The endothelial glycocalyx controls interactions of nanoparticles with the endothelium and their translocation across the blood-tissue border

A prerequisite for the use of nanoparticles (NPs) in diagnostic and therapeutic applications is the targeted delivery to the site of injury. The endothelial glycocalyx (eGCX) is a glycoprotein-polysaccharide meshwork coating... [ view full abstract ]

A prerequisite for the use of nanoparticles (NPs) in diagnostic and therapeutic applications is the targeted delivery to the site of injury. The endothelial glycocalyx (eGCX) is a glycoprotein-polysaccharide meshwork coating the luminal surface of the vasculature. Its role for the regulation of interactions between blood-borne NPs and the microvascular endothelium, however, remains obscure.
Multiphoton in vivo microscopy was employed on the cremasteric microvasculature of wildtype mice to analyze the structure of the eGCX and the deposition of NPs. The eGCX was visualized using labeled wheat germ agglutinin. Carboxyl quantum dots (QDs) were chosen as model NPs. Heparinase, hyaluronidase, and neuraminidase were used to systemically degrade the eGCX. Direct binding of NPs to endothelial molecules was examined in vitro using flow chambers. The uptake and translocation of NPs were addressed in vivo employing transmission electron microscopy (TEM). The effect of ischemia-reperfusion (I/R) injury on the eGCX and the deposition of NPs were examined using an I/R model.
In the microvasculature of control animals, a high eGCX layer was found in all vessel segments, while interactions of QDs with the endothelium were low. Upon enzymatic degradation of the eGCX, however, its size was significantly reduced and NP-endothelium interactions increased considerably. Moreover, endothelial uptake and transendothelial translocation of NPs after enzymatic degradation of the eGCX were demonstrated in vivo using TEM. Binding of QDs to endothelial signaling and adhesion molecules, which were exposed to the bloodstream upon enzymatic degradation of the eGCX, was observed by in vivo microscopy and confirmed in flow chambers. Employing I/R on the cremaster muscle caused a significant reduction of the eGCX and a dramatic increase in NP-endothelium interactions.
Consequently, the eGCX effectively controls NP-endothelium interactions in the microvasculature. It was found to physically cover endothelial adhesion and signaling molecules thereby preventing endothelial attachment, uptake, and translocation of NPs through different layers of the vessel wall. Conversely, degradation of the eGCX under pathologic conditions promoted interactions of NPs with microvascular endothelial cells thus identifying the injured eGCX as an essential element of the blood-tissue border facilitating the targeted delivery of nanomaterials to diseased tissue.