A Thermosensitive Liposome Formulation of Vinorelbine for the Treatment of Recurrent Rhabdomyosarcoma
Bibliographic record
Abstract
Approximately one third of rhabdomyosarcoma (RMS) patients experience disease recurrence and subsequently face a dismal prognosis. In most cases, the disease recurrence involves or is confined to the primary disease site, highlighting the need for effective treatment approaches that can improve local control. Chemotherapy continues to play an important role in treating residual disease and preventing local recurrence but is often associated with severe adverse effects. Common strategies to improve efficacy and toxicity profiles of chemotherapy, including liposomal encapsulation, heavily rely on passive tumor targeting via the enhanced permeability and retention (EPR) effect. Due to the recognized heterogeneity associated with the EPR effect in humans, other approaches for achieving tumor targeted drug delivery are needed. This thesis aims (1) to develop a thermosensitive-liposome formulation of vinorelbine (ThermoVRL) to provide EPR-independent drug delivery targeted to the tumor, (2) to evaluate the therapeutic efficacy of ThermoVRL in combination with localized mild hyperthermia (HT) compared to treatment with a non-thermosensitive liposomal formulation of vinorelbine (NTSL-VRL) in murine models of RMS and to identify the underlying pharmacokinetics and biodistribution, and (3) to determine the therapeutic efficacy of ThermoVRL and HT in an immunocompetent model of RMS and to explore if the addition of immunotherapy (i.e., immune checkpoint inhibition therapy (ICI)) to this treatment approach can enhance systemic anti-tumor effects. In summary, this work successfully developed a ThermoVRL formulation. Treatment with ThermoVRL and HT afforded superior therapeutic efficacy relative to treatment with free drug in a mouse xenograft model of RMS. Importantly, pharmacokinetic and biodistribution assessments of vinorelbine revealed an increase in tumor specific drug delivery when administered as ThermoVRL compared to administration as NTSL-VRL. Studies employing a bilateral RMS tumor model in immunocompetent mice revealed that anti-tumor effects following treatment with ThermoVRL and HT remain largely localized to the primary tumor site. However, the addition of ICI significantly enhanced the systemic treatment effects of ThermoVRL in combination with HT. The results of these studies demonstrate that this delivery approach can confer targetability to an untargeted drug molecule and open the door to treatment combinations with ICI to enhance the systemic treatment capabilities of thermosensitive liposomes.
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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".