Selective transvascular delivery of oligodeoxynucleotides to experimental brain tumors

Optimal therapeutic strategy for malignant brain tumors is controversial. R ecent studies of viral or nonviral gene therapy in rats emphasize the need for a selective delivery system. We examined whether phosphorothioate oligo deoxynucleotides (lacZ 2157, 5'-GTGGCGTCTGGCGGAAAACC-3') could be selective ly delivered transvascularly into experimental brain tumors following intra carotid infusion of bradykinin, a specific blood-tumor barrier opener. The specificity of (3)2P-labeled complementary antisense lacZ 2157 and the stab ility of lacZ 2157 in vivo were confirmed using slot-blotting hybridization method and polyacrylamide gel electrophoresis. Concentrations of lacZ 2157 after intracarotid injection (2 mg/kg, 10 mu g/kg/min) with or without bra dykinin were determined in the brain, tumor tissue, liver, kidney, and plas ma. The transfer ratio of lacZ 2157 from the plasma to the tissues was calc ulated and expressed as tissue content relative to plasma content of lacZ 2 157 per mg tissue (Do, mu l/mg). Delivery of lacZ 2157 to tumor tissue incr eased 3.24 times with bradykinin over delivery in controls (0.0243 +/- 0.01 76 vs. 0.00750 +/- 0.00389; p < 0.05). Delivery of lacZ 2157 to ipsilateral and contralateral cerebral cortex to the tumor, and delivery to the contra lateral basal ganglia, did not increase significantly with bradykinin. Thes e results indicate that such transvascular delivery with bradykinin can del iver a relatively large amount of oligodeoxynucleotide selectively to brain tumors without affecting normal brain.