Determination of bioavailable drug levels from liposomal doxorubicin in murine orthotopic breast tumors
Bibliographic record
Abstract
631 Two liposomal formulations of doxorubicin (DXR), CaelyxR and MyocetR, having very different physical properties and side effects, have received clinical approval for the treatment of refractory breast cancer. Drugs entrapped in liposomes are not bioavailable - they must be released to exhibit activity. The rate at which the drugs are released and the site of release will, we hypothesize, have significant effects on both the therapeutic activity of the formulations and their side effects. To date, only methods to measure total drug in solid tumors (liposomal + released drug) have been available. We have devised methods to also measure bioavailable (released) drug. Total drug was determined in orthotopically implanted murine breast cancer tumors by acidified isopropanol extraction of tumor homogenates at various times after treatment with either liposomal or free DXR. Since only released DXR can reach tumor nuclei and intercalate with DNA, released drug was measured by extracting intercalated drug from nuclei purified from tumor homogenates. After administration of free DXR to tumor-bearing mice, tumor levels of total DXR and nuclear DXR were very similar (i.e., nearly 100% bioavailable), and peak levels for both occured by the first time point (12 h). Total DXR levels in tumor for mice administered free DXR (18 mg/kg) were approximately 50-fold lower than total DXR levels for mice administered liposomal DXR (Caelyx). Peak levels of total drug from liposomal DXR occured at 24 h post-administration, while peak levels of nuclear DXR were delayed until 48-72 h post-administration. Over 7 days, approximately 40% of DXR from liposomal DXR was bioavailable. It is now possible to correlate the levels of bioavailable drug with therapeutic activity for liposomes having different sizes, compositions and release rates. These studies will be supplemented with apoptotic assays and will help to guide the rational design of drug carriers.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".