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GLP -1 in phospholipid micelles against acute lung injury

2017-01-03 16:05:52 | 日記

Medicilon is a Preclinical Research Outsourcing (CRO) company. With our more than 10 years experience on preclinical research services, we dedicated to provide our clients with customized preclinical services program in drug metabolism, pharmacokinetics, efficacy studies, and toxicology. We provide our clients a high-quality data and rapid turnaround time to support their drug development, preclinical studies and clinical research and to help them to select the most valuable drug candidates into clinical trials stage. Our preclinical research services consist in three major parts: pharmacokinetics, disease transplantation models and drug safety evaluation. Our services cover all of the aspects including design, in vivo studies, sample analysis, professional data analysis, IACUC review, and the preparation of application materials.
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The focus of this dissertation research is to develop a novel, safe and stable nanomedicine of human native glucagon-like peptide 1 (GLP-1) for a new therapeutic indication: sepsis-induced acute lung injury. Acute lung injury (ALI) is a potentially fatal condition induced by insult(s) to the lungs, most commonly due to sepsis, resulting in disruption in the integrity and function of the alveolar-capillary unit. The pathophysiological basis of the disease is hallmarked by an excessive and protracted inflammation of the lungs leading to increased vascular permeability, pulmonary edema, infiltration of neutrophils and inactivation of lung surfactant. The current pharmacological treatments are fraught with drug-induced side effects which has at times even been associated with increased patient mortality rate. Therefore, treatment of sepsis-induced ALI clearly represents an unmet medical need that urgently necessitates improved therapeutic management.
GLP-1 is an incretin hormone with 30 amino acid residues. It has established efficacy in regulating postprandial plasma glucose level and is indicated for the treatment of diabetes. More recently, GLP-1 has been reported to exhibit anti-inflammatory activity through inhibition of pro-inflammatory cytokine release in cultured rat astrocytes. In addition, it was also published that obese African American adolescents showed increased response in subclinical inflammatory markers in relation to lower GLP-1 level. These studies thereby suggested an anti-inflammatory effect of GLP-1. On this basis, we believe that GLP-1 would be effective against the lung hyper-inflammatory condition characteristic of sepsis-induced ALL
However, despite the well documented glucose lowering efficacy of GLP- 1, preclinical trial application of the native peptide has been vastly limited by its short plasma half-life (1-2 min) secondary to rapid enzymatic degradation and renal clearance. To overcome this shortcoming, various analogues of the peptide have been developed, among which exenatide (Byetta®) is commercially available. However, chemical modification of GLP-1 increases risk of immunogenicity. Exenatide has been reported to induce auto-antibodies production in treated patients. Episodes of hemorrhagic and necrotizing pancreatitis have also been associated with this drug, necessitating discontinuation in affected patients. Moreover, none of those GLP-1 analogues has been tested as anti-inflammatory agent against ALL
Therefore, to minimize induction of immunogenicity while increasing the therapeutic efficacy of GLP-1 peptide, we proposed the development of a novel formulation composed of human GLP-1 self-associated to sterically stabilized phospholipid micelles. Sterically stabilized phospholipid simple micelles (SSM) and mixed micelles (SSMM) were investigated in this preclinical research project to determine the preferred micellar nanocarriers for GLP-1. Our study aimed to develop a new anti-inflammatory therapy against sepsis-induced ALI without the adverse side effects of currently used therapeutic agents. GLP-1 has shown only minor side effects such as gastrointestinal discomforts that include nausea and vomiting in the clinics. By delivering GLP-1 in sterically stabilized phospholipid micelles, enzymatic degradation of GLP-1 should be reduced, leading to potentially greater therapeutic efficacy and lower effective dose compared to the free peptide. Furthermore, steric stabilization imparted by the PEGylated micellar carriers would also minimize recognition by the reticuloendothelial system and hence reduce immunogenicity. The resulting nanosized peptide-micelle construct (-15 nm) could additionally induce preferential biodistribution to sites of leaky vasculature (via enhanced permeability and retention effect) when injected parenterally, increasing drug distribution to the inflamed lungs (as well as other inflamed sites) to bring about desirable anti-inflammatory activities in sepsisinduced ALL On these bases, the hypothesis of my dissertation research was that GLP-1 would associate with sterically stabilized phospholipid micelles to form a novel, anti-inflammatory peptide nanomedicine against sepsis-induced ALL.
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