Abstract 3698: Development of a hydrophobic docetaxel prodrug nanoparticle with enhanced plasma circulation lifetime and improved efficacy
Bibliographic record
Abstract
Abstract Amphiphilic block co-polymers can form highly stable micellar-nanoparticles which can be used to trap hydrophobic chemotherapeutic agents. While block co-polymer formulations effectively retain drugs in vitro, nanoparticles frequently display burst release of trapped agents upon injection into animals. As a result, nanoparticles often show only limited improvements in drug circulation lifetime and likely provide little improvement in drug delivery to the tumor site. To address this issue, we previously generated hydrophobic prodrugs of paclitaxel to enhance retention within the nanoparticle and observed a correlation between drug circulation lifetime and the hydrophobicity of the anchor. When these formulations were evaluated for anti-tumor efficacy, the longest circulating paclitaxel prodrugs were the most efficacious. We have now extended our assessment to hydrophobic docetaxel prodrug formulations and have related plasma circulation characteristics of the docetaxel prodrug nanoparticles to suppression of tumor growth in mice bearing HT-29 human colorectal tumor xenographs. Docetaxel-docosanyl diglycolate (procet 7), and docetaxel-cholesteryl diglycolate (procet 8) were formulated in PS-PEG nanoparticles at a drug:polymer weight ratio of1:2 and injected i.v. into mice. The plasma half-life of the docetaxel prodrug was enhanced relative to the corresponding paclitaxel prodrug and significantly greater than docetaxel formulated in polysorbate 80. When dosed at their respective maximum tolerated dose (MTD), docetaxel, procet 7 and procet 8 nanoparticles resulted in a tumor growth delay (TGD) of 66%, 213% and 241% respectively. In addition docetaxel prodrugs administered at equimolar doses to docetaxel displayed greater antitumor activity than the free drug (77% and 105% TGD for procet 7 and procet 8 nanoparticles respectively). We attribute the increased potency of docetaxel prodrugs over paclitaxel prodrugs to the extended plasma circulation lifetimes of the former. These results confirm that hydrophobic docetaxel prodrugs can be formulated into block co-polymer nanoparticles to achieve prolonged circulation kinetics which result in enhanced therapeutic activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3698.
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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".