Human pancreatic polypeptide in a phospholipid-based micellar formulation

Pharm Res. 2012 Jun;29(6):1698-711. doi: 10.1007/s11095-012-0718-4. Epub 2012 Mar 8.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chemistry, Pharmaceutical
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Drug Carriers*
  • Drug Compounding
  • Drug Stability
  • Freeze Drying
  • Humans
  • Hydrogen-Ion Concentration
  • Hypoglycemic Agents / chemistry*
  • Light
  • Micelles*
  • Nanoparticles
  • Nanotechnology
  • Neuroblastoma / metabolism
  • Pancreatic Polypeptide / chemistry*
  • Particle Size
  • Phosphatidylethanolamines / chemistry*
  • Polyethylene Glycols / chemistry*
  • Protein Denaturation
  • Protein Precursors / chemistry*
  • Receptors, Neuropeptide Y / drug effects
  • Receptors, Neuropeptide Y / metabolism
  • Scattering, Radiation
  • Sodium Chloride / chemistry
  • Spectrometry, Fluorescence
  • Technology, Pharmaceutical / methods
  • Time Factors

Substances

  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
  • Drug Carriers
  • Hypoglycemic Agents
  • Micelles
  • PPY protein, human
  • Phosphatidylethanolamines
  • Protein Precursors
  • Receptors, Neuropeptide Y
  • Colforsin
  • Polyethylene Glycols
  • Sodium Chloride
  • neuropeptide Y4 receptor
  • Pancreatic Polypeptide
  • Cyclic AMP