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.
Highlights
We have shown that this novel chemoradiotherapeutic agent exhibits a strong nanoscale supraadditive and selective cytotoxic effect when combined with copper-64 (64 Cu)
The design of our NOTA-C3-terpyridine platinum (TP) conjugate with a flexible spacer was inspired by a library of ligands developed by Stafford et al showing that cyclen-TP-based bi-metallic complexes had higher affinity toward G-quadruplex DNA as compared to their TP-based mono-metallic counterparts [13]
Considering these promising results, we propose to optimize the design of the TP conjugate by using a NOTA chelator instead of a cyclen for a stronger Cu2+ complexation with a radionuclide such as 64 Cu, which shows great potential for use in radiotherapy and imaging [31,32]
Summary
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 [64 Cu]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 (64 Cu). The cytotoxicity of Pt-based drugs is due to their binding with DNA and the formation of DNA adducts, including intrastrand and interstrand crosslinks and monofunctional adducts [3] These adducts disturb DNA conformation by destabilization of the double helix, which interferes with replication and the mitotic process, and induces cell death.
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