Brain tumor therapy by combined vaccination and antisense oligonucleotide delivery with nanoparticles.
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.
Schneider
Thomas
T
Department of Neurosurgery (TS, AB, RF), Germany. thomas.schneider@med.ovgu.de
Becker
Andreas
A
Ringe
Kerstin
K
Reinhold
Annegret
A
Firsching
Raimund
R
Sabel
Bernhard A
BA
D000818:Animals; D001772:Blood Cell Count; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D005822:Genetic Vectors; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053758:Nanoparticles / Q000648:ultrastructure; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D014611:Vaccination
D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta