A Novel Peptide Nanomedicine Against Acute Lung Injury: GLP-1 in Phospholipid Micelles
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- Lim, S.B., Rubinstein, I., Sadikot, R.T. et al. Pharm Res (2011) 28: 662. doi:10.1007/s11095-010-0322-4
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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, ~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 α-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.
KEY WORDSacute lung injury anti-inflammation GLP-1 gram-negative sepsis PEGylated phospholipid micelles
acute lung injury
analysis of variance
acute respiratory distress syndrome
bronchoalveolar lavage fluid
cyclic adenosine monophosphate
critical micelle concentration
distearoyl phosphatidylethanolamine-polyethylene glycol2000
enzyme-linked immunosorbent assay
fetal bovine serum
glucagon-like peptide 1 (7–36)
GLP-1 peptide self-associated to SSM
revolutions per minute
sterically stabilized phospholipid simple micelles
tumor necrosis factor-α
vasoactive intestinal peptide