Department of Reparative Materials, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-Cho, Shogoin, Sakyo-Ku, Kyoto 606-8507, Japan.
J Control Release. 2011 Mar 10;150(2):229-34. doi: 10.1016/j.jconrel.2010.11.011. Epub 2010 Nov 24.
Transplantation of islets of Langerhans is a promising method for treating patients with insulin-dependent diabetes mellitus. The major obstacle in clinical settings is early graft loss due to inflammation triggered by blood coagulation and complement activation on the surface of the islets after intraportal transplantation. We propose a versatile method for modifying the surface of islets with the fibrinolytic enzyme urokinase and the soluble domain of the anticoagulant enzyme thrombomodulin. The surfaces of islets were modified with a poly(ethylene glycol)-phospholipid conjugate bearing a maleimide group (Mal-PEG-lipid; PEG MW = 5000 kDa). The Mal-PEG-lipid anchored to the cell membranes of islets, resulting in the presentation of functional maleimide groups on the islet surface. The surface was further treated with thiolated urokinase and thrombomodulin that conjugated by thiol/maleimide bonding. No practical islet volume increase was observed after surface modification, and the modifications did not impair insulin release in response to glucose stimulation. Furthermore, the activity of the immobilized urokinase and thrombomodulin was maintained. These modifications could help to improve graft survival by preventing thrombus formation on the surface of transplanted islets.
胰岛细胞移植是治疗胰岛素依赖型糖尿病患者的一种很有前途的方法。在临床环境中，主要的障碍是由于门静脉内移植后胰岛表面的血液凝固和补体激活引发的炎症导致早期移植物丢失。我们提出了一种通用的方法，即用纤溶酶尿激酶和抗凝酶血栓调节蛋白的可溶性结构域修饰胰岛的表面。通过带有马来酰亚胺基团的聚（乙二醇）-磷脂缀合物（Mal-PEG-脂质；PEG MW = 5000 kDa）修饰胰岛的表面。Mal-PEG-脂质锚定在胰岛的细胞膜上，导致胰岛表面呈现功能性马来酰亚胺基团。表面进一步用巯基化尿激酶和通过巯基/马来酰亚胺键合连接的血栓调节蛋白处理。表面修饰后没有观察到胰岛实际体积增加，并且修饰不会损害对葡萄糖刺激的胰岛素释放。此外，固定化尿激酶和血栓调节蛋白的活性得以维持。这些修饰可以通过防止移植胰岛表面血栓形成来帮助提高移植物的存活率。
