A novel anti-inflammatory peptide nanomedicine against acute lung injury: GLP-1 in phospholipid micelles

Acute lung injury (ALI) is a potentially fatal, hyper-inflammatory condition of the lungs that frequently occurred as a result of sepsis. The current pharmacological treatments are fraught with various side effects that can induce further co-morbidity. In this research, we proposed to develop and evaluate the efficacy of a peptide nanomedicine, GLP-1 in sterically stabilized phospholipid simple micelles (SSM), as a novel anti-inflammatory therapeutic agent against sepsis-induced ALI. GLP-1 is an incretin hormone with well documented glucose lowering ability. More recently, it has also been shown to inhibit in vitro production and activity of pro-inflammatory cytokines, suggesting potential anti-inflammatory effect. However, GLP-1 has a short plasma half-life (1--2 min). To prolong and enhance its activity in vivo, we thereby proposed the delivery of GLP-1 in SSM. Our research hypothesis was that GLP-1 would associate with sterically stabilized phospholipid micelles to form a novel, anti-inflammatory peptide nanomedicine against sepsis-induced ALI.;To this end, we have successfully prepared and characterized the novel formulation of GLP-1 using SSM as the nanocarrier system. The resulting formulation (GLP1-SSM) could be lyophilized and sterilized (via sterile filtration) without any significant changes in its physical characteristics. Study of the new formulation in in vitro cell culture systems showed that the micelle associated peptide exhibited similar biological activities as the free peptide in saline. Following in vivo experiments indicated reduced lung inflammation in lipopolysaccharide-induced ALI mice treated (s.c.) with GLP1-SSM. Since no apparent anti-inflammatory activity was observed in ALI mice given GLP-1 in saline, the data demonstrated importance of the micelle carriers in delivering and protecting the enzyme-labile GLP-1 peptide in vivo to achieve therapeutic efficacy. The results of these experiments suggested that GLP1-SSM is a promising anti-inflammatory agent and formed the basis for further pre-clinical testing of GLP1-SSM as a potentially safe and effective peptide nanomedicine for sepsis-induced ALI.