caa a22 4500 445312858 CHVBK 20180317142636.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s11095-010-0322-4 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0322-4 A Novel Peptide Nanomedicine Against Acute Lung Injury: GLP-1 in Phospholipid Micelles [Elektronische Daten] [Sok Lim, Israel Rubinstein, Ruxana Sadikot, James Artwohl, Hayat Önyüksel] ABSTRACT: Purpose: Treatment of acute lung injury (ALI) observed in Gram-negative sepsis represents an unmet medical need due to a high mortality rate and lack of effective treatment. Accordingly, we developed and characterized a novel nanomedicine against ALI. We showed that when human glucagon-like peptide 1(7-36) (GLP-1) self-associated with PEGylated phospholipid micelles (SSM), the resulting GLP1-SSM (hydrodynamic size, ~15nm) exerted effective anti-inflammatory protection against lipopolysaccharide (LPS)-induced ALI in mice. Methods: GLP1-SSM was prepared by incubating GLP-1 with SSM dispersion in saline and characterized using fluorescence spectroscopy and circular dichroism. Bioactivity was tested by in vitro cAMP induction, while in vivo anti-inflammatory effects were determined by lung neutrophil cell count, myeloperoxidase activity and pro-inflammatory cytokine levels in LPS-induced ALI mice. Results: Amphipathic GLP-1 interacted spontaneously with SSM as indicated by increased α-helicity and fluorescence emission. This association elicited increased bioactivity as determined by in vitro cAMP production. Correspondingly, subcutaneous GLP1-SSM (5-30nmol/mouse) manifested dose-dependent decrease in lung neutrophil influx, myeloperoxidase activity and interleukin-6 in ALI mice. By contrast, GLP-1 in saline showed no significant anti-inflammatory effects against LPS-induced lung hyper-inflammatory responses. Conclusions: GLP1-SSM is a promising novel anti-inflammatory nanomedicine against ALI and should be further developed for its transition to clinics. Springer Science+Business Media, LLC, 2010 acute lung injury nationallicence anti-inflammation nationallicence GLP-1 nationallicence gram-negative sepsis nationallicence PEGylated phospholipid micelles nationallicence ALI : acute lung injury nationallicence ANOVA : analysis of variance nationallicence ARDS : acute respiratory distress syndrome nationallicence BALF : bronchoalveolar lavage fluid nationallicence cAMP : cyclic adenosine monophosphate nationallicence CD : circular dichroism nationallicence CMC : critical micelle concentration nationallicence DPP-4 : dipeptidyl peptidase-4 nationallicence DSPE-PEG2000 : distearoyl phosphatidylethanolamine-polyethylene glycol2000 nationallicence ELISA : enzyme-linked immunosorbent assay nationallicence FBS : fetal bovine serum nationallicence GLP-1 : glucagon-like peptide 1 (7-36) nationallicence GLP-1R : GLP-1 receptor nationallicence GLP1-SSM : GLP-1 peptide self-associated to SSM nationallicence HTAB : hexadecyltrimethylammonium bromide nationallicence IBMX : 3-isobutyl-1-methylxanthine nationallicence IL-6 : interleukin-6 nationallicence LPS : lipopolysaccharide nationallicence MPO : myeloperoxidase nationallicence PEG : polyethylene glycol nationallicence RES : reticuloendothelial system nationallicence RIA : radioimmunoassay nationallicence RPM : revolutions per minute nationallicence SD : standard deviation nationallicence SSM : sterically stabilized phospholipid simple micelles nationallicence TNF-α : tumor necrosis factor-α nationallicence VIP : vasoactive intestinal peptide nationallicence Lim Sok Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA aut Rubinstein Israel Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA aut Sadikot Ruxana Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA aut Artwohl James Biologic Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA aut Önyüksel Hayat Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 662-672 0724-8741 28:3<662 2011 28 11095 https://doi.org/10.1007/s11095-010-0322-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0322-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lim Sok Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Rubinstein Israel Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Sadikot Ruxana Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Artwohl James Biologic Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA aut NATIONALLICENCE 700 1- Önyüksel Hayat Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 662-672 0724-8741 28:3<662 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer