Nucleus targeting-functionalized cell-membrane nanovesicles for intranasal delivery of therapeutic plasmid DNA into the brain for the treatment of glioblastoma

Abstract

In the gene delivery to the glioblastoma, intranasal delivery has been developed for delivery of drugs into the brain. However, nose-to-brain delivery of plasmid DNA (pDNA) has been unsuccessful, due to the large size of pDNA and low efficiency of nuclear translocation in the cells. In this study, a novel pDNA delivery system with enhanced nuclear translocation function was developed using a cell-membrane (CM)/dexamethasone-conjugated polyethylenimine (PD) hybrid nanovesicle. PD and CM from C6 glioblastoma cells were mixed at a 2:1 wt ratio to produce hybrid-nanovesicle. Addition of negatively charged pDNA to hybrid nanovesicles formed the spherical shaped complexes. Confocal microscopy study showed that the pDNA/PD/CM nanovesicle-complex entered the nuclei of cells efficiently, due to the nuclear translocation effect of the glucocorticoid receptor on binding to dexamethasone. In orthotopic glioblastoma rat models, the pSV-HSVtk/PD/CM nanovesicle-complex had higher delivery efficiency than naked pSV-HSVtk and pSV-HSVtk/PD complex into the brain. As a result, pSV-HSVtk/ PD/CM had higher apoptosis and lower Ki67 level than the other groups. Tumor size was effectively reduced by pSV-HSVtk/PD/CM, compared with the other groups. The results suggest that pDNA/PD/CM nanovesiclecomplex may be an efficient intranasal delivery carrier of pDNA and may be useful for the treatment of glioblastoma.