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

Sharma, Vijay; Beatty, Alicia M.; Wey, Shiaw-Pyng; Dahlheimer, Julie L.; Pica, Christina M.; Crankshaw, Carolyn L.; Bass, Laura A.; Green, M. A.; Welch, Michael J.; Piwnica‐Worms, David

doi:10.1016/s1074-5521(00)00111-3

Cited by 60 publications

(59 citation statements)

References 34 publications

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“…Employing the procedure described earlier [41,42], the ligand 4 (0.147 g, 0.2708 mmol) was dissolved in methanol (2 mL) was treated with dropwise addition of gallium(III)acetylacetonate (99.9 g, 0.2697 mmol) dissolved in methanol. The contents were refluxed for 3h.…”

Section: {Bis-nn′-[n-(-3-methoxynaphthalen-2-oxy -1-ylmethylene)-3-amentioning

confidence: 99%

Metalloprobes: Synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

Harpstrite

Prior

Rath

et al. 2007

Journal of Inorganic Biochemistry

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Multidrug resistance (MDR) mediated by overexpression of the MDR1 gene product, Pglycoprotein (Pgp), represents one of the best characterized barriers to chemotherapeutic treatment in cancer and may be a pivotal factor in progression of Alzheimer's disease (AD). Thus, agents capable of probing Pgp-mediated transport could be beneficial in biomedical imaging. Herein, we synthesized and structurally characterized a gallium(III) complex of the naphthol-Schiff base ligand (5). The crystal structure revealed octahedral geometry for the metallodrug. Cytotoxicity profiles of 5 were evaluated in KB-3-1 (Pgp−) and KB-8-5 (Pgp+) human epidermal carcinoma cell lines. Compared with an LC 50 (the half-maximal cytotoxic concentration) value of 1.93 μM in drug-sensitive (Pgp−) cells, the gallium(III) complex 5 demonstrated an LC 50 value > 100 μM in drug-resistant (Pgp+) cells, thus indicating that 5 was recognized by the Pgp as its substrate, thereby extruded from the cells and sequestered away from their cytotoxic targets. Radiolabeled analogues of 5 could be beneficial in noninvasive imaging of Pgp-mediated transport in vivo.

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Section: {Bis-nn′-[n-(-3-methoxynaphthalen-2-oxy -1-ylmethylene)-3-amentioning

confidence: 99%

Metalloprobes: Synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

Harpstrite

Prior

Rath

et al. 2007

Journal of Inorganic Biochemistry

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“…Current approaches to obtaining pharmacokinetic data in tumors include non-invasive techniques such as positron emission tomography (PET) [12,[19][20] and nuclear magnetic resonance (NMR) [17]. Naturally, 19 F NMR requires either that a fluorine atom already be an integral part of the drug of interest, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Naturally, 19 F NMR requires either that a fluorine atom already be an integral part of the drug of interest, e.g. 5-fluorouracil, or the incorporation of fluorine into the drug molecule.…”

Section: Introductionmentioning

confidence: 99%

“…This method, while highly useful, is also compromised by lack of sensitivity, with a detection limit in the range of 0.01 to 0.1 mmol for fluorinated drugs. Deuterium ( 2 H) NMR has also been used, but it has an effective sensitivity about 10-to 100-fold less than 19 F NMR [13]. Positron emission tomography is a powerful imaging tool for the quantification of positron emitting radiotracers and can provide very detailed spatiotemporal data without biopsy sampling.…”

Section: Introductionmentioning

confidence: 99%

“…Positron emission tomography is a powerful imaging tool for the quantification of positron emitting radiotracers and can provide very detailed spatiotemporal data without biopsy sampling. Several labeled substrates for MDR-related drug transporters have been synthesized for imaging of the MDR phenotype in tumors [12,[19][20]. However, PET's main limitations are the short half-life of the isotopes used and the specialized equipment and syntheses required [22].…”

Section: Introductionmentioning

confidence: 99%

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Accelerator mass spectrometry allows for cellular quantification of doxorubicin at femtomolar concentrations

DeGregorio

Dingley

Wurz

et al. 2005

Cancer Chemother Pharmacol

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Accelerator mass spectrometry (AMS) is a highly sensitive analytical methodology used to quantify the content of radioisotopes, such as 14 C, in a sample. The primary goals of this work were to demonstrate the utility of AMS in determining cellular [ 14 C]doxorubicin (DOX) concentrations and to develop a sensitive assay that is superior to high performance liquid chromatography (HPLC) for the quantification of DOX at the tumor level. In order to validate the superior sensitivity of AMS versus HPLC with fluorescence detection, we performed three studies comparing the cellular accumulation of DOX: one in vitro cell line study, and two in vivo xenograft mouse studies. Using AMS, we quantified cellular DOX content up to 4 hours following in vitro exposure at concentrations ranging from 0.2 pg/ml (345 fM) to 2 Fg/ml (3.45The results of this study show that, compared to standard fluorescence-based HPLC, the AMS method was over five orders of magnitude more sensitive. Two in vivo studies compared the sensitivity of AMS to HPLC using a nude mouse xenograft model in which breast cancer cells were implanted subcutaneously. After sufficiently large tumors formed, DOX was administered intravenously at two dose levels. Additionally, we tested the AMS method in a nude mouse xenograft model of multidrug resistance (MDR) in which each mouse was implanted with both wild type and MDR+ cells on opposite flanks. The results of the second and third studies showed that DOX concentrations were significantly higher in the wild type tumors compared to the MDR+ tumors, consistent with the MDR model. The extreme sensitivity of AMS should facilitate similar studies in humans to establish target site drug delivery and to potentially determine the optimal treatment dose and regimen.3

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ABC Proteins and Oncology: Expression, Detection, and Implication of ABC Proteins in Solid Tumors

Bernaudin

Fajac

Fleury‐Feith

et al. 2009

ABC Transporters and Multidrug Resistance

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

Abstract: 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.

Cited by 60 publications

References 34 publications

Metalloprobes: Synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

Metalloprobes: Synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

Accelerator mass spectrometry allows for cellular quantification of doxorubicin at femtomolar concentrations

ABC Proteins and Oncology: Expression, Detection, and Implication of ABC Proteins in Solid Tumors

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