Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport

Jothilingam Sivapackiam, Scott E. Harpstrite, Julie L. Prior, Hannah Gu, Nigam P. Rath, Vijay Sharma

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 67Ga-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. 67Ga-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 μM) 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 67Ga-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 67/68Ga-metalloprobes could enable non-invasive monitoring of the blood-brain barrier, tumors, and tissues in vivo.

Original languageEnglish
Pages (from-to)5842-5850
Number of pages9
JournalDalton Transactions
Issue number25
StatePublished - 2010


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