Enhancement of docetaxel solubility via conjugation of formulation-compatible moieties
Bibliographic record
Abstract
Computer-based theoretical calculations were employed to direct the design of docetaxel conjugates with enhanced solubility in the internal phase of a nano-emulsion formulation. The theoretically-identified optimal docetaxel conjugates were synthesized by direct attachment of lauroyl moieties through an ester linkage to docetaxel. In comparison to docetaxel, the conjugates exhibited significantly improved solubility in oil, as predicted by our theoretical calculations. This contributed to high drug entrapment efficiencies (up to 97%) and a high drug loading capacity (5.7% w/w) for the docetaxel conjugates. The mono-substitution of an acyl group at C-2' of docetaxel resulted in a conjugate with 37- to 46-fold lower cytotoxicity than that of the parent drug in two human cancer cell lines. Importantly, the activity exerted by the mono-substituted docetaxel on the cancer cells was due in part to the cytotoxicity of the parent drug that was released via hydrolysis of the ester bond between the lauroyl moiety and the drug under biologically relevant conditions. In contrast, di- and tri-substitution of acyl groups at C-2', C-7 and/or C-10 of docetaxel resulted in non-hydrolysable conjugates that were found to be inactive. Overall, our results show that computer-based theoretical calculation is a promising strategy for guiding the enhancement of material-drug compatibility in formulation development. Also, these studies confirm that chemical modification of docetaxel for enhancement of material-drug compatibility should be limited to mono-substitution at C-2' and result in a prodrug that is hydrolysable at a moderate rate under biologically relevant conditions.
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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) | 0.001 | 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 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".