Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage
Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage
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DOI：
10.1021/acsnano.5b06025
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发表时间：
2016-01-01
期刊：
影响因子：
17.1
通讯作者：
Kibbe, Melina R.
中科院分区：
文献类型：
--
作者：
Morgan, Courtney E.;Dombrowski, Amanda W.;Kibbe, Melina R.
不可压缩的躯干出血是平民和战场创伤死亡的主要原因。我们试图开发一种静脉注射-注射，组织因子（TF）靶向纳米治疗，以阻止出血。选择组织因子作为靶点，因为其仅在血管破裂时暴露于血管内空间。选择自组装成纳米纤维的肽两亲物（PA）单体作为递送载体。三个TF结合序列被确定（EGR，RLM，RTL），共价结合到PA的骨干，并显示自组装成纳米纤维的冷冻透射电子显微镜。RLM和RTL肽两者在体外结合重组TF。所有三种TF靶向纳米纤维都结合到体内打孔活检诱导的肝出血部位，但与假手术相比，只有RTL纳米纤维减少了失血量（减少53%，p < 0.05）。增加RTL纳米纤维的靶向配体密度产生了与损伤部位的定性更好的结合和体内失血的更大减少（p < 0.05）。事实上，与假手术相比，100%RTL可减少60%的总失血量（p < 0.05）。对RTL生物相容性的评估显示，它不会诱导RBC溶血，不会在肝损伤部位诱导中性粒细胞或巨噬细胞炎症，并且70%在30分钟后在血浆中保持完整。这些研究证明了肽与TF在体外的成功结合以及TF-100的成功归巢。将PA β靶向至出血部位，同时减少体内失血。因此，这种治疗方法可能治疗不可压缩性出血。
Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryotransmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL-nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible heinorrhage.