Pharmaceutical Research

, Volume 28, Issue 3, pp 662–672

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

  • Sok Bee Lim
  • Israel Rubinstein
  • Ruxana T. Sadikot
  • James E. Artwohl
  • Hayat Önyüksel
Research Paper

DOI: 10.1007/s11095-010-0322-4

Cite this article as:
Lim, S.B., Rubinstein, I., Sadikot, R.T. et al. Pharm Res (2011) 28: 662. doi:10.1007/s11095-010-0322-4

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, ~15 nm) 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 (5–30 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.

Conclusions

GLP1-SSM is a promising novel anti-inflammatory nanomedicine against ALI and should be further developed for its transition to clinics.

KEY WORDS

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

ABBREVIATIONS

ALI

acute lung injury

ANOVA

analysis of variance

ARDS

acute respiratory distress syndrome

BALF

bronchoalveolar lavage fluid

cAMP

cyclic adenosine monophosphate

CD

circular dichroism

CMC

critical micelle concentration

DPP-4

dipeptidyl peptidase-4

DSPE-PEG2000

distearoyl phosphatidylethanolamine-polyethylene glycol2000

ELISA

enzyme-linked immunosorbent assay

FBS

fetal bovine serum

GLP-1

glucagon-like peptide 1 (7–36)

GLP-1R

GLP-1 receptor

GLP1-SSM

GLP-1 peptide self-associated to SSM

HTAB

hexadecyltrimethylammonium bromide

IBMX

3-isobutyl-1-methylxanthine

IL-6

interleukin-6

LPS

lipopolysaccharide

MPO

myeloperoxidase

PEG

polyethylene glycol

RES

reticuloendothelial system

RIA

radioimmunoassay

RPM

revolutions per minute

SD

standard deviation

SSM

sterically stabilized phospholipid simple micelles

TNF-α

tumor necrosis factor-α

VIP

vasoactive intestinal peptide

Supplementary material

11095_2010_322_MOESM1_ESM.doc (51 kb)
Esm 1(DOC 51 kb)

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sok Bee Lim
    • 1
  • Israel Rubinstein
    • 2
    • 5
  • Ruxana T. Sadikot
    • 2
    • 5
  • James E. Artwohl
    • 4
  • Hayat Önyüksel
    • 1
    • 3
    • 6
  1. 1.Department of Biopharmaceutical SciencesUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Biologic Resources LaboratoryUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Jesse Brown VA Medical CenterChicagoUSA
  6. 6.Department of Biopharmaceutical Sciences (M/C 865)College of Pharmacy, University of Illinois at ChicagoChicagoUSA

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