Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Nanomedicine. 2018 Apr;14(3):633-642. doi: 10.1016/j.nano.2017.12.022. Epub 2018 Jan 6.
The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (μPn); CLT recognizes fibrin-fibronectin complexes in clots, μPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-μPn) into nanocage structure protects the activated-μPn from its circulating inhibitors. Importantly, activated CLT-sFt-μPn thrombolytic nanocage showed a prolonged circulatory life over activated-μPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-μPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies.
溶栓治疗的应用受到全身出血风险增加的限制，这是由于止血栓子的溶解。我们试图开发一种基于纤溶酶的溶栓纳米笼，它可以有效地溶解血栓，而不会引起全身纤维蛋白溶解或破坏止血栓子。在这里，我们生成了一种双室短链铁蛋白（sFt）构建体，其 N 端区域融合了多价血栓靶向肽（CLT：CNAGESSKNC），C 端融合了微纤溶酶（μPn）；CLT 识别血栓中的纤维蛋白-纤维连接蛋白复合物，μPn 有效地溶解血栓，双室 sFt（CLT-sFt-μPn）组装成纳米笼结构保护激活的 μPn 免受其循环抑制剂的影响。重要的是，激活的 CLT-sFt-μPn 溶栓纳米笼在循环中的寿命比激活的 μPn 长，并能有效地溶解动脉和静脉血栓模型中已存在的血栓。因此，CLT-sFt-μPn 溶栓纳米笼平台代表了一种高效、安全的靶向溶栓药物原型，优于现有的溶栓治疗方法。
