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Vol. 285, Issue 2, 920-928, May 1998
Divisions of
Clinical Pharmacology (G.H., A.K., U.H., A.E., S.E.)
and
of Neuroendocrinology (M.B., C.J.S.), Monocytes are important target cells for anti-inflammatory antisense
strategies. However, monocytes are characterized by strong phagocytic
and catalytic activity which may limit the effect of antisense
oligonucleotides. Intracellular distribution of oligonucleotides in
monocytes and the effect of cationic lipids on oligonucleotide uptake
in monocytes and other leukocytes have not been evaluated. We
investigated cationic lipid-mediated uptake of oligonucleotides in
human monocytes and lymphocyte subpopulations. Incorporation of
oligonucleotides was quantified by flow cytometry and by confocal microscopy. In the absence of cationic lipids, nearly 100% of monocytes and of B lymphocytes incorporated oligonucleotides compared with only 12% of natural killer cells and 1% of T lymphocytes. The
amount of oligonucleotide uptake per cell, as determined by mean
fluorescence intensity of positive cells, was four times higher in
monocytes than in B lymphocytes. Cationic lipids, which form complexes
with oligonucleotides, markedly enhanced the amount of oligonucleotide
uptake in all cell types and were most effective at a ratio of 1.1 of
positive-to-negative molar charges. In monocytes, oligonucleotides
incorporated spontaneously (without a lipid carrier) were trapped in
cytoplasmic vesicles. In contrast, cationic lipid-mediated uptake of
fluorescence-labeled oligonucleotides resulted in cytoplasmic and
nuclear staining. We conclude that 1) monocyte and lymphocyte subpopulations differ in the degree of spontaneous oligonucleotide uptake, and 2) lipofectin both quantitatively and qualitatively affects
this uptake. Our results may explain the necessary role of cationic
lipids in most antisense models with leukocytes as target cells.
0022-3565/98/2852-0920$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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