Sustained Intraperitoneal Chemotherapy via an Injectable Depot Delivery System for the Treatment of Ovarian Cancer
Bibliographic record
Abstract
Ovarian cancer has the highest mortality rate of all gynecological malignancies, due to inadequate treatment strategies and poor early diagnosis. Intraperitoneal (IP) chemotherapy administered on an intermittent schedule has been pursued for ovarian cancer treatment. However, local toxicities and complications associated with indwelling IP catheters required to deliver the chemotherapeutics have been documented. Furthermore, shortening or completely removing treatment-free periods between each chemotherapy cycle has shown improved efficacy compared to intermittent chemotherapy. The focus of this thesis was to develop and characterize a biocompatible and biodegradable IP injectable depot sustained drug delivery system as a new treatment strategy for ovarian cancer. A polymer-lipid injectable formulation (PoLigel) was developed and used for sustained docetaxel (DTX) delivery. The PoLigel resulted in homogeneous DTX peritoneal distribution and sustained plasma levels in healthy mice, which was in contrast to Taxotere®, the clinically used formulation of DTX. Sustained plasma, tissue, tumor and ascites DTX concentrations were observed in mice bearing IP SKOV3 tumors or ID8 ascites over a 3 week period following IP administration of the PoLigel. The intratumoral distribution and tumor penetration of DTX in subcutaneous (SC) and IP SKOV3 tumors were characterized. DTX distributed more towards the tumor core and diffused 1.5 fold further from blood vessels of the IP tumors compared to the SC tumors. The high efficacy observed in the IP SKOV3 and ID8 models and the SC SKOV3 model was attributed to favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure. Sustained chemotherapy with DTX alone and in combination with a drug efflux transporter inhibitor was investigated in multidrug resistant (MDR) ovarian cancer. In vitro, combination delivery via the PoLigel resulted in more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in MDR ovarian cancer cells. Sustained combination chemotherapy was more than twice as efficacious as intermittent Taxotere® treatment in MDR ovarian cancer. Significant anti-tumor efficacy was also observed in the MDR model following sustained DTX chemotherapy compared to intermittent Taxotere®. Overall, results presented here encourage the clinical investigation of IP sustained chemotherapy for ovarian cancer treatment.
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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".