Intraarterial delivery of adenovirus vectors and liposome-DNA complexes toexperimental brain neoplasms

This study investigated the intraarterial delivery of genetically engineere d replication-deficient adenovirus vectors (AVs) and cationic liposome-plas mid DNA complexes (lipoDNA) to experimental brain tumors, Adenovirus or lip oDNA was injected into the internal carotid artery (ICA) of F344 rats harbo ring intracerebral 9L gliosarcomas, using bradykinin (BK) to selectively pe rmeabilize the blood-tumor barrier (BTB), Brain and internal organs of the animals were collected 48 hr after vector injection and stained for express ion of the marker gene product, beta-galactosidase (beta-Gal). Intracarotid delivery of AV to 9L rat gliosarcoma without BTB disruption resulted in tr ansgene expression in 3-10% of tumor cells distributed throughout the tumor , Virus-mediated expression of beta-gal gene products in this tumor model w as particularly high in small foci (less than or equal to 10.5 mm), which h ad invaded the normal brain tissue surrounding the main tumor mass, In thes e foci more than 50% of tumor cells were transduced, BK infusion increased the amount of transgene-expressing cells in larger tumor foci to 15-30%. In the brain parenchyma only a few endothelial cells expressed beta-gal owing to AV-mediated gene transfer, Intracarotid delivery of lipoDNA bearing a c ytoplasmic expression cassette rendered more than 30% of the tumor cells po sitive for the marker gene without BTB disruption, The pattern of distribut ion was in general homogeneous throughout the tumor, BK infusion was able t o increase further the number of transduced tumor cells to more than 50%, A lthough lipoDNA-mediated gene transfer showed increased efficacy as compare d with AV-mediated gene transfer, it had less specificity since a larger nu mber of endothelial and glial cells also expressed the transgene, AV and li poDNA injections, in the absence and presence of BK, also resulted in trans duction of peripheral organs, AV showed its known predilection for liver an d lung, In the case of lipoDNA, parenchymal organs such as liver, lung, tes tes, lymphatic nodes, and especially spleen, were transduced, These finding s indicate that intracarotid application of AV and lipoDNA vectors can effe ctively transduce tumor cells in the brain, and that BTB modulation by BK i nfusion can further increase the number of transgene-expressing tumor cells .