Details:

Alternative Title:
Biomacromolecules
Publisher's site:
http://dx.doi.org/10.1021/bm400619v
Personal Author:
Shoffstall, Andrew J. ; Everhart, Lydia M. ; Varley, Matthew E. ; Soehnlen, Eric S. ; Shick, Adam M. ; ... More +
Shoffstall, Andrew J. ; Everhart, Lydia M. ; Varley, Matthew E. ; Soehnlen, Eric S. ; Shick, Adam M. ; Ustin, Jeffrey S. ; Lavik, Erin B. ; Less -
Description:
Targeted nanoparticles are being pursued for a range of medical applications. Here we utilized targeted nanoparticles (synthetic platelets) to halt bleeding in acute trauma. One of the major questions that arises in the field is the role of surface ligand density in targeted nanoparticles' performance. We developed intravenous hemostatic nanoparticles (GRGDS-NP1) and previously demonstrated their ability to reduce bleeding following femoral artery injury and increase survival after lethal liver trauma in the rat. These nanoparticles are made from block copolymers, poly(lactic-co-glycolic acid)-b-poly L-lysine-b-poly(ethylene glycol). Surface-conjugated targeting ligand density can be tightly controlled with this system, and here we investigated the effect of varying density on hemostasis and biodistribution. We increased the targeting peptide (GRGDS) concentration 100-fold (GRGDS-NP100) and undertook an in vitro dose-response study using rotational thromboelastometry, finding that GRGDS-NP100 hemostatic nanoparticles were efficacious at doses at least 10 times lower than the GRGDS-NP1. These results were recapitulated in vivo, demonstrating efficacy at eight-fold lower concentration after lethal liver trauma. 1 h survival increased to 92% compared with a scrambled peptide control, 45% (OR = 14.4, 95% CI = [1.36, 143]), a saline control, 47% (OR = 13.5, 95% CI = [1.42, 125]), and GRGDS-NP1, 80% (OR = 1.30, n.s.). This work demonstrates the impact of changing synthetic platelet ligand density on hemostasis and lays the foundation for methods to determine optimal ligand concentration parameters.
Subject:
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Administration, Intravenous
Animals
Article
Coagulation
Hemorrhage
Hemostasis
Hemostatics
Ligands
Liver
Liver Diseases
Nanomedicine
Nanoparticles
Oligopeptides
Particle Size
Polyethylene Glycols
Rats
Rats, Sprague-Dawley
ROTEM
Synthetic Platelets
Thrombelastography
Tissue Distribution
Wounds, Nonpenetrating
Hemorrhage

Source:
Biomacromolecules. 14(8):2790-2797. ;
Pubmed ID:
23841817
Pubmed Central ID:
PMC3758899
Document Type:
Journal Article ;
Funding:
DP2 OD007338/OD/NIH HHS/United States ; DP20D007338/DP/NCCDPHP CDC HHS/United States ;
DP2 OD007338/OD/NIH HHS/United States ; DP20D007338/DP/NCCDPHP CDC HHS/United States ; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:66bb2b4a6820cdb74e2964f700c16e574af597153b65c6ccfff9b78f481e4dfa
File Type:

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