Abstract
Real-time monitoring of tumor drug delivery in vivo is a daunting challenge due to the heterogeneity and complexity of the tumor microenvironment. In this study, we developed a biomimetic microfluidic tumor microenvironment (bMTM) comprising co-culture of tumor and endothelial cells in a 3D environment. The platform consists of a vascular compartment featuring a network of vessels cultured with endothelial cells forming a complete lumen under shear flow in communication with 3D solid tumors cultured in a tumor compartment. Endothelial cell permeability to both small dye molecules and large liposomal drug carriers were quantified using fluorescence microscopy. Endothelial cell intercellular junction formation was characterized by immunostaining. Endothelial cell permeability significantly increased in the presence of either tumor cell conditioned media (TCM) or tumor cells. The magnitude of this increase in permeability was significantly higher in the presence of metastatic breast tumor cells as compared to non-metastatic ones. Immunostaining revealed impaired endothelial cell-cell junctions in the presence of either metastatic TCM or metastatic tumor cells. Our findings indicate that the bMTM platform mimics the tumor microenvironment including the EPR effect. This platform has a significant potential in applications such as cell-cell/cell-drug carrier interaction studies and rapid screening of cancer drug therapeutics/carriers.
Highlights
Similar to normal tissue microenvironment, cells in tumor microenvironment are embedded in the extracellular matrix surrounded by blood vessels which supply nutrition and oxygen[2]
This novel in vitro biomimetic microfluidic tumor microenvironment platform featuring co-culturing of human breast cancer cells and human breast tumor associated endothelial cells (HBTAEC), replicates the 3D morphology of cellular architecture observed in vivo, and mimics the tumor environment using specific tumor derived matrices from tumor tissue constructs
To allow for realtime monitoring of tumor-endothelial cell interaction in both tumor and vascular compartments, the platform is constructed from optically clear PDMS assembled on a microscope slide (Fig. 1B)
Summary
Similar to normal tissue microenvironment, cells in tumor microenvironment (including tumor and stromal cells, fibroblasts, and immune cells) are embedded in the extracellular matrix surrounded by blood vessels which supply nutrition and oxygen[2]. Many 3D in vitro tumor models, such as the widely used spheroid hanging drop method, comprise of cancer cells and have the potential to better represent the in vivo conditions[11] These static spheroid models do not account for transport across the vascular endothelium and do not reproduce the complex network structure and fluid shear observed in the in vivo tumor microenvironment. The goal of the current study is to establish an in vitro tumor microenvironment that approximates in vivo tumor barrier characteristics to reproduce the enhanced permeability and retention (EPR) effect with permeability values similar to those reported in vivo This novel in vitro biomimetic microfluidic tumor microenvironment (bMTM) platform featuring co-culturing of human breast cancer cells and human breast tumor associated endothelial cells (HBTAEC), replicates the 3D morphology of cellular architecture observed in vivo, and mimics the tumor environment using specific tumor derived matrices from tumor tissue constructs. We hypothesize that endothelial cells co-cultured with metastatic MDA-MB-231 tumor cells in the bMTM platform will cause the vascular channels to become leakier than those co-cultured with non-metastatic MCF-7 tumor cells
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