Breast cancer aberrantly expresses
tissue factor (TF) in
cancer tissues and
cancer vascular endothelial cells (VECs). TF plays a central role in
cancer angiogenesis, growth, and
metastasis and, as such, is a target for
therapy and
drug delivery. TF is the cognate receptor of
factor VIIa (fVIIa). We have coupled PTX (
paclitaxel, also named
Taxol) with a tripeptide,
phenylalanine-
phenylalanine-
arginine chloromethyl ketone (
FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-
FFRck-fVIIa against a PTX-resistant
breast cancer cell line.
Matrigel mixed with
VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-
FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-
FFRck-fVIIa conjugate significantly reduces microvessel density in
matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX. The
breast cancer lung
metastasis model in athymic nude mice was developed by
intravenous injection of MDA-231 cells expressing
luciferase. Animals were similarly treated intravenously with the PTX-
FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung
metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic
carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective
drug delivery and inhibiting angiogenesis.