چاپ صفحه |  صفحه نخست سامانه |  نویسندگان |  اطلاعات تفضیلی |  دانلود مقاله | دانشگاه علوم پزشکی تبریز |
| نویسنده ثبت کننده مقاله | رعنا جهانبان اسفهلان |
| مرحله جاری مقاله | تایید نهایی |
| دانشکده/مرکز مربوطه | دانشکده علوم نوین پزشکی |
| کد مقاله | 64500 |
| عنوان فارسی مقاله | RGD DELIVERY OF TRUNCATED COAGULASE TO TUMOR VASCULATURE AFFORDS LOCAL THROMBOTIC ACTIVITY TO INDUCE INFARCTION AND REGRESSION OF TUMOR XENOGRAFTS IN MICE |
| عنوان لاتین مقاله | RGD DELIVERY OF TRUNCATED COAGULASE TO TUMOR VASCULATURE AFFORDS LOCAL THROMBOTIC ACTIVITY TO INDUCE INFARCTION AND REGRESSION OF TUMOR XENOGRAFTS IN MICE |
| نوع ارائه | سخنرانی |
| عنوان کنگره / همایش | (International Conference of Current Cancer Medicine (I4CM |
| نوع کنگره / همایش | بین المللی |
| کشور محل برگزاری کنگره/ همایش | Poland |
| شهر محل برگزاری کنگره/ همایش | Warsaw |
| سال انتشار/ ارائه شمسی | 1396 |
| سال انتشار/ارائه میلادی | 2017 |
| تاریخ شمسی شروع و خاتمه کنگره/همایش | 1396/06/16 الی 1396/06/16 |
| آدرس لینک مقاله/ همایش در شبکه اینترنت | http://i4cm.net/rgd-delivery-of-truncated-coagulase-to-tumor-vasculature-affords-local-thrombotic-activity-to-induce-infarction- |
| آدرس علمی (Affiliation) نویسنده متقاضی | department Of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Ir |
| نویسنده | نفر چندم مقاله |
|---|---|
| نصرت اله ضرغامی | پنجم |
| خالد صیدی | دوم |
| رعنا جهانبان اسفهلان | اول |
| عنوان | متن |
|---|---|
| خلاصه مقاله | Purpose: We combined unique intrinsic coagulation properties of Staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel fusion protein consisting of truncated Coagulase (tCoa) bearing an RGD motif on its c-terminus, to induce selective infarction of tumor-feeding blood vessels for cancer therapy. Engineered tCoa-RGD binds simultaneously to the prothrombin through its N-terminus and to αvβ3 integrin receptors on tumor endothelial cells by C-terminal RGD motif, where targeted Coagulase affords efficient local thrombosis through conformational activation of prothrombin. Material and methods: Full Coagulase gene (AN: KX914667.1) was isolated from S. aureus (ATCC: 29213). Using specific primers, gene constructs encoding tCoa and tCoa-RGD were constructed and cloned into pet28 vector, and expressed in Ecoli BL21 (DE3). Recombinant proteins were purified by Ni-NTA and FPLC chromatography and identified by western blotting. Dual binding capacity of tCoa-RGD with prethrombin, and αvβ3 receptors were assessed by molecular modeling, docking and dynamics simulation. Binding potential to αvβ3 integrins was verified by ELISA, FACS, and whole body animal imaging using FITC-tagged fusion proteins. Mice bearing 4T1, CT26 and SKOV3 xenografts were established to evaluate thrombogenic activity and tumor growth inhibition potential of the novel fusion proteins. Results: Our results confirmed retaining of coagulase activity and favorable interaction of fusion protein with prothrombin and αvβ3 receptors, as verified by in vitro, in silico, and in vivo experiments. Moreover, whole body imaging showed selective accumulation of FITC conjugated tCoa-RGD in the neovasculature of SKOV3 human ovarian xenografts in mice. Furthermore, systemic injection of three consecutive doses of tCoa-RGD (15µg, q24hr×3) produced striking tumor growth inhibition of mammary, colon and ovarian tumor xenografts, compared to tCoa and saline groups (P<0.01). Similarly, H&E and mason-trichrome histology staining revealed that tCoa-RGD resulted in extensive thrombosis, and subsequent infarction and massive necrosis of 4T1, CT26 and SKOV3 solid tumors in mice. Conclusion: Altogether, 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 novel promising anticancer therapeutics for human trials. |
| کلمات کلیدی | Coagulase-RGD (tCoa-RGD); tumor vascular infarction; induction of thrombosis; tumor growth inhibition |
| نام فایل | تاریخ درج فایل | اندازه فایل | دانلود |
|---|---|---|---|
| img118.pdf | 1397/08/11 | 849432 | دانلود |
| (30) Scientific_Reports.pdf | 1397/08/11 | 3652448 | دانلود |
