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Abstract
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Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer.
Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired
functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion
protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer
therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity.
Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction
of fusion proteins with prothrombin and αvβ3 endothelial cell receptors, as verified by in silico, in
vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro,
only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent
infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian
tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor
growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature,
unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of
thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion
proteins as a novel and promising anticancer therapy for human trials.
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