Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption.

Abstract

The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the nude rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intratumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstrated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administration without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administration of viral vectors may offer a method of global delivery to treat disseminated brain tumors.

Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain

“…42 In general, these studies indicate that the distribution and number of infected cells is greater in the tumor than in normal brain, suggesting that the blood-tumor barrier is more permissive to viral transit after disruption than the BBB. 27,28 We also found that almost all of the X-gal staining after G47D intracarotid artery injection occurred in the tumor, even in the absence of BBBD, although the degree of tumor labeling was considerably increased after BBBD. While we did not undertake a detailed analysis of infected cell phenotypes, one would only expect to see X-gal staining of individual infected normal cells, not foci as with tumor cells, and only within a few days of infection.…”

“…26 BBBD even enhanced the delivery of oncolytic HSV to brain tumors in rat models. 27,28 For the most part, BBBD tumor therapy studies have been performed in rats because of size considerations. However, mice have a number of advantages for studying brain tumor therapy: (1) a variety of syngeneic tumor models; (2) spontaneously arising tumors in transgenic models; and (3) knockout mice to study the role of genetic alterations on therapeutic efficacy.…”

Widespread distribution of β-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol

“…Hyperosmotic concentrations of mannitol have often been used to disrupt the blood-brain barrier after intra-arterial injections. [17][18][19] In a different strategy, intracerebral coadministration of mannitol with gene transfer vectors has been described to generate an enhancement of gene delivery into the rat brain. 13 The benefit of mannitol can be explained as a local osmotic effect accompanied by a shrinkage of the cells and an enlargement of the interstitial space, facilitating the diffusion of the vector.…”

Gene therapy in the CNS

“…Other routes of delivery to cells in the CNS have included: injection into fluid spaces, such as the vitreous humor in the eye; 125 or the CSF through intrathecal or intraventricular routes for delivery to the choroid plexus, ependymal/meningeal layers, and from there into the adjacent brain through processes extending into these layers; 126,127 and passage across the blood-brain or bloodtumor barriers by intra-arterial injection combined with temporary osmotic 128,129 or pharmacologic [130][131][132] disruption. Brain tumors can be preferentially targeted due to the relatively high permeability of the tumor neovasculature, as compared with the blood-brain barrier that has tight junctions between endothelial cells and is surrounded by an astrocytic sheath.…”