Development of Optimized Tissue-Factor-Targeted Peptide Amphiphile Nanofibers to Slow Noncompressible Torso Hemorrhage.
Development of Optimized Tissue-Factor-Targeted Peptide Amphiphile Nanofibers to Slow Noncompressible Torso Hemorrhage.
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DOI：
10.1021/acsnano.9b09243
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发表时间：
2020-06-23
期刊：
影响因子：
17.1
通讯作者：
Kibbe MR
中科院分区：
文献类型：
--
作者：
Klein MK;Kassam HA;Lee RH;Bergmeier W;Peters EB;Gillis DC;Dandurand BR;Rouan JR;Karver MR;Struble MD;Clemons TD;Palmer LC;Gavitt B;Pritts TA;Tsihlis ND;Stupp SI;Kibbe MR
不可压缩的躯干出血在可预防的创伤死亡中占很大比例。我们在此报道了基于肽两亲分子（PA）的可注射靶向超分子纳米治疗剂的研发情况，这些分子旨在靶向组织因子（TF），从而选择性地定位到损伤部位以减缓出血。确定了8种靶向TF的序列，将其合成为PA分子，与非靶向主链PA以不同的重量百分比共组装，并通过圆二色光谱、透射电子显微镜和X射线散射进行了表征。在大鼠肝脏出血模型中静脉注射后，与对照组相比，其中两种PA纳米纤维共组装体对损伤部位表现出最特异的定位（p<0.05），这是通过对受伤肝脏和未受伤器官进行免疫荧光成像量化得出的。为了确定纳米纤维在体内是否靶向TF，进行了小鼠隐静脉激光损伤模型实验，结果表明靶向TF的纳米纤维与纤维蛋白共定位，显示在富含TF的部位纳米纤维水平增加。使用含有TF的肝素化大鼠全血样本获得的血栓弹力图表明，在没有靶向TF的纳米纤维时没有形成血栓。最后，与假手术组和主链纳米纤维对照组相比，两种PA纳米纤维共组装体都使失血量减少了35% - 59%（p<0.05）。这些数据表明一种最佳的靶向TF的纳米纤维能选择性地定位到损伤部位和TF暴露部位，并且有趣的是，能减少失血。这项研究代表了开发一种靶向TF的可注射治疗剂以减少出血导致的可预防死亡的有希望的初始阶段。
Non-compressible torso hemorrhage accounts for a significant portion of preventable trauma deaths. We report here on the development of injectable, targeted supramolecular nanotherapeutics based on peptide amphiphile (PA) molecules that are designed to target tissue factor (TF) and, therefore, selectively localize to sites of injury to slow hemorrhage. Eight TF-targeting sequences were identified, synthesized into PA molecules, co-assembled with non-targeted backbone PA at various weight percentages, and characterized via circular dichroism spectroscopy, transmission electron microscopy, and X-ray scattering. Following intravenous injection in a rat liver hemorrhage model, two of these PA nanofiber co-assemblies exhibited the most specific localization to the site of injury compared to controls (p<0.05), as quantified using immunofluorescence imaging of injured liver and uninjured organs. To determine if the nanofibers were targeting to TF in vivo, a mouse saphenous vein laser injury model was performed and showed that TF-targeted nanofibers co-localized with fibrin, demonstrating increased levels of nanofiber at TF-rich sites. Thromboelastograms obtained using samples of heparinized rat whole blood containing TF demonstrated that no clots were formed in the absence of TF-targeted nanofibers. Lastly, both PA nanofiber co-assemblies decreased blood loss in comparison to sham and backbone nanofiber controls by 35% to 59% (p<0.05). These data demonstrate an optimal TF-targeted nanofiber that localizes selectively to sites of injury and TF exposure, and, interestingly, reduces blood loss. This research represents a promising initial phase in the development of a TF-targeted injectable therapeutic to reduce preventable deaths from hemorrhage.
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