Human Pancreatic Polypeptide in a Phospholipid-Based Micellar Formulation
Pancreatic polypeptide (PP) has important glucoregulatory functions and thereby holds significance in the treatment of diabetes and obesity. However, short plasma half-life and aggregation propensity of PP in aqueous solution, limits its therapeutic application. To address these issues, we prepared and characterized a formulation of PP in sterically stabilized micelles (SSM) that protects and stabilizes PP in its active conformation.
PP-SSM was prepared by incubating PP with SSM dispersion in buffer. Peptide-micelle association and freeze-drying efficacy of the formulation was characterized in phosphate buffers with or without sodium chloride using dynamic light scattering, fluorescence spectroscopy and circular dichroism. The degradation kinetics of PP-SSM in presence of proteolytic enzyme was determined using HPLC and bioactivity of the formulation was evaluated by in vitro cAMP inhibition study.
PP self-associated with SSM and this interaction was influenced by presence/absence of sodium chloride in the buffer. The formulation was effectively lyophilized, demonstrating feasibility for its long-term storage. The stability of peptide against proteolytic degradation was significantly improved and PP in SSM retained its bioactivity in vitro.
Self-association of PP with phospholipid micelles addressed the delivery issues of the peptide. This nanomedicine should be further developed for the treatment of diabetes.
KEY WORDSchronic pancreatitis pancreatic polypeptide pancreatogenic diabetes peptide nanomedicine sterically stabilized micelles
analysis of variance
cyclic adenosine monophosphate
critical micellar concentration
dynamic light scattering
distearoyl phosphatidylethanolamine-polyethylene glycol2000
eagle’s minimum essential media
phosphate buffered saline
peversed phase high pressure liquid chromatography
sterically stabilized micelles
ACKNOWLEDGMENTS & DISCLOSURES
The authors thank Dr. Bao-Shiang Lee for synthesizing PP used in the research.
The study was supported in part by NIH grant CA121797 and UIC university scholar award.
- 10.Seymour NE, Andersen DK. Pancreatic polypeptide and glucose metabolism. In: Jr G, editor. Gastrointestinal endocrinology. New Jersey: Humana; 1999. p. 321–34.Google Scholar
- 21.Baxter J, Minnion J, Shilto-Cuenco J, Tan T, Murphy K, Ghatei M, et al. Pancreatic polypeptide: a novel substrate for the endopeptidase neprilysin. Endocr Abstr. 2010;21:P133.Google Scholar