Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system.
We report experiments in the rat demonstrating the feasibility of intraventricular administration of oligodeoxynucleotides (ODNs) as a regional treatment approach to disorders within the central nervous system (CNS). Although we find little intrinsic nuclease activity in cerebrospinal fluid (CSF), phosphodiester ODNs are rapidly degraded by brain-associated alpha-exonuclease activity. Phosphorothioate ODNs, however, appear resistant to degradation in the CNS and, after intraventricular administration, we find they are cleared in a manner consistent with CSF bulk flow. Continuous infusion of ODN at 1.5 nmol/hr by miniosmotic pump can maintain micromolar concentrations of intact phosphorothioate ODN in CSF for at least 1 week without obvious neurologic or systemic toxicity. After infusion, extensive brain penetration and marked cellular uptake, especially by astrocytic cells, is demonstrated.
Tumor Cell Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
L
L
Whitesell
D
D
Geselowitz
C
C
Chavany
B
B
Fahmy
S
S
Walbridge
J R
JR
Alger
L M
LM
Neckers
D000818:Animals; D001483:Base Sequence; D005260:Female; D007276:Injections, Intraventricular; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000737:chemistry; D014018:Tissue Distribution
D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides