Tissue-factor targeted peptide amphiphile nanofibers as an injectable therapy to control hemorrhage

Courtney E. Morgan, Amanda W. Dombrowski, Charles M Rubert Pérez, Edward S M Bahnson, Nick D. Tsihlis, Wulin Jiang, Qun Jiang, Janet M. Vercammen, Vivek S. Prakash, Timothy A. Pritts, Samuel I. Stupp, Melina R. Kibbe*

*Corresponding author for this work

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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 hemorrhage.

Original languageEnglish (US)
Pages (from-to)899-909
Number of pages11
JournalACS nano
Volume10
Issue number1
DOIs
StatePublished - Jan 26 2016

Keywords

  • Animal model
  • Hemorrhage
  • Hemostasis
  • Nanotherapy
  • Peptide amphiphile
  • Self-assembly
  • Tissue factor

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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    Morgan, C. E., Dombrowski, A. W., Pérez, C. M. R., Bahnson, E. S. M., Tsihlis, N. D., Jiang, W., Jiang, Q., Vercammen, J. M., Prakash, V. S., Pritts, T. A., Stupp, S. I., & Kibbe, M. R. (2016). Tissue-factor targeted peptide amphiphile nanofibers as an injectable therapy to control hemorrhage. ACS nano, 10(1), 899-909. https://doi.org/10.1021/acsnano.5b06025