Abstract
Metastatic breast cancer is the second most common cancer in US women. The mortality rate has decreased approximately 40% in the last 25 years due to advancement in treatment and diagnostics. However, it is estimated that 20–30% of all breast cancer patients will develop metastatic breast cancer. Therefore, there is a need to develop targeted therapeutics to reduce cancer cell migration and subsequent metastasis. The novel small molecule MBQ‐167 inhibits Rac and Cdc‐42, proteins involved in cancer cell growth, migration and invasion. In vivo studies have shown that MBQ‐167 inhibits mammary tumor growth and metastasis in immunocompromised mice by ~90% (Humphries‐Bickley, et al., 2017). However, to continue validating this drug for FDA approval, it is necessary to study the pharmacokinetic profile of the drug, which includes elucidating the tissue distribution of the compound in the body. Hence, it is necessary to develop a rapid and sensitive method to quantify MBQ‐167 in tissues. The purpose of this study was to develop and validate a method for the quantification of MBQ‐167 in mouse tissues using Supercritical fluid chromatography coupled with electrospray ionization tandem mass spectrometry (SFC‐MS/MS). Mouse livers were homogenized, spiked with MBQ‐167, and liquid‐liquid extractions were performed with different organic solvents (heptane, ethyl acetate, 2‐propanol, toluene, and acetonitrile), in order to determine the optimal sample preparation method to selectively separate the drug MBQ‐167 from endogenous material in mouse tissue. Separation was performed on an ACQUITY UPC2BEH (3.0 × 100 mm, 1.7 μm) column at 40 °C with a mobile phase consisting of CO2 and methanol 0.1 % formic acid (95:5, v/v) at a flow rate of 1 mL/min. A tandem triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) mode. High recovery of MBQ‐167 (> 65%) and lower matrix effects were observed upon extraction with heptane:ethyl acetate (1:1). Consistent recovery was observed in other tissues such as kidney, lungs and heart. The method was sensitive with a lower limit of quantification (LLOQ) of 10 ng/mL. Linearity was observed over the concentration range of 10–1000 ng/mL. The data obtained supports the use of SFC‐MS/MS as a highly specific method to evaluate the tissue distribution of MBQ‐167 in mice.Support or Funding InformationThis study is supported by MARC grant NIH/NIGMS 5T34GM007821‐39 (to GRG) and NIGMS‐RISE 25 GM061838 (to MM).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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