Pharmacokinetics and organ clearance of a 3'-biotinylated, internally [32P]-labeled phosphodiester oligodeoxynucleotide coupled to a neutral avidin/monoclonal antibody conjugate.
The pharmacokinetics and organ uptake of a 3'-biotinylated, [32P] internally labeled 36-mer phosphodiester oligodeoxynucleotide (PO-ODN) were measured after intravenous injection in the anesthetized adult rat. The PO-ODN was antisense to the tat gene of the human immunodeficiency virus, and was 3'-biotinylated to a) protect against serum and tissue 3'-exonuclease activity, and b) facilitate coupling to a neutral avidin-based transcellular drug delivery vector. The latter was comprised of a covalent conjugate of neutral avidin (NLA) and the OX26 murine monoclonal antibody to the rat transferrin receptor. The PO-ODN was internally labeled at the 21-nucleotide position to prevent rapid hydrolysis [32P] label by serum and tissue 5'-phosphatases. The uptake of the 3'-bio-[32P21]PO-ODN by brain, heart, kidney, lung, and liver was measured. The studies show that the unconjugated 3'-bio-[32P21]PO-ODN was rapidly removed from plasma, with a mean residence time of 22 +/- 1 min and a systemic clearance of 9.2 +/- 0.5 ml/min/kg. Large amounts of [32P] radioactivity were recovered in the urine following the injection of the PO-ODN, and when this fraction was included in the calculation of the renal clearance parameter, the renal clearance was 20-fold higher, indicating the principal site of organ clearance of the unconjugated PO-ODN was the kidney. Conjugation of the 3'-bio-PO-ODN to the NLA-OX26 vector reduced the systemic clearance 50%, owing to a > 10-fold reduction in renal clearance. Following conjugation of the 3'-bio-PO-ODN to the NLA-OX26 vector, the major clearance organ was the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Kang
Y S
YS
Department of Medicine, UCLA School of Medicine 90024.
Boado
R J
RJ
Pardridge
W M
WM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001345:Autoradiography; D001360:Avidin / Q000493:pharmacokinetics*; D001483:Base Sequence; D001710:Biotin / Q000493:pharmacokinetics*; D015756:Genes, tat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D009841:Oligonucleotides; D001360:Avidin; D001710:Biotin