Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Haematopoiesis and Leukocyte Biology, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
J Thromb Haemost. 2017 May;15(5):972-982. doi: 10.1111/jth.13666. Epub 2017 Apr 9.
Essentials Vessel stenosis due to large thrombus formation increases local shear 1-2 orders of magnitude. High shear at stenotic sites was exploited to trigger eptifibatide release from nanocapsules. Local delivery of eptifibatide prevented vessel occlusion without increased tail bleeding times. Local nanocapsule delivery of eptifibatide may be safer than systemic antiplatelet therapies.
Background Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that the effective concentrations are limited because of bleeding complications. Targeted delivery of antiplatelet drug to sites of thrombosis would overcome these limitations. Objectives Here, we have exploited a key biomechanical feature specific to thrombosis, i.e. significantly increased blood shear stress resulting from a reduction in the lumen of the vessel, to achieve site-directed delivery of the clinically used antiplatelet agent eptifibatide by using shear-sensitive phosphatidylcholine (PC)-based nanocapsules. Methods PC-based nanocapsules (2.8 × 10 ) with high-dose encapsulated eptifibatide were introduced into microfluidic blood perfusion assays and into in vivo models of thrombosis and tail bleeding. Results Shear-triggered nanocapsule delivery of eptifibatide inhibited in vitro thrombus formation selectively under stenotic and high shear flow conditions above a shear rate of 1000 s while leaving thrombus formation under physiologic shear rates unaffected. Thrombosis was effectively prevented in in vivo models of vessel wall damage. Importantly, mice infused with shear-sensitive antiplatelet nanocapsules did not show prolonged bleeding times. Conclusions Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.
由于形成大血栓导致的血管狭窄会使局部剪切力增加 1-2 个数量级。在狭窄部位利用高剪切力触发纳米胶囊中依替巴肽的释放。局部给予依替巴肽可防止血管闭塞而不增加尾部出血时间。局部纳米胶囊给予依替巴肽可能比全身抗血小板治疗更安全。
背景心肌梗死和中风仍然是死亡和发病的主要原因。目前抗血小板治疗的主要局限性在于由于出血并发症而使有效浓度受到限制。将抗血小板药物靶向递送到血栓部位将克服这些局限性。目的在这里，我们利用了血栓形成的一个关键生物力学特征，即由于血管内腔缩小而导致的血液剪切应力显著增加，通过使用对剪切力敏感的磷脂酰胆碱（PC）基纳米胶囊来实现临床使用的抗血小板药物依替巴肽的靶向递药。方法将载有高剂量包封依替巴肽的 PC 基纳米胶囊（2.8×10 ）引入微流控血液灌注测定法和血栓形成及尾部出血的体内模型中。结果剪切力触发的依替巴肽纳米胶囊递药选择性地抑制了狭窄和高剪切流条件下的体外血栓形成，而在生理剪切率下的血栓形成不受影响。在血管壁损伤的体内模型中有效地预防了血栓形成。重要的是，输注对剪切力敏感的抗血小板纳米胶囊的小鼠没有出现延长的出血时间。结论通过对剪切力敏感的纳米胶囊进行靶向递药提供了特异性抗血小板的潜力，并可能为开发更有效和更安全的抗血小板药物提供基础。
