Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Sharma
V
V
Department of Molecular Biology and Pharmacology, Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, MO 63110, USA.
Beatty
A
A
Wey
S P
SP
Dahlheimer
J
J
Pica
C M
CM
Crankshaw
C L
CL
Bass
L
L
Green
M A
MA
Welch
M J
MJ
Piwnica-Worms
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D007624:KB Cells; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
C409662:(bis(3-ethoxy-2-hydroxybenzylidene)-N,N''-bis(2,2-dimethyl-3-aminopropyl)ethylenediamine)gallium(III) perchlorate; C409664:(bis(5-ethoxy-2-hydroxybenzylidene)-N,N''-bis(2,2-dimethyl-3-aminopropyl)ethylenediamine)gallium(III) iodide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals