Document Detail


Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport.
MedLine Citation:
PMID:  20505882     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The human genome is known to consist of 49 ATP-binding cassette (ABC) transporter genes. Among these ABC proteins, overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp/ABCB1) is the best characterized barrier to successful chemotherapeutic treatments, impacts pharmacokinetics of numerous recognized drugs, and is also quickly emerging as an important target in the development of neurodegenerative diseases. Therefore, there exists an urgent need to seek radiopharmaceuticals, incorporated with generator-produced radionuclides to assist their widespread deployment, for noninvasive assessment of Pgp-mediated functional transport activity in vivo. METHODS: gallium(III) complexes (5a and 5b) possessing octahedral geometry were synthesized, analytically characterized, and evaluated for their potential to serve as probes of Pgp-mediated functional transport activity in cellulo and in vivo. While unlabeled compounds (5a and 5b) were examined via cell cytotoxicity assays, the (67)Ga-labeled counterparts (6a and 6b) were evaluated via cell transport studies and quantitative biodistribution studies in mdr1a/1b((-/-)) gene-deleted mice and their wild-type (WT) counterparts. RESULTS: cytotoxicity data of 5a and 5b displayed profiles modified by the expression of Pgp in drug-resistant cells. (67)Ga-metalloprobes (6a and 6b) showed high accumulation in human epidermal carcinoma drug-sensitive KB-3-1 cells (Pgp-), human breast carcinoma MCF-7 (Pgp-) cells; an inhibitor (LY335979, 1 microM) induced accumulation in multidrug resistant (MDR, Pgp+) KB-8-5, KB-8-5-11 cells, and stably transfected MCF-7/MDR1 cells, thus demonstrating their ability to interrogate Pgp-mediated functional transport activity in cellulo. In mdr1a/1b((-/-)) gene-deleted mice, the (67)Ga-metalloprobe (6b) showed 8-fold greater brain uptake and retention compared with WT counterparts and no significant difference in blood pharmacokinetics. CONCLUSION: molecular imaging of the functional transport activity of MDR1 Pgp (ABCB1) with (67/68)Ga-metalloprobes could enable non-invasive monitoring of the blood-brain barrier, tumors, and tissues in vivo.
Authors:
Jothilingam Sivapackiam; Scott E Harpstrite; Julie L Prior; Hannah Gu; Nigam P Rath; Vijay Sharma
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-05-27
Journal Detail:
Title:  Dalton transactions (Cambridge, England : 2003)     Volume:  39     ISSN:  1477-9234     ISO Abbreviation:  Dalton Trans     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-15     Completed Date:  2010-09-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101176026     Medline TA:  Dalton Trans     Country:  England    
Other Details:
Languages:  eng     Pagination:  5842-50     Citation Subset:  IM    
Affiliation:
Mallinckrodt Institute of Radiology, Washington University School of Medicine, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Transport
Blood-Brain Barrier / metabolism
Carcinoma, Squamous Cell / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Gallium Radioisotopes / chemistry*,  pharmacokinetics
Humans
Mice
Mice, Knockout
Models, Molecular
Molecular Probes / chemical synthesis,  chemistry*,  pharmacokinetics
P-Glycoprotein / chemistry*,  metabolism*
Radiopharmaceuticals / chemistry*,  metabolism
Tissue Distribution
Grant Support
ID/Acronym/Agency:
AG030498/AG/NIA NIH HHS; AG033328/AG/NIA NIH HHS; P50 CA94056/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Gallium Radioisotopes; 0/Molecular Probes; 0/P-Glycoprotein; 0/Radiopharmaceuticals

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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