Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis
Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis
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DOI：
10.2217/17435889.2.4.533
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发表时间：
2007-08-01
期刊：
影响因子：
5.5
通讯作者：
Lanza, G. M.
中科院分区：
文献类型：
--
作者：
Marsh, J. N.;Senpan, A.;Lanza, G. M.
背景：缺血性脑再灌注是治疗急性卒中最有效的方法，它可以恢复受威胁组织的血流。在症状发作后3小时内给予溶栓药物（如重组组织纤溶酶原激活剂）可改善神经系统结局，尽管不良出血事件的可能性将其使用限制在不到3%的急性缺血性卒中患者中。通过将可用药物集中在所需部位并允许较低的全身剂量，靶向溶解血栓的治疗剂有可能降低并发症的频率，同时提高治疗效果。目的：我们的目标是开发一种纤维蛋白特异性的液体全氟化碳纳米颗粒，其表面经过修饰以递送纤溶酶原激活剂链激酶。我们还旨在使用定量声学显微镜评价其体外靶向溶栓的有效性。方法：在体外形成人血浆凝块，并以载链激酶纳米粒、对照纳米粒或两者的混合物为靶向。根据治疗组，然后将凝块暴露于磷酸盐缓冲盐水（PBS）、含纤溶酶原的PBS或含纤溶酶原和游离链激酶的PBS。以15分钟间隔进行空间配准超声扫描1小时，以量化凝块形态和反向散射的变化。结果：与凝块结合的纳米颗粒显著增加了靶向凝块表面的声学对比度，允许体积估计。检测到的凝块表面的轮廓图表明，在纤溶酶原存在下，负载链激酶的纤维蛋白靶向全氟辛基溴纳米颗粒诱导快速纤维蛋白溶解（< 60分钟），而不同时产生微泡和空化。在PBS中超声处理的负载链激酶或靶向纤维蛋白的对照纳米颗粒不会诱导凝块溶解。治疗组的形态学变化伴随着后向散射的时间和空间变化。超声波暴露对消化过程没有影响。靶向链激酶的有效浓度比游离药物的等效有效水平低几个数量级。此外，增加纤维蛋白结合的链激酶纳米颗粒的竞争性抑制以单调的方式减少凝块溶解。链激酶纳米颗粒的低至1%的表面靶向在1小时内产生凝块体积的显著降低（类似于30%）。结论：这种新的基于纳米颗粒的血栓溶解剂在体外提供特异性和快速的纤维蛋白溶解，并可能在急性缺血性卒中的早期再灌注中发挥临床作用。
Background: Reperfusion of the ischemic brain is the most effective therapy for acute stroke, restoring blood flow to threatened tissues. Thrombolytics, such as recombinant tissue plasminogen activator, administered within 3 h of symptom onset can improve neurologic outcome, although the potential for adverse hemorrhagic events limits its use to less than 3% of acute ischemic stroke patients. Targeting of clot-dissolving therapeutics has the potential to decrease the frequency of complications while simultaneously increasing treatment effectiveness, by concentrating the available drug at the desired site and permitting a lower systemic dose. Objectives: We aimed to develop a fibrin-specific, liquid perfluorocarbon nanoparticle that is surface modified to deliver the plasminogen activator streptokinase. We also aimed to evaluate its effectiveness for targeted thrombolysis in vitro using quantitative acoustic microscopy. Methods: Human plasma clots were formed in vitro and targeted with streptokinase-loaded nanoparticles, control nanoparticles or a mixture of both. Depending on the treatment group, clots were then exposed to either phosphate-buffered saline (PBS), PBS with plasminogen or PBS with plasminogen and free streptokinase. Spatially registered ultrasound scans were performed at 15-min intervals for 1 h to quantify changes in clot morphology and backscatter. Results: Nanoparticles bound to the clot significantly increased the acoustic contrast of the targeted clot surface, permitting volumetric estimates. Profile plots of detected clot surfaces demonstrated that streptokinase-loaded, fibrin-targeted perfluoro-octylbromicle nanoparticles in the presence of plasminogen induced rapid fibrinolysis (< 60 min) without concurrent microbubble production and cavitation. Streptokinase-loaded or fibrin-targeted control nanoparticles insonified in PBS did not induce clot lysis. Morphologic changes in the treated group were accompanied by temporal and spatial changes in backscatter. Ultrasound exposure had no effect on the digestion process. Effective concentrations of targeted streptokinase were orders of magnitude lower than equivalently efficacious levels of free drug. Moreover, increasing competitive inhibition of fibrin-bound streptokinase nanoparticles reduced clot lysis in a monotonic fashion. As little as 1 % surface targeting of streptokinase nanoparticles produced significant decreases in clot volumes (similar to 30%) in 1 h. Conclusion: This new nanoparticle-based thrombolytic agent provides specific and rapid fibrinolysis in vitro and may have a clinical role in early reperfusion during acute ischemic stroke.