Abstract 5785: Characterization of a novel microfluidic in vitro model of the blood-tumor and blood-brain barrier

Abstract

Abstract Background: There is a need for a cost-effective and reliable in vitro model of the blood-tumor barrier (BBB) and blood-brain barrier (BTB) for primary and metastatic lesions in brain. Current models do not accurately recapitulate physiological conditions and are unreliable with up to a 100-fold variance in predicting drug permeability into brain tumors. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured with either CTX-TRD2 rat astrocytes (BBB) or Met-1 murine breast cancer cells (BTB) in a microfluidic chip, which contained chambers separated by a porous wall. Shear stress was induced on HUVECs by perfusion of media through the apical chamber, and permeability was characterized by the diffusion of fluorescent tracers, one of which is subject to P-gp efflux. Data was compared to in-vivo work. Results: Permeability of free Texas Red was significantly higher (p<0.05) in BTB chips (kin= 13.1 ± 1.3 X 10-3) than in the BBB chips (Kin=2.5 ± 0.3 X 10-3). There was a similar trend observed in larger markers, but these were not significantly different. The movement of Rhodamine 123 was also restricted, indicating functional P-gp efflux in vitro, similar to data from published in vivo studies. In the BBB model, diffusion of Rho123 increased 14-fold in the presence of verapamil (kin=14.7 ± 7.5 X 10-3) and eight fold with the addition of Cyclosporine A (kin=8.8 ± 1.8 X 10-3). In the BTB model, this increase was also observed, but to a lesser extent, as only 3 and 2-fold increases in permeability were observed, respectively. The magntidue of permeability changes were not significantly different from in-vivo models in both passive diffusion and active efflux experiments. Conclusion: The novel microfluidic chip is a cost-effective in vitro model which recapitulates the BTB and BBB physiology and can predict permeability more reliably than current in-vitro models. Citation Format: Jessica Griffith, Tori Terrell-Hall, Amanda Ammer, Paul Lockman. Characterization of a novel microfluidic in vitro model of the blood-tumor and blood-brain barrier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5785. doi:10.1158/1538-7445.AM2017-5785