Development of highly efficacious hydrophobic paclitaxel prodrugs delivered in nanoparticles for fixed-ratio drug combination applications
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 5734 In vitro evidence has revealed that many drug combinations can act either synergistically or antagonistically, depending on the exposed drug ratio. Since the pharmacokinetic behavior of the individual drugs cannot be controlled when administered in a conventional aqueous based cocktail, drug delivery systems must be utilized to maintain optimal drug ratios. We report here the development of nanoparticle delivery systems for hydrophobic drugs where plasma drug levels can be controlled in a manner that can be readily adapted to deliver drug combinations. Paclitaxel is a hydrophobic chemotherapeutic drug that is typically used in combination with other agents to treat breast, lung and ovarian cancer. Poor drug solubility necessitates its formulation into a mixture of Cremophor and ethanol. Toxicity associated with the use of Cremophor has resulted in formulation efforts using polymer micelles or nanoparticles with hydrophobic cores to serve as a drug reservoir. While paclitaxel can be efficiently solubilized in these delivery systems, the drug is rapidly cleared from circulation following injection. We have generated a series of hydrophobic paclitaxel prodrugs with the objective of enhancing and controlling drug circulation lifetime through changes in the hydrophobic lipid anchor composition. Paclitaxel prodrugs were stably incorporated into amphiphilic block copolymer nanoparticles and administered intravenously into mice. The nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo . The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release rates ranging from 1h to 24 h. The nanoparticle formulations could be stored stably at 4°C for several months. To evaluate the therapeutic activity of the various paclitaxel prodrugs, nanoparticle formulations were administered intravenously into mice bearing HT29 human colon xenograph tumors. As the plasma half-life and area under the curve of the prodrug increased, activity against HT29 tumors also increased. Paclitaxel prodrug nanoparticles more than doubled the time for HT29 tumors to reach 400 mg relative to commercial paclitaxel in Cremophor, when both treatments were administered at MTD using optimal treatment regimens. The paclitaxel prodrugs could be co-formulated with hydrophobic prodrug analogues of water-soluble agents such as doxorubicin and dual-drug nanoparticles maintained the two agents at the injected drug:drug ratio in the plasma for extended times after injection. Formulating hydrophobic prodrugs in nanoparticles provides a novel approach to co-deliver anticancer drug combinations with widely differing physicochemical properties and maintain optimal drug:drug ratios in vivo .
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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) | 0.000 | 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 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".