Exosome-membrane and polymer-based hybrid-complex for systemic delivery of plasmid DNA into brains for the treatment of glioblastoma
Youngki Lee, Subin Kang, Lê Thị Thanh Thủy, M. H. Son, Jae Young Park, Seo‐Yeon Ahn, Minji Kang, Jihun Oh, Joon Sig Choi, Minhyung Lee
Abstract
Herpes simplex virus thymidine kinase (HSVtk) gene therapy is a promising strategy for glioblastoma therapy. However, delivery of plasmid DNA (pDNA) encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the blood-brain barrier. In this study, an exosome-membrane (EM) and polymer-based hybrid-complex was developed for systemic delivery of pDNA into the brain. Histidine/arginine-linked polyamidoamine (PHR) was used as a carrier. PHR binds to pDNA by electrostatic interaction. The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid-complex. For glioblastoma targeting, T7 peptide was attached to the pDNA/PHR-EM complex. pDNA/PHR-EM and T7-decorated pDNA/PHR-EM (pDNA/PHR-EM-T7) had a surface-charge of –5 mV and a size of 280 nm. Transfection assay indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHR-EM. Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo . pHSVtk/PHR-EM-T7 had a higher delivery efficiency than pHSVtk/PHR-EM. As a result, the HSVtk expression and apoptosis levels of the pHSVtk/PHR-EM-T7 group in the tumors were higher than those of the other control groups. Therefore, the pDNA/PHR-EM-T7 hybrid-complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.