Development of a glycoliposomal delivery system to improve dynantin antagonism of the kappa opioid receptor

Abstract

κ opioid receptors (KOP) play a role in the addictive properties of nicotine by opposing its rewarding effects. Using a KOP antagonist, we aim to modulate this relationship, and prevent the negative effects of withdrawal that causes individuals to relapse. A novel glycoliposomal delivery system was used to improve the stability of dynantin, a KOP antagonist peptide, in human plasma. Reverse phase high-performance liquid chromatography (RP-HPLC) was used to study the entrapment and stability of dynantin. Subsequently, the in vitro Parallel Receptor-ome Expression and Screening via Transcriptional Output–Transcriptional activation following arrestin translocation (PRESTO-TANGO) system was used to study the affinity and selectivity of dynantin at the KOP compared to the δ and μ opioid receptors (DOP and MOP). Results showed that dynantin had good selectivity for KOP without activating or blocking DOP or MOP. The ratio of peptide: mannose lipid: cholesterol was modified to improve the stability of dynantin in human plasma. Dynantin was completely degraded in plasma after 24 hours with no cholesterol present, while a 1:5:2 ratio (peptide: mannose lipid: cholesterol), had 71±4% of dynantin remaining after 24 hours. Importantly, the delivery system had no effect on the affinity of dynantin at the KOP. Our delivery system therefore shows promise in its ability to increase the bioavailability of therapeutic peptides such as dynantin, for which we demonstrate here a promising ability to act selectively as an antagonist at the KOP.