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

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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.

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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

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ACKNOWLEDGMENTS

This study was supported, in part, by Parenteral Drug Association Pre-Doctoral Fellowship, NIH grants AG024026, CA121797 and by VA Merit Review grant. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06RR15482 from the National Center for Research Resources, NIH. The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois, USA

    Sok Bee Lim & Hayat Önyüksel

  2. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

    Israel Rubinstein & Ruxana T. Sadikot

  3. Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA

    Hayat Önyüksel

  4. Biologic Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA

    James E. Artwohl

  5. Jesse Brown VA Medical Center, Chicago, Illinois, 60612, USA

    Israel Rubinstein & Ruxana T. Sadikot

  6. Department of Biopharmaceutical Sciences (M/C 865), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois, 60612-7231, USA

    Hayat Önyüksel

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  1. Sok Bee Lim
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Correspondence to Hayat Önyüksel.

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Lim, S.B., Rubinstein, I., Sadikot, R.T. et al. A Novel Peptide Nanomedicine Against Acute Lung Injury: GLP-1 in Phospholipid Micelles. Pharm Res 28, 662–672 (2011). https://doi.org/10.1007/s11095-010-0322-4

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  • DOI: https://doi.org/10.1007/s11095-010-0322-4

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