An important hurdle in the development of effective drug carriers for intravenous injection is that of their transport across the endothelial layer that separates the blood stream from the subjacent tissue and further tissue penetration. Targeting carriers to endocytic receptors on the surface of endothelial and tissue cells facilitates said transport. Most receptors associate with clathrin or caveolar pathways, which are constantly used by natural (competing) ligands and limit the geometry of carriers amenable to transport. The recently described cell adhesion molecule (CAM)-mediated route induced by targeting ICAM-1 overcomes these limitations. It provides transport of drug carriers across endothelial linings in cell culture and in mice, release of MMPs for penetration through ECM, and uptake into tissue cells and their subcellular compartments, for a wide range of carrier geometries. The regulation and potential of this pathway are being investigated through our current projects, which use simple cell models (coverslips, membranes). These projects involve validation in mice. However, there is a considerable need for platforms that better recapitulate physiological conditions, such as proper architecture and composition of the cellular barrier, the basal membrane, and the surrounding tissue parenchyma (cells and ECM), which are all subjected to physical and chemical cues reflective of their natural environment.
In collaboration with CECT, we will examine blood-to-tissue transport of carriers as well as tissue penetration and uptake by cells through the design and fabrication of in vitro models that capture key aspects of native physiology. This project will enable fundamental and translational transport studies from a broad perspective and will provide technical and intellectual support on these aspects to the greater community. This will accelerate progress and guide in vivo validation in a time- and cost-efficient manner.
Images courtesy TEBL(UMD)