HPLC-MS/MS method for quantitative determination of the novel dual inhibitor of FGF and VEGF receptors E-3810 in tumor tissues from xenograft mice and human biopsies

Monique Zangarini, Laura Ceriani, Ezia Bello, Giovanna Damia, Roberta Cereda, Maria Gabriella Camboni, Massimo Zucchetti

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Abstract

We developed and validated a high-performance liquid chromatography-tandem mass spectrometry analytical method to measure E-3810, a novel dual inhibitor of fibroblast growth factor receptor 1 and vascular endothelial growth factor receptor 1-3 in tissues and determined the drug concentration in a biopsy of human breast cancer for the first time. The method is a modification of our previous one in plasma to study the clinical pharmacokinetics of the drug during the phase I/II trial. In view of the changes in matrix, we applied a partial validation protocol to determine recovery, sensitivity, range of linearity, precision, accuracy and stability of the method over three runs in a mouse tumor tissue and liver. The recovery of E-3810 from liver or tumor homogenate was >69%, and the lower limit of quantification was 5 ng/ml. The method was linear in the concentration range 5.0-500.0 ng/ml, as demonstrated by a determination coefficient R2x ≥ 0.9955. The range of the calibration curve was appropriate for the analysis, as demonstrated by the accuracy, which was between 91.4% and 106.7%. Interday precision and accuracy on quality control samples at 9, 30 and 300 ng/ml were 3.1-11.2%and 98.3-111.4%, respectively. The assay was applied successfully to determine the intratumor concentration of E-3810 in different mouse xenograft tumor models and in a biopsy of a patient with breast cancer included in the phase I/II trial of the drug. In mouse tumors, the concentrations of E-3810 were higher than necessary to exert antitumor activity in vitro (1 μM). Even more of interest was the result obtained in a human biopsy of few milligrams, where E-3810 reached 4.9 μg/g (11 μM).

Original languageEnglish
Pages (from-to)19-26
Number of pages8
JournalJournal of Mass Spectrometry
Volume49
Issue number1
DOIs
Publication statusPublished - 2014

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Keywords

  • E-3810
  • FGFR/VEGFR inhibitor
  • HPLC-MS/MS
  • Tumor distribution
  • Validation study

ASJC Scopus subject areas

  • Spectroscopy

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