Improving the Toxicity Profile and Pharmacokinetics of Vasoactive Intestinal Peptide with the PGC Hydrophobic Core Carrier

摘要

The protected graft co-polymer (PGC~(TM)) is a nanocarrier consisting of a polylysine backbone and protective polyethyleneglycol (PEG) side chains. The addition of fatty acid side chains creates a hydrophobic core in the molecule that accommodates binding of hydrophobic molecules. After injection (i.v. or s.c.) of such a formulation, the load molecule is protected from degradation by serum proteases and, due to the size of the molecule (~20 nm) from excretion by the kidneys. The result is an improved in vivo half-life and mean residence time. Additionally, sequestering of a large amount of the load molecule in the PGC carrier can improve the toxicity profile of the load molecule.Vasoactive intestinal peptide was formulated into a long-acting formulation using the PGC-hydrophobic core (PGC-HC) that provides for the presence of significant VIP-serum levels for more than 72 h in rats after a subcutaneous injection of 1 mg/kg. The dose limiting safety concern for injectable VIP, a clinically relevant blood pressure lowering, is reduced in mice at a subcutaneous injection dose of 50 ug/kg.