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Development of a capillary electrophoresis method for the simultaneous determination of CDK 4/6 and aromatase inhibitors

Abemaciclib, palbociclib and ribociclib are novel anticancer agents, inhibitors of the cyclin dependent kinase (CDK) 4 and 6. They are used in combination with aromatase inhibitors anastrozole and letrozole in breast cancer therapy. Since these therapeutic combinations are relatively new and prone to CYP-mediated interactions, as well as showing a risk of toxicity in higher doses, it is advisable to employ therapeutic drug monitoring (TDM) for therapy individualisation [1]. A viable alternative to conventional techniques used in TDM is capillary electrophoresis, as it provides advantageous efficacy, high throughput, cost-effectiveness, automation, low sample and solvent consumption, and simplified sample preparation [2]. All measurements were performed on a bare-fused silica capillary, diameter 50 μm, total length 40 cm and effective length 8.3 cm, as injection was carried out at the outlet end. The analytes were detected using a diode-array detector with total run times of 10 min. Acidic conditions, in which all analytes are either neutral or protonated, proved superior to alkaline in the preliminary studies. pH was varied in a range of 2.5 to 5, using 20 - 150 mM phosphate, acetate and citrate buffers, with pH values around 3.1 showing best resolutions (Rs>1.5) between the positively charged CDK inhibitors. At the same time, the neutral anastrozole and letrozole required a charged buffer additive in order to achieve separation. Different additive concentrations, 15 - 50 mM sodium dodecylsulphate (SDS), 0.5 - 10 mM cetyltrimethylammonium bromide (CTAB) and 2 - 30 mM sulfobutylether-β-cyclodextrin (SBE-β-CD), were tested alone or in combination with organic modifiers (5 - 15 % v/v isopropanol, methanol or acetonitrile). Other conditions such as sample diluent (diluted background electrolyte, organic solvents or water), voltage (5 - 30 kV) and temperature (17.5 - 35 °C) were also optimized to achieve shorter run times and better peak shapes. The proposed method provides a basis for the quantification of these compounds in biological samples using capillary electrophoresis.

capillary electrophoresis ; CDK 4/6 inhibitors ; aromatase inhibitors ; breast cancer

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