Abstract 2206: Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer
Bibliographic record
Abstract
Abstract Clioquinol is an FDA approved antifungal and antiprotozoal drug that has recently garnered attention for its anti-cancer activities. In vitro studies with CQ activity suggest that its mechanism of activity may be dependent its ability to bind and transport copper. CQ binds copper to form a stable dimeric complex (2 mol CQ:1 mol Cu ((CuCQ2)). Although therapeutically interesting, CuCQ2 is virtually insoluble in aqueous solutions and therefore it has been difficult to develop formulations suitable for administration. To address this, a liposomal CuCQ2 formulation was developed and characterized for maximum tolerated dose, pharmacokinetics and efficacy in xenograft models. Liposomes (∼100nm) composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio) were prepared to contain 300 mM CuSO4. CQ is added to the outside of these pre-formed liposomes; at the appropriate incubation temperature CQ crosses the liposomal membrane where it can interact with the encapsulated Cu to form the insoluble CuCQ2 complex which becomes trapped. The maximum tolerated dose of the resultant formulation was determined in CD-1 mice. The pharmacokinetics of the formulation (liposomal lipid, CQ and Cu) were measured following intravenous administration at a well tolerated dose. Efficacy was measured in two cancer models (sc U251 glioblastoma and i.p A2780 ovarian). The maximum tolerated dose of liposomal CuCQ2 was 30 mg/kg when administered i.v (q2d for two weeks) and 15 mg/kg when administered i.p (QD for two weeks). Pharmacokinetics studies with liposomalCuCQ2 administered iv at 30 mg/kg indicated an terminal elimination half-life (t1/2) of 5.4 hr and an AUC of 994 ug•hr/mL. Results demonstrate that the CuCQ2 complex remains intact upon injection. When used to treat animals bearing established sc U251 glioblastoma tumors showed 30% smaller tumours than those treated with vehicle alone. The activity of liposomal CuCQ2 in the A2780 intraperitoneal cancer model will be presented. This work describes, for the first time, a novel injectable formulation of CuCQ2; this formulation is active against established xenograft models. The activity of this formulation will now be assessed in the context of copper-dependent inhibition of NFκB signalling. Citation Format: Moe Wehbe, Malathi Anantha, Ian Backstrom, Armaan Malhotra, Katarina Edwards, Marcel Bally. Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2206.
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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".