Ultrasound contrast microbubbles targeted to tumor angiogenesis specifically bind tumor-derived endothelial cells

摘要

Angiogenesis is a key phenomenon in the continued growth of clinically-significant tumors. Endothelial cells (ECs) of tumor vasculature are phenotypically dissimilar from those in normal tissues, and are characterized by altered expression of molecular markers on the EC surface. Various peptides have been identified that specifically bind to tumor angiogenic endothelium, including the tripeptide Arg-Arg-Leu (MW3). Previously, we have shown that lipid-based ultrasound contrast microbubbles (MBs) can be specifically targeted to EC inflammatory markers. Here, we hypothesized that MBs targeted via MW3 would specifically adhere to tumor angiogenic ECs in vitro. Microbubbles were conjugated via avidin/biotin bridging chemistry to cyclic peptides containing either MW3 or glycine control tripeptides. In a parallel plate chamber, MBs were perfused across coverslips of cultured human coronary artery ECs (HCAECs) or mouse tumor-derived ECs (TDECs) (3 min; wall shear rate 100s{sup}(-1)) and washed. Adhesion to ECs was quantified in 20 random microscopic fields per coverslip. Mw3-MB adherence was 3 to 6-fold greater than glycine-MB (p<0.01). MW3MB adherence to TDECs was 3 times greater than to HCAECs (p<0.01). These data demonstrate that MW3-MBs specifically adhere to tumor angiogenic ECs in vitro, potentially offering a means for noninvasive functional imaging of tumor neovascularization and therapeutic tumor targeting.