Targeted Drug Delivery to Endothelial Adhesion Molecules
Figure 4
Chronic and acute flows differently regulate endocytosis of anti-PECAM/NC. Intracellular delivery of CAM-targeted nanocarriers (anti-CAM/NC) is controlled by their design and target cell phenotype, microenvironment, and functional status. Endothelial cells (EC) in vivo are constantly or intermittently (during ischemia-reperfusion) exposed to blood flow, which influences carrier-target interactions by changing NC transport properties and/or by direct mechanical effects upon the mechanisms involved in NC binding and uptake. EC adaptation to chronic flow, manifested by cellular alignment with flow direction and formation of actin stress fibers, inhibited anti-PECAM/NC endocytosis consistent with lower rates of anti-PECAM/NC endocytosis in vivo in arterial compared to capillary vessels (a). In contrast, acute flow without stress fiber formation, stimulated anti-PECAM/NC endocytosis (b). PECAM cytosolic tail deletion and disruption of cholesterol-rich plasmalemma domains abrogated anti-PECAM/NC endocytosis stimulation by acute flow, suggesting complex regulation of a flow-sensitive endocytic pathway in EC. Schema illustrates the tentative mechanism for this phenomenon: (a) sustained exposure of EC to flow induces formation of actin stress fibers involved in cellular alignment, which impairs recruitment of actin in the fibers needed for endocytosis of Ab/NC and (b) acute exposure of EC to flow stimulates endocytosis of Ab/NC likely via mechanisms involving cholesterol-rich domains of plasmalemma such as caveolae (cav). From Han et al. [194].
