Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide

Heptapeptide ATWLPPR (A7R) binds specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However, in vivo application of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhance in vivo stability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier (BBB) and be uptaken by glioma cells. Furthermore, a novel glioma-targeted drug delivery system was constructed successfully employing glycopeptide as the targeting moiety and nanodisk as the carrier of paclitaxel (PTX). Physicochemical characterization showed that the nanodisk presented suitable size of 50 nm and adequate loading capacity of PTX. Compared to non-glycosylated nanodisk, glycopeptide modification could significantly enhance the uptake of disks by brain capillary endothelial cells through glucose transporter 1 (GLUT1). In vivo imaging and glioma fluorescence section results also indicated that nanodisks modified with glycopeptide showed a higher accumulation in glioma. The glycopeptide-enabled PTX delivery system exhibited superior anti-glioma efficacy in intracranial glioma xenograft model. These results suggested that glycosylation of peptides provided an efficient pathway to design multifunctional and stable brain targeting ligands.