Development of 64Cu/NOTA-terpyridine platinum conjugates as chemoradiotheranostic agents
Why this work is in the frame
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Bibliographic record
Abstract
Abstract: Colorectal cancer is one of the most prevalent cancers worldwide and in Canada that displays both intrinsic and acquired resistance to platinum based chemotherapeutic agents (Pt-CAs). Several mechanisms are involved in tumour resistance to Pt-CAs, including reduced internalization and increased efflux as well as efficient repair. To overcome platinum drug resistance new classes of Pt-CAs have been proposed, including terpyridine (TP) compounds that have a square planar structure that targets the G-quadruplex higher-ordered structure on DNA. In targeting these regions, an increased stabilization of the G-quadruplexes will occur, and, in turn, cause removal of the protective Shelterin complex from telomeres. This will trigger a DNA damage response, telomer attrition followed by the induction of cell senescence and apoptosis. The novelty of our research is first to target the DNA damaging effects of Pt-CAs toward G-rich regions of the genome, and second to attach a radioisotope as a in situ generator of reactive species that could further enhance DNA damage. Prior to my PhD thesis project, our studies suggested that low-energy electrons (LEE) were integral in the enhanced DNA damaging effects caused by ionizing radiation using radiolabeled Pt-CA. Accordingly, we synthesized two novel agents by conjugating TP to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator labeled with copper-64 (64Cu) (T1/2 = 12.7 h; EC, [43.1%]; β+, 0.653 MeV [17.8 %]; β−, 0.579 MeV [38.4 %]). 64Cu also contains a prolific and local source of LEEs known as Auger electrons that provide a potential avenue to destroy G-quadruplex domains and interfere with telomerase activity, induction of telomer shortening, and interfere with oncogene promoter activity. My main objective is to construct [64Cu]Cu-NOTA-TP conjugates 1 and 2 and investigate effects of combined chemo-radiation therapy (CRT). Mechanistically, I will investigate the interference of telomerase activity to be caused by the formation of DNA lesions and modifications due to intercalation of the Pt-CA into G-quadruplexes and determine the impact on tumor cell death. Specific objectives are as follows: 1) To assess cytotoxicity, cellular and subcellular uptake as well as efflux kinetic of [64Cu]Cu-NOTA-TP conjugates 1 and 2. 2) To investigate the therapeutic potential and safety of the most promising [64Cu]Cu-NOTA-TP conjugate. 3) To carry out positron emission tomography (PET) imaging, biodistribution and dosimetry in appropriate animal models of 1 and 2 and, thereby, determine the potential of [64Cu]Cu-NOTA-TP as a theranostic agent.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it