Intranasal Absorption Enhancement of Antidiabetic Therapeuticals by the Functional Peptide Segment of Latroeggtoxin-VI.

Latroeggtoxin-VI (LETX-VI) is an active peptide found from the eggs of the spider Latrodectus tredecimguttatus. Previous studies demonstrated that LETX-VI can penetrate the plasma membrane of secretory PC12 cells and its 17-residue C-terminal sequence is the functional peptide segment (FPS), suggesting that the FPS may act as a vector for drug transmembrane delivery. In the present proof-of-concept study, the ability and efficiency of FPS to transmembrane delivery of antidiabetic therapeuticals were preliminarily evaluated. The FPS was covalently fused with a glucagon-like peptide-1 analogue (FPS-GLP) or insulin (FPS-Ins) using solid phase chemical synthesis or heterologous expression, respectively. Western blot analysis indicated that, compared with GLP-1 analogue that itself could hardly enter the cultured A549 cells, FPS-GLP efficiently entered the cells in a concentration-dependent manner, confirming the vector role of FPS in transmembrane delivery of drugs. When intranasally administrated to mice, FPS-GLP showed the hypoglycemic effect significantly superior to that of GLP-1 analogue, and the hypoglycemic effect of intranasally administrated FPS-Ins was approximately comparable to that of the intramuscularly injected FPS-Ins. These observations demonstrated that FPS can act as a vector to efficiently enhance the intranasal absorption of proteinaceous drugs, showing application prospect in combating diabetes mellitus and related CNS disorders.