SELECTIVE UPTAKE OF VIRAL AND MONOCRYSTALLINE PARTICLES DELIVERED INTRAARTERIALLY TO EXPERIMENTAL BRAIN NEOPLASMS

In this study we investigated the intra-arterial delivery of viral and nonviral particles to experimental brain tumors. A herpes simplex vir us (HSV) vector and monocrystalline iron oxide nanoparticles (MION) we re injected into the internal carotid artery of Fisher 344 rats harbor ing intracerebral 9L gliosarcomas, using bradykinin to disrupt the blo od-tumor barrier, Brain and internal organs were stained both for viru s-mediated gene expression and for iron. Quantitative comparisons of g ene expression and MION uptake with and without blood-tumor barrier di sruption were performed in the center and at the periphery of the tumo r mass, as well as in normal brain. In addition, MION distribution was traced in vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cel ls was greatly enhanced by intra-carotid bradykinin infusion. Virus-me diated expression of the HSV-thymidine kinase (TK) and beta-galactosid ase gene products was highest at the tumor periphery as compared to th e tumor center, Selective HSV infection of multiple tumor foci was ach ieved in both hemispheres without affecting normal brain. MION uptake was high at the tumor periphery even without blood-tumor barrier disru ption. Bradykinin increased MION uptake predominantly in the center of the tumor with virtually no effect at the periphery. These findings s how that selective blood-tumor barrier disruption by bradykinin can be used to enhance HSV-mediated gene delivery to tumor cells in the peri phery of brain tumors. A crucial aspect in the treatment of malignant brain tumors is the eradication of tumor cells infiltrating the brain; bradykinin may facilitate access of vectors to these areas by selecti ve disruption of their neovasculature.