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

V. Sharma, A. Beatty, S. P. Wey, J. Dahlheimer, C. M. Pica, C. L. Crankshaw, L. Bass, Mark Green, M. J. Welch, D. Piwnica-Worms

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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 67Ga-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. Furthermore, 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 68Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

Original languageEnglish (US)
Pages (from-to)335-343
Number of pages9
JournalChemistry and Biology
Volume7
Issue number5
DOIs
StatePublished - May 1 2000
Externally publishedYes

Fingerprint

Gallium
Positron emission tomography
P-Glycoprotein
Positron-Emission Tomography
Imaging techniques
Multiple Drug Resistance
Tumors
Tissue
Lead compounds
MDR Genes
Molecular imaging
Gene therapy
Neoplasms
Molecular Imaging
Pharmacokinetics
Chemotherapy
Radiopharmaceuticals
Schiff Bases
Blood-Brain Barrier
Scaffolds

Keywords

  • Gallium complexes
  • Molecular imaging
  • Multidrug resistance
  • P-glycoprotein
  • Positron emission tomography

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel gallium(III) complexes transported by MDR1 P-glycoprotein : Potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo. / Sharma, V.; Beatty, A.; Wey, S. P.; Dahlheimer, J.; Pica, C. M.; Crankshaw, C. L.; Bass, L.; Green, Mark; Welch, M. J.; Piwnica-Worms, D.

In: Chemistry and Biology, Vol. 7, No. 5, 01.05.2000, p. 335-343.

Research output: Contribution to journalArticle

Sharma, V. ; Beatty, A. ; Wey, S. P. ; Dahlheimer, J. ; Pica, C. M. ; Crankshaw, C. L. ; Bass, L. ; Green, Mark ; Welch, M. J. ; Piwnica-Worms, D. / Novel gallium(III) complexes transported by MDR1 P-glycoprotein : Potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo. In: Chemistry and Biology. 2000 ; Vol. 7, No. 5. pp. 335-343.
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abstract = "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 67Ga-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. Furthermore, 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 68Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.",
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T2 - Potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo

AU - Sharma, V.

AU - Beatty, A.

AU - Wey, S. P.

AU - Dahlheimer, J.

AU - Pica, C. M.

AU - Crankshaw, C. L.

AU - Bass, L.

AU - Green, Mark

AU - Welch, M. J.

AU - Piwnica-Worms, D.

PY - 2000/5/1

Y1 - 2000/5/1

N2 - 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 67Ga-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. Furthermore, 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 68Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

AB - 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 67Ga-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. Furthermore, 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 68Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

KW - Gallium complexes

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KW - Positron emission tomography

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