title: Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage.
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 cryo-transmission 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.
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Morgan
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Dombrowski
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rubert Pérez
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Edward S M
authors.initials: ES
authors.lastname: Bahnson
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Nick D
authors.initials: ND
authors.lastname: Tsihlis
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Wulin
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Vercammen
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Vivek S
authors.initials: VS
authors.lastname: Prakash
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Pritts
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
authors.affiliation: Simpson Querrey Institute for BioNanotechnology, ‡Department of Surgery, Feinberg School of Medicine, and §Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois 60611, United States.|Department of Materials Science & Engineering, ▲Biomedical Engineering, and ∥Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.|Department of Surgery and #Institute for Military Medicine, University of Cincinnati , Cincinnati, Ohio 45220, United States.
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000293:injuries; D005449:Fluorenes / Q000737:chemistry; D006470:Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D015552:Injections, Intralesional; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000293:injuries; D008297:Male; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D057139:Nanofibers / Q000737:chemistry / Q000627:therapeutic use*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013925:Thromboplastin / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D005449:Fluorenes; D010455:Peptides; D013925:Thromboplastin
keywords: animal model; hemorrhage; hemostasis; nanotherapy; peptide amphiphile; self-assembly; tissue factor