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Selective transvascular delivery of oligodeoxynucleotides to experimental brain tumors
1Department of Neurosurgery, Neurological Institute, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Abstract:
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.
Insights
Bradykinin enables selective transvascular delivery of phosphorothioate oligodeoxynucleotides to experimental brain tumors. This targeted approach enhances therapeutic potential for malignant brain tumors without affecting normal brain tissue.
Area of Science:
- Neuro-oncology
- Molecular Therapy
- Drug Delivery Systems
Background:
- Optimal treatment for malignant brain tumors remains a challenge.
- Gene therapy requires selective delivery systems for efficacy.
- The blood-tumor barrier impedes drug delivery to brain tumors.
Purpose of the Study:
- To investigate the selective transvascular delivery of phosphorothioate oligodeoxynucleotides (oligonucleotides) into experimental brain tumors.
- To evaluate the role of bradykinin in enhancing oligonucleotide delivery across the blood-tumor barrier.
Main Methods:
- Phosphorothioate oligodeoxynucleotides (lacZ 2157) were administered via intracarotid infusion in rats with experimental brain tumors.
- Bradykinin was used to open the blood-tumor barrier selectively.
- Oligonucleotide concentrations in brain, tumor, liver, kidney, and plasma were quantified using slot-blotting hybridization and polyacrylamide gel electrophoresis.
Main Results:
- Bradykinin significantly increased the delivery of oligonucleotides to tumor tissue by 3.24 times compared to controls.
- Oligonucleotide delivery to normal brain regions (cerebral cortex, basal ganglia) did not show significant increase with bradykinin.
- The specificity and in vivo stability of the oligonucleotide were confirmed.
Conclusions:
- Transvascular delivery facilitated by bradykinin allows for selective and enhanced delivery of oligonucleotides to brain tumors.
- This method holds promise for targeted gene therapy in malignant brain tumors.
- The approach avoids significant delivery to normal brain tissue, suggesting improved safety.