Selective transvascular delivery of oligodeoxynucleotides to experimental brain tumors.
Optimal therapeutic strategy for malignant brain tumors is controversial. Recent studies of viral or nonviral gene therapy in rats emphasize the need for a selective delivery system. We examined whether phosphorothioate oligodeoxynucleotides (lacZ 2157, 5'-GTGGCGTCTGGCGGAAAACC-3') could be selectively delivered transvascularly into experimental brain tumors following intracarotid infusion of bradykinin, a specific blood-tumor barrier opener. The specificity of 32P-labeled complementary antisense lacZ 2157 and the stability 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 microg/kg/min) with or without bradykinin were determined in the brain, tumor tissue, liver, kidney, and plasma. The transfer ratio of lacZ 2157 from the plasma to the tissues was calculated and expressed as tissue content relative to plasma content of lacZ 2157 per mg tissue (Do, microl/mg). Delivery of lacZ 2157 to tumor tissue increased 3.24 times with bradykinin over delivery in controls (0.0243 +/- 0.0176 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 contralateral basal ganglia, did not increase significantly with bradykinin. These results indicate that such transvascular delivery with bradykinin can deliver a relatively large amount of oligodeoxynucleotide selectively to brain tumors without affecting normal brain.
Koga
H
H
Department of Neurosurgery, Neurological Institute, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Inamura
T
T
Ikezaki
K
K
Samoto
K
K
Matsukado
K
K
Fukui
M
M
D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002339:Carotid Arteries; D015316:Genetic Therapy; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D007261:Infusions, Intra-Arterial; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015345:Oligonucleotide Probes; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D020319:Oligodeoxyribonucleotides, Antisense; D015345:Oligonucleotide Probes; D013873:Thionucleotides; D001616:beta-Galactosidase; D001920:Bradykinin