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.
Whitesell
L
L
Tumor Cell Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Geselowitz
D
D
Chavany
C
C
Fahmy
B
B
Walbridge
S
S
Alger
J R
JR
Neckers
L M
LM
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