Brain tumor therapy by combined vaccination and antisense oligonucleotide delivery with nanoparticles.

Abstract

We examined a "double-punch" approach to overcome the escape of glioblastoma cells to the immune surveillance: increasing the immune systems activation by an active specific immunization (ASI) with Newcastle-Disease-Virus infected tumor cells and blocking the TGF-beta production by delivery of TGF-beta antisense oligonucleotides using polybutyl cyanoacrylate nanoparticles (NPs). Gene delivery was first evaluated using the CMV-beta-gal plasmid as a reporter gene. Fischer rats received implantation of glioblastoma cells into the brain and were then treated with combined ASI/NP-anti-TGF-beta formulation. Massive staining of tumor cells was seen after NP delivery of the plasmid beta-galactosidase, indicating gene transfer by nanoparticles to tumor cells. When treated with NP-anti-TGF-beta after having been immunized, the rats survived longer than untreated controls, had reduced TGF-beta-levels and showed increased rates of activated CD25+ T cells. In summary, nanoparticles are useful to deliver plasmids and antisense oligonucleotides to brain tumors. A combined immunization/gene delivery of TGF-beta antisense oligonucleotides may be a promising approach for brain tumor therapy.