Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model

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.