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Vol. 53, Issue 2, 262-269, February 1998
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug
Research, 2300 RA Leiden, The Netherlands
The therapeutic activity of antisense oligodeoxynucleotides (ODNs)
often is impaired due to premature degradation and poor ability to
reach the (intra)cellular target. In this study, we addressed the
in vivo fate of ODNs and characterized the major sites
responsible for the clearance of intravenously injected phosphodiester
ODN. On injection into rats, 32P-ODNs (miscellaneous
sequences and GT-containing ODNs with variable G content) are rapidly
cleared from the bloodstream (t1/2 = 0.6-0.7 min), with the liver being the main site of elimination. The
contribution of the liver to ODN clearance depended on its sequence and
varied considerably. Hepatic uptake tended to be lower for G-rich ODNs
as a result of increased bone marrow uptake. Within the liver, both
Kupffer cells (KC) and endothelial cells (EC) were responsible for
32P-ODN uptake. To elucidate the mechanism of liver uptake,
32P-ODN binding studies using isolated EC and KC were
performed. Binding to both cell types seemed to be saturable, of
moderate affinity, and mediated by a membrane-bound protein. The
inhibition profiles of 32P-ODN binding to EC and KC by
various (poly)anions were essentially equal and corresponded closely to
those of 125I-acetylated low-density lipoprotein. In
summary, the results indicate that scavenger receptors on
nonparenchymal liver and bone marrow cells contribute to the
elimination of ODNs from the bloodstream. Minor changes in ODN sequence
markedly affect receptor recognition, resulting in considerable shifts
in the biodistribution of antisense ODNs.
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