Avidity and shear stress-linked anchoring to tumor endothelium: transfer the principles of leukocyte adhesion for tumor-specific drug delivery

Avidity and shear stress-linked anchoring to tumor endothelium: transfer the principles of leukocyte adhesion for tumor-specific drug delivery

Site-specific leukocyte adhesion to endothelium is usually controlled by two factors: by increase of molecule avidity and by hydrodynamic shear force. In the present project, we tested these principles for specific anchoring of tumor endothelial cells (TEC) in HCC. First, we analysed the cell surface expression changes of various endothelial markers in murine/human HCC and liver tissue in the process of tumor vessel capillarization using immunofluorescence. We identified one molecule (CD146) which is ubiquitously overexpressed on the intraluminal surface of tumor endothelium in murine HCC and the majority of human HCC samples. Using ELISA of murine HCC and liver isolated endothelial cells (AlbTag mice), we found that CD146 expression on TECs was approximately 2.6-fold higher than in hepatic sinusoidal endothelial cells (HSECs) (4.4 fg/cell and 1.6 fg/cell respectively).

Different approaches to achieve selective enrichment of labeled anti-CD146 mAb in vivo were tested. (I) Intravenous injection of anti-CD146 mAb in HCC-bearing (AlbTag) mice. (ii) Direct injection of mAb into hepatic artery. (iii) Evaluation of the impact of shear stress on specific anchoring of nanoparticles to TECs. Shear stress-dependent binding of anti-CD146-coated nanoparticles to endothelial cells was found on histological sections of murine HCC in vitro.

Our findings support the basic hypothesis that the combination of targeting a TEC specific marker and avidity- and shear stress-linked anchoring to tumor endothelium can be used for selective therapeutic drug delivery in HCC.