Selective Uptake of Viral and Monocrystalline Particles Delivered Intra-Arterially to Experimental Brain Neoplasms

Abstract
In this study we investigated the intra-arterial delivery of viral and nonviral particles to experimental brain tumors. A herpes simplex virus (HSV) vector and monocrystalline iron oxide nanoparticles (MION) were injected into the internal carotid artery of Fisher 344 rats harboring intracerebral 9L gliosarcomas, using bradykinin to disrupt the blood–tumor barrier. Brain and internal organs were stained both for virus-mediated gene expression and for iron. Quantitative comparisons of gene expression and MION uptake with and without blood–tumor barrier disruption were performed in the center and at the periphery of the tumor mass, as well as in normal brain. In addition, MION distribution was traced in vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cells was greatly enhanced by intra-carotid bradykinin infusion. Virus-mediated expression of the HSV-thymidine kinase (TK) and β-galactosidase gene products was highest at the tumor periphery as compared to the tumor center. Selective HSV infection of multiple tumor foci was achieved in both hemispheres without affecting normal brain. MION uptake was high at the tumor periphery even without blood–tumor barrier disruption. Bradykinin increased MION uptake predominantly in the center of the tumor with virtually no effect at the periphery. These findings show that selective blood–tumor barrier disruption by bradykinin can be used to enhance HSV-mediated gene delivery to tumor cells in the periphery 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 selective disruption of their neovasculature. Selective delivery of particles was achieved to multifoci 9L gliosarcoma tumors in rat brain by intra-arterial injection combined with disruption of the brain–tumor barrier with bradykinin. Particles consisted of monocrystalline iron oxide nanoparticles (MION), which can be used for nuclear magnetic resonance imaging, and a herpes simplex virus (HSV) vector (hrR3), which replicates selectively in dividing cells and bears a lacZ gene for histochemistry. MION uptake was high in the tumor periphery, even without barrier disruption, but was increased in the center of tumors with bradykinin. There was essentially no uptake of virus into tumors without bradykinin, but marked uptake into their periphery with bradykinin. There was essentially no uptake of particles into normal brain. The studies show that imaging agents and genes can be targetted to the infiltrating margin of brain tumors by selective disruption of the newly forming tumor vasculature. Vascular delivery has the potential of delivering therapeutic and imaging agents to newly forming tumor foci throughout the brain, which present one of the major obstacles to effective therapy.