Effect of Knockout of <i>Mdr1a</i> and <i>Mdr1b</i> ABCB1 Genes on the Systemic Exposure of a Doxorubicin-Conjugated
Block Copolymer in Mice
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Abstract
We
previously elucidated that ATP-binding cassette subfamily B
member 1 (ABCB1) mediates the efflux of doxorubicin-conjugated block
copolymers from HeLa cells. Here, we investigated the role of ABCB1
in the in vivo behavior of a doxorubicin-conjugated polymer in <i>Mdr1<i>a</i>/1b(−/−)</i> mice. The area
under the curve for intravenously administered polymer in <i>Mdr1<i>a</i>/1b(−/−)</i> mice was 2.2-fold
greater than that in wild-type mice. The polymer was mostly distributed
in the liver followed by spleen and less so in the brain, heart, kidney,
and lung. The amount of polymer excreted in the urine was significantly
decreased in <i>Mdr1<i>a</i>/1b(−/−)</i> mice. The amounts of polymers excreted in the feces were similar
in both groups despite the higher systemic exposure in <i>Mdr1<i>a</i>/1b(−/−)</i> mice. Confocal microscopy
images showed polymer localized in CD68<sup>+</sup> macrophages in
the liver. These results show that knockout of ABCB1 prolonged systemic
exposure of the doxorubicin-conjugated polymer in mice. Our results
suggest that ABCB1 mediated the excretion of doxorubicin-conjugated
polymer in urine and feces. Our results provide valuable information
about the behavior of block copolymers in vivo, which is important
for evaluating the pharmacokinetics of active substances conjugated
to block copolymers or the accumulation of block copolymers in vivo