مشخصات پژوهش

صفحه نخست /RGD delivery of ...
عنوان
RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice
نوع پژوهش مقاله چاپ شده
کلیدواژه‌ها
RGD; truncated coagulase; tumor vasculature
چکیده
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.
پژوهشگران رعنا جهانبان (نفر اول)، خالد صیدی (نفر دوم)، حسن منهمی (نفر سوم)، امیر دایی (نفر چهارم)، بابک مینوفر (نفر پنجم)، پیمان زارع (نفر ششم به بعد)، داود فرج زاده (نفر ششم به بعد)، صفر فرج نیا (نفر ششم به بعد)، رمضان بهزادی (نفر ششم به بعد)، مهران مسگری عباسی (نفر ششم به بعد)، نصرت اله ضرغامی سلطان احمدی (نفر ششم به بعد)، طاهره جواهری (نفر ششم به بعد)