colorectal cancer.

SUBMITTER: Khosravifarsani M

PROVIDER: S-EPMC8469169 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:The chemokine receptor 4 (CXCR4) is an important molecular target for both visualization and therapy of tumors. The aim of the present study was the synthesis and preclinical evaluation of a 64Cu-labeled, CXCR4-targeting peptide for positron emission tomography (PET) imaging of CXCR4 expression in vivo. Methods:For this purpose, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), or 1,4,7-triazacyclononane-triacetic acid (NOTA) was conjugated to the highly affine CXCR4-targeting pentixather scaffold. Affinities were determined using Jurkat T-lymphocytes in competitive binding assays employing [125I]FC131 as the radioligand. Internalization and efflux studies of [64Cu]NOTA-pentixather were performed in chem-1 cells, stably transfected with hCXCR4. The stability of the tracer was evaluated in vitro and in vivo. Small-animal PET and biodistribution studies at different time points were performed in Daudi lymphoma-bearing severe combined immunodeficiency (SCID) mice. Results:[64Cu]NOTA-pentixather was rapidly radiolabeled at 60 °C with high radiochemical yields ?90% and purities >99%. [64Cu]NOTA-pentixather offered the highest affinity of the evaluated peptides in this study (IC50?=?14.9?±?2.1 nM), showed efficient CXCR4-targeting in vitro and was stable in blood and urine with high resistance to transchelation in ethylenediaminetetraacetic acid (EDTA) challenge studies. Due to the enhanced lipophilicity of [64Cu]NOTA-pentixather (logP?=?-1.2), biodistribution studies showed some nonspecific accumulation in the liver and intestines. However, tumor accumulation (13.1?±?1.5% ID/g, 1.5 h p.i.) was CXCR4-specific and higher than in all other organs and resulted in high resolution delineation of Daudi tumors in PET/CT images in vivo. Conclusions:[64Cu]NOTA-pentixather was fast and efficiently radiolabeled, showed effective CXCR4-targeting, high stability in vitro and in vivo and resulted in high resolution PET/CT images accompanied with a suitable biodistribution profile, making [64Cu]NOTA-pentixather a promising tracer for future application in humans.

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Design, Synthesis, and Cytotoxicity Assessment of [64Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker.

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Design, Synthesis, and Cytotoxicity Assessment of [⁶⁴Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker.