Vinorelbine liposomes injection results in greater tumor drug exposure compared to conventional vinorelbine in tumor-bearing nude mice
Bibliographic record
Abstract
C109 Background: Conventional vinorelbine tartrate (VRL) is a lipophilic, cell-cycle-specific anticancer agent that inhibits tumor cell growth by disrupting microtubule assembly during metaphase. AlocrestTM (vinorelbine liposomes injection) is a proprietary sphingomyelin/cholesterol liposome (OPTISOMETM) encapsulated formulation of VRL with an extended circulating half-life and the potential for enhanced tumor tissue targeting, exposure, and antitumor activity. This study evaluated and compared the pharmacokinetic (PK) profiles and tissue distributions (TD) of Alocrest and VRL in tumor-bearing CD-1 female nude mice. Methods: Mice were subcutaneously implanted with MX-1 human breast tumors. When tumor volumes reached 150 mm3,twenty-four mice per group received a single IV bolus dose of 20 mg/kg (60 mg/m2) of either VRL (3H-VRL) or Alocrest (3H-Alocrest) via the tail vein in a vehicle volume of 10 µL/g body weight. Blood/plasma and tissue samples (gall bladder/bile, heart, kidneys, liver, lungs, muscle, ovaries, small intestine, spleen, and tumor) were collected at 5 min, 1 h, 4 h, 8 h, 24 h, and 96 h post dosing. The total radioactivity from parent compound and metabolites in tissue, VRLeq, was analyzed by liquid scintillation counting. Results: The concentrations of VRLeq in blood/plasma were higher after administration of Alocrest resulting in higher AUCinf in Alocrest-treated mice compared to VRL-treated mice. The steady state volume of distribution and clearance were lower for Alocrest compared to VRL, supporting slower distribution and removal of Alocrest from the plasma compartment. The TD profile of Alocrest showed that, depending on the tissue, VRLeq concentrations peaked at 4 or 8 hours compared to VRL Tmax at 5 minutes or 1 hour. Tumor AUClast values (h*mcg/g) for VRLeq were 1166 in the Alocrest group and 123 in the VRL group. The AUClast for Alocrest was 9.5-fold greater in the tumor, 7.0-fold higher in spleen, 2.4-fold higher in ovaries and 1.0-1.6-fold higher in most other tissues (lower in lung) compared to the AUClast for conventional VRL. The greatest amount of radioactivity as a percent of injected dose (%ID) following Alocrest was found in liver > spleen > tumor while following VRL the greatest %ID was in liver > kidneys > lungs > small intestine. The %ID following Alocrest peaked at 4 to 8 hours before declining except in tumor where %ID peaked at 24 hours and remained constant for up to 96 hours. Conclusions: Optisomal encapsulation of VRL, Alocrest, protects the drug from initial rapid distribution observed with conventional VRL and provides longer drug retention in the circulation. Alocrest results in targeted delivery of drug, accumulation of drug in tumor tissue, and gradual drug release over several days. These unique characteristics result in greater tumor drug exposure and the potential for enhanced anti-tumor activity without increased toxicity. Human clinical trials are ongoing at this time.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".