Fibrin-specific poly(N-isopropylacrylamide) nanogels for targeted delivery of tissue-type plasminogen activator to treat thrombotic complications are well tolerated in vivo.
Fibrin-specific poly(N-isopropylacrylamide) nanogels for targeted delivery of tissue-type plasminogen activator to treat thrombotic complications are well tolerated in vivo.
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DOI：
10.1002/btm2.10277
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发表时间：
2022-05
影响因子：
7.4
通讯作者：
Brown, Ashley C.
中科院分区：
文献类型：
--
作者：
Mihalko, Emily P.;Nellenbach, Kimberly;Krishnakumar, Manasi;Moiseiwitsch, Nina;Sollinger, Jennifer;Cooley, Brian C.;Brown, Ashley C.
关键词：
维持血液流动性的靶向给药可以降低与全身抗凝剂相关的风险，这些风险可能导致脱靶出血。最近，人们对靶向递送组织型纤溶酶原激活剂（tPA）治疗血栓性并发症产生了很大兴趣。本文介绍的工作表征了用于靶向递送tPA以治疗血栓性并发症的纤维蛋白特异性纳米凝胶（FSN）设计。在体外表征了纳米凝胶结合和凝块降解，并且使用血栓形成的动物模型来检查纳米凝胶对凝血参数的影响。体外试验显示，tPA-FSN以剂量依赖性方式附着于纤维蛋白，与tPA负载无关。在血栓形成的动物模型中，包括电解损伤以真实的实时监测凝块性质，以及脂多糖诱导的弥散性血管内凝血（DIC）动物模型，tPA-FSN调节纤维蛋白/纤维蛋白原和血小板掺入凝块，并在优化剂量下可恢复DIC中的消耗性凝血病。未加载和tPA加载的FSN的分布显示，24小时后tPA-FSN可能被清除，尽管未加载的FSN可能保留在纤维蛋白沉积部位。最大耐受剂量研究表明，tPA-FSN具有最小的毒性，高达最佳治疗剂量的20倍。总体而言，这些研究证明了靶向纤溶对系统性微血栓的治疗效果，并开始评估tPA‐FSN治疗的关键转化参数，包括啮齿动物DIC模型中的最佳tPA‐FSN剂量和静脉内tPA‐FSN治疗的安全性。
Targeted drug delivery for maintaining blood fluidity can reduce the risks associated with systemic anticoagulants that can lead to off‐target bleeding. Recently, there has been much interest in targeted delivery of tissue‐type plasminogen activator (tPA) for treating thrombotic complications. The work presented here characterizes a fibrin‐specific nanogel (FSN) design for targeted delivery of tPA to treat thrombotic complications. Fibrin binding and clot degradation were characterized in vitro, and animal models of thrombosis were used to examine nanogel effects on coagulation parameters. In vitro assays showed tPA‐FSNs attach to fibrin in a dose‐dependent manner independent of tPA loading. In animal models of thrombosis, including an electrolytic injury to monitor clot properties in real time, and a lipopolysaccharide‐induced disseminated intravascular coagulation (DIC) animal model, tPA‐FSNs modulated fibrin/fibrinogen and platelet incorporation into clots and at optimized dosing could recover consumptive coagulopathy in DIC. Distribution of unloaded and tPA‐loaded FSNs showed potential clearance of tPA‐FSNs after 24 h, although unloaded FSNs may be retained at sites of fibrin deposits. Maximum tolerated dose studies showed tPA‐FSNs have minimal toxicity up to 20 times the optimized therapeutic dose. Overall, these studies demonstrate the therapeutic efficacy of targeted fibrinolysis for systemic microthrombi and begin to evaluate key translational parameters for tPA‐FSN therapeutics, including optimal tPA‐FSN dosage in a DIC rodent model and safety of intravenous tPA‐FSN therapeutics.
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影响因子：
3.8
作者：
Choi, Jonghoon;Reipa, Vytas;Malinauskas, Richard A.
通讯作者：
Malinauskas, Richard A.
影响因子：
4
作者：
Hoffman, M
通讯作者：
Hoffman, M
DOI：
10.5339/gcsp.2014.46
发表时间：
2014
期刊：
Global cardiology science & practice
影响因子：
--
作者：
El-Sherbiny IM;Elkholi IE;Yacoub MH
通讯作者：
Yacoub MH
影响因子：
48
作者：
Alexandrov, Andrei, V;Kohrmann, Martin;Schellinger, Peter D.
通讯作者：
Schellinger, Peter D.
DOI：
10.1161/atvbaha.111.225334
发表时间：
2011-06-01
影响因子：
8.7
作者：
Cooley, Brian C.
通讯作者：
Cooley, Brian C.