A Novel Peptide Nanomedicine Against Acute Lung Injury: GLP-1 in Phospholipid Micelles

作者：Lim Sok Bee; Rubinstein Israel; Sadikot Ruxana T; Artwohl James E; Oenyueksel Hayat

来源：Pharmaceutical Research, 2011, 28(3): 662-672.

DOI：10.1007/s11095-010-0322-4

• acute lung injury
• anti-inflammation
• GLP-1
• gram-negative sepsis
• PEGylated phospholipid micelles

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, similar to 15 nm) exerted effective anti-inflammatory protection against lipopolysaccharide (LPS)-induced ALI in mice.
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.
Amphipathic GLP-1 interacted spontaneously with SSM as indicated by increased alpha-helicity and fluorescence emission. This association elicited increased bioactivity as determined by in vitro cAMP production. Correspondingly, subcutaneous GLP1-SSM (5-30 nmol/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.
GLP1-SSM is a promising novel anti-inflammatory nanomedicine against ALI and should be further developed for its transition to clinics.

• 出版日期2011-3