Development of new IRE-activated pro-drug triggers for the treatment of pancreatic cancer, and new aza-BODIPY dyes
Bibliographic record
Abstract
Cancer has been the leading cause of death in Canada, with pancreatic cancer being responsible for approximately 7% of cancer deaths. Traditional cancer treatments include oral and intravenous drug cocktails, external-beam radiation therapy, and surgery. Many new and innovative cancer treatments are emerging and irreversible electroporation (IRE, or NanoKnife) is a locally available and unique treatment modality that stands out. Unlike other ablation modalities that use thermal energy, IRE does not generate heat and causes little to no damage to surrounding tissues, requires less treatment time, can be used in larger tumors, and creates a sharp boundary between the area affected and unaffected by treatment. However, while the use of IRE shows relatively good results, there is still room for improvement, particularly for aggressive cancers with poor outcomes such as pancreatic cancer. In this thesis, the development and synthesis of new prodrug triggers activated by IRE is studied to evaluate the possibility of use in conjunction with IRE treatment to improve the results of ablation therapy. Selective activation of prodrugs via the electrical current produced by IRE electrodes in tumors could provide a site-selective chemotherapy that reduces exposure of healthy tissues to highly cytotoxic drugs. Given there is no previous work on IRE prodrug triggers to build on, we designed several linkers/triggers based on chemical moieties that become reactive when reduced and could facilitate linker cleavage. These include linkers based on either 2-nitroimidazole, the self-immolative spacer p-aminobenzyl alcohol (PABA), disulfide bonds, or a derivative of a known nitroreductase substrate. Preliminary research focused on the development of synthetic routes for model compounds containing these prodrug triggers and fluorescent dyes in place of drugs. Following synthesis, model compounds were exposed to either benchtop or clinical IRE conditions and the cleavage products were evaluated by HPLC and mass spectrometry. The nitroimidazole trigger prodrug has shown a response to IRE conditions, while the nitro-PABA based trigger was not activated by the electricity. The model compounds were generally hydrophobic and poorly water soluble, but IRE exposure tests need to be performed in solvent conditions that are as close to saline as possible to best simulate IRE conditions (e.g. conductivity) in tumors. These experiments required addition of varying percentages of organic solvents such as DMSO to achieve reasonable levels of solubility. Future model compounds should be designed to include hydrophilic moieties such as sugars, amino acids, or other polar moieties to ensure full solubility in saline. Additionally, previous research in the Price Group on the synthesis of new near-infrared emitting BODIPY dyes was continued. The previously developed synthetic route and purification procedures were optimized to improve the yields of the different steps, and the conjugation of BODIPY dyes with a bone-targeting bisphosphonate moiety via copper activated click reactions was investigated as a new extension of this research. Further testing is needed to ascertain the possibility of using the developed molecules as bone cancer probes.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".