Human Pancreatic Polypeptide in a Phospholipid-Based Micellar Formulation

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. 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 PP nanomedicine should be further developed for the treatment of diabetes.

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

“…Examples of such studies include pancreatic polypeptide (PP), and neuropeptide Y (NPY) loaded micelles [147,148]. Banerjee et al encapsulated an endogenous peptide hormone, PP, in a phospholipid micellar formulation [147]. PP is secreted by F cells of the islets of langerhans of pancreas.…”

Improvement of drug safety by the use of lipid-based nanocarriers

“…We have observed that various amphipathic peptide drugs undergo spontaneous association with SSM in aqueous media [20,33,[75][76][77][78][79]. Peptides such as vasoactive intestinal peptide (VIP), glucagon-like peptide 1 [GLP-1(7-36)] and gastric inhibitory peptides, associate most probably with the PEG region of PEGylated micelles, in view of the molecular net charge and relative hydrophilicity/hydrophobicity of these peptide candidates, rather than the more hydrophobic micelle cores as demonstrated in our previous fluorescence emission spectroscopic studies [76].…”

“…Peptides such as vasoactive intestinal peptide (VIP), glucagon-like peptide 1 [GLP-1(7-36)] and gastric inhibitory peptides, associate most probably with the PEG region of PEGylated micelles, in view of the molecular net charge and relative hydrophilicity/hydrophobicity of these peptide candidates, rather than the more hydrophobic micelle cores as demonstrated in our previous fluorescence emission spectroscopic studies [76]. Micelles stabilize the associated peptides against physical aggregation and hydrolytic degradation in vitro to increase their shelf stability in aqueous media [33,79,80]. When administered in vivo, SSM protects the associated peptides from plasma enzymes inactivation, bringing about enhanced and significantly prolonged biological activities (Fig.…”

A New Lipid-Based Nano Formulation of Vinorelbine

“…Data were analyzed by volume and intensity-weighted distributions (31). Particle size determination assay was repeated after 3 days for all prepared formulations.…”