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Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model
Kristina Haase1, Giovanni S Offeddu1, Mark R Gillrie2
1Massachusetts Institute of Technology, Massachusetts, 02139, USA.
Abstract:
Drug discovery and efficacy in cancer treatments are limited by the inability of pre-clinical models to predict successful outcomes in humans. Limitations remain partly due to their lack of a physiologic tumor microenvironment (TME), which plays a considerable role in drug delivery and tumor response to therapy. Chemotherapeutics and immunotherapies rely on transport through the vasculature, via the smallest capillaries and stroma to the tumor, where passive and active transport processes are at play. Here, a 3D vascularized tumor on-chip is used to examine drug delivery in a relevant TME within a large bed of perfusable vasculature. This system demonstrates highly localized pathophysiological effects of two tumor spheroids (Skov3 and A549) which cause significant changes in vessel density and barrier function. Paclitaxel (Taxol) uptake is examined through diffusivity measurements, functional efflux assays and accumulation of the fluorescent-conjugated drug within the TME. Due to vascular and stromal contributions, differences in the response of vascularized tumors to Taxol (shrinkage and CD44 expression) are apparent compared with simpler models. This model specifically allows for examination of spatially resolved tumor-associated endothelial dysfunction, likely improving the representation of in vivo drug distribution, and has potential for development into a more predictable model of drug delivery.
Insights
A novel 3D vascularized tumor-on-chip model improves cancer drug delivery prediction by mimicking the tumor microenvironment (TME). This platform enhances understanding of drug transport and efficacy, offering a more accurate preclinical assessment for cancer treatments.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Drug Delivery Systems
Background:
- Pre-clinical cancer models often fail to predict drug efficacy due to lacking a physiological tumor microenvironment (TME).
- The TME, including vasculature and stroma, significantly influences drug delivery and therapeutic response.
- Current models do not adequately represent the complex interactions governing drug transport in vivo.
Purpose of the Study:
- To develop and utilize a 3D vascularized tumor-on-chip platform for studying drug delivery within a relevant TME.
- To investigate the impact of pathophysiological changes in a vascularized TME on drug transport and efficacy.
- To compare drug response in a vascularized model versus simpler systems.
Main Methods:
- Fabrication of a 3D tumor-on-chip model with a perfusable vasculature network.
- Introduction of tumor spheroids (Skov3 and A549) to induce localized pathophysiological changes.
- Assessment of paclitaxel (Taxol) uptake using diffusivity, efflux assays, and fluorescence measurements.
- Evaluation of tumor response, including shrinkage and CD44 expression, in vascularized versus non-vascularized models.
Main Results:
- The 3D vascularized model demonstrated localized pathophysiological effects, altering vessel density and barrier function.
- Paclitaxel uptake and accumulation were influenced by vascular and stromal components within the TME.
- Vascularized tumors showed distinct responses to paclitaxel, including shrinkage and altered CD44 expression, compared to simpler models.
- The model allowed for spatially resolved examination of tumor-associated endothelial dysfunction.
Conclusions:
- The 3D vascularized tumor-on-chip model provides a more physiologically relevant platform for studying drug delivery in cancer.
- This system enhances the prediction of in vivo drug distribution by incorporating TME factors.
- The model holds potential for improving the accuracy of preclinical drug efficacy testing for cancer therapies.
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