Development of Optimized Tissue-Factor-Targeted Peptide Amphiphile Nanofibers to Slow Noncompressible Torso Hemorrhage.

Autor:	Klein MK; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Kassam HA; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Lee RH; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, United States.; UNC Blood Research Center, University of North Carolina, Chapel Hill, North Carolina 27514, United States., Bergmeier W; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, United States.; UNC Blood Research Center, University of North Carolina, Chapel Hill, North Carolina 27514, United States., Peters EB; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Gillis DC; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Dandurand BR; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Rouan JR; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Karver MR; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States., Struble MD; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States., Clemons TD; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States.; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.; School of Molecular Sciences, University of Western Australia, Perth, WA 6009, Australia., Palmer LC; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States.; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States., Gavitt B; United States Air Force School of Aerospace Medicine, Wright-Patterson AFB, Ohio 45433, United States., Pritts TA; Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267, United States., Tsihlis ND; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Stupp SI; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States.; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.; Department of Materials Science and Engineering, Northwestern University,, Evanston, Illinois 60208, United States.; Department of Medicine, Northwestern University, Chicago, Illinois 60611, United States.; Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States., Kibbe MR; Department of Surgery and Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, North Carolina 27599, United States.; Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
Jazyk:	angličtina
Zdroj:	ACS nano [ACS Nano] 2020 Jun 23; Vol. 14 (6), pp. 6649-6662. Date of Electronic Publication: 2020 Jun 03.
DOI:	10.1021/acsnano.9b09243
Abstrakt:	Noncompressible 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, coassembled with nontargeted 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 coassemblies 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 TF in vivo , a mouse saphenous vein laser injury model was performed and showed that TF-targeted nanofibers colocalized 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 coassemblies decreased blood loss in comparison to sham and backbone nanofiber controls by 35-59% ( 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.
Databáze:	MEDLINE
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