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Novel technetium (III)-Q complexes for functional imaging of multidrug resistance (MDR1) P-glycoprotein
C L Crankshaw1, M Marmion, G D Luker
1Mallinckrodt Institute of Radiology, and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA.
Unlabelled:
Overexpression of the multidrug resistance (MDR1) P-glycoprotein (Pgp) correlates with cancer chemotherapeutic failure. Lipophilic cationic radiopharmaceuticals such as 99mTc-sestamibi, 99mTc-tetrofosmin and 99Tc-furifosmin (Tc-Q12) have been validated as transport substrates for the MDR1 Pgp and may enable functional imaging of the MDR phenotype in cancer by observing enhanced washout rates of the tracers in those tumor areas expressing Pgp. To further explore and optimize the Pgp recognition properties of Schiff base phosphine mixed-ligand complexes of the Tc-Q series of nonreducible (Tc(III) cations, a variety of Tc-Q complexes were synthesized and tested in vitro for recognition as transport substrates by the human MDR1 Pgp.
Methods:
Tracer assays with human drug-sensitive KB-3-1 epidermal carcinoma and MDR KB-8-5 cells expressing nonimmunodetectable and modest levels of MDR1 Pgp, respectively, were used to screen and pharmacologically characterize 37 novel 99mTc-Q analogs.
Results:
The ideal agent should have low nonspecific binding, high distinction in net uptake between drug-sensitive cells and MDR tumor cells, and high enhancement of uptake in resistant cells after treatment with an MDR modulator, indicating selective blockade of Pgp-mediated efflux of the radiotracer. Three analogs, trans-[5,5'-(1,2-ethanediyldiimino)bis(2-OEt-2-Me-4-penten-3 -one)]bis[dimethyl(3-OMe-1-propyl)phosphine]99mTc(III) (99mTc-Q63) and two trans-[bis(methyl-bis(3-OMe-1-propyl)phosphine)] analogs (99mTc-Q57 and 99mTc-Q58) displayed transport distinctions between drug-sensitive and MDR cell lines that were equal to or greater than all previously available agents. Cyclosporin A, an MDR modulator, had no significant effect in KB-3-1 cells for these 99mTc-complexes but enhanced tracer accumulations in KB-8-5 cells with IC50 values of approximately 1 microM. In contrast, the non-MDR agents methotrexate and cisplatin had no effect on accumulation of 99mTc-Q complexes and 99mTc-sestamibi in KB-8-5 cells.
Conclusion:
Technetium-99m-Q57, 99mTc-Q58 and 99mTc-Q63 are avid transport substrates recognized by the human MDR1 Pgp, and have enhanced in vitro properties that may enable functional imaging of Pgp in vivo with improved signal-to-noise ratios and tissue contrast compared to currently available agents.
Insights
New technetium-99m-Q complexes show promise for imaging multidrug resistance (MDR) in cancer. These novel agents effectively identify P-glycoprotein (Pgp) activity, potentially improving cancer treatment monitoring.
Area of Science:
- Radiopharmaceutical chemistry
- Molecular imaging
- Cancer biology
Background:
- Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) is a major cause of cancer chemotherapy failure.
- Radiopharmaceuticals like 99mTc-sestamibi are Pgp substrates, enabling potential imaging of the MDR phenotype.
- Optimizing Pgp recognition properties of technetium complexes is crucial for improved functional imaging.
Purpose of the Study:
- To synthesize and evaluate novel Tc-Q complexes as transport substrates for human MDR1 Pgp.
- To explore the potential of these complexes for functional imaging of Pgp-mediated MDR in cancer.
- To optimize Pgp recognition and in vitro properties for enhanced imaging.
Main Methods:
- Synthesis of novel Schiff base phosphine mixed-ligand technetium complexes (Tc-Q series).
- In vitro evaluation of 37 novel 99mTc-Q analogs using drug-sensitive KB-3-1 and MDR KB-8-5 cell lines.
- Pharmacological characterization using MDR modulators like Cyclosporin A.
Main Results:
- Three analogs (99mTc-Q63, 99mTc-Q57, 99mTc-Q58) demonstrated transport distinctions between sensitive and MDR cells comparable to or exceeding existing agents.
- Cyclosporin A significantly enhanced tracer accumulation in MDR cells (IC50 ~1 microM), confirming Pgp-mediated efflux.
- Non-MDR agents did not affect the accumulation of Tc-Q complexes or 99mTc-sestamibi in MDR cells.
Conclusions:
- Technetium-99m-Q57, 99mTc-Q58, and 99mTc-Q63 are effective transport substrates recognized by human MDR1 Pgp.
- These complexes exhibit enhanced in vitro properties for functional Pgp imaging.
- Improved signal-to-noise ratios and tissue contrast are anticipated for in vivo imaging compared to current agents.