Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo
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Abstract
Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents
one of the best characterized barriers to chemotherapy in cancer patients. Positron
emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity
in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene
therapy.
Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their
heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated
a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled
(67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-))
and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated
antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore,
compared with wild-type control, quantitative pharmacokinetic analysis showed markedly
increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-))
gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary
blood-brain barrier and hepatocellular biliary cannalicular surface in vivo.
These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an
avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals
for molecular imaging of Pgp transport activity in tumors and tissues in vivo using
PET.