Abstract
Therapeutic delivery from microvasculature to cancerous sites is influenced by many factors including endothelial permeability, vascular flow rates/pressures, cancer secretion of cytokines and permeabilizing agents, and characteristics of the chosen therapeutics. This work uses bi-layer microfluidics capable of studying dye and therapeutic transport from a simulated vessel to a cancerous region while allowing for direct visualization and quantification of endothelial permeability. 2.5 to 13 times greater dye transport was observed when utilizing small dye sizes (FITC) when compared to larger molecules (FITC-Dextran 4 kDa and FITC-Dextran 70 kDa), respectively. The use of lower flow rates/pressures is shown to improve dye transport by factors ranging from 2.5 to 5 times, which result from increased dye diffusion times within the system. Furthermore, subjecting confluent endothelial monolayers to cancerous cells resulted in increased levels of vascular permeability. Situations of cancer induced increases in vascular permeability are shown to facilitate enhanced dye transport when compared to non-diseased endothelial monolayers. Subsequent introduction of paclitaxel or doxorubicin into the system was shown to kill cancerous cells resulting in the recovery of endothelial confluency overtime. The response of endothelial cells to paclitaxel and doxorubicin is quantified to understand the direct influence of anti-cancer therapeutics on endothelial growth and permeability. Introduction of therapeutics into the system showed the recovery of endothelial confluency and dye transport back to conditions experienced prior to cancer cell introduction after 120 h of continuous treatment. Overall, the system has been utilized to show that therapeutic transport to cancerous sites depends on the size of the chosen therapeutic, the flow rate/pressure established within the vasculature, and the degree of cancer induced endothelial permeability. In addition, treatment of the cancerous region has been demonstrated with anti-cancer therapeutics, which are shown to influence vascular permeability in direct (therapeutics themselves) and indirect (death of cancer cells) manners. Lastly, the system presented in this work is believed to function as a versatile testing platform for future anti-cancer therapeutic testing and development.