Distribution analysis of epertinib in brain metastasis of HER2-positive breast cancer by imaging mass spectrometry and prospect for antitumor activity

Abstract

Epertinib (S-222611) is a potent, reversible, and selective tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2), and human EGFR4. We developed experimental brain metastasis models by intraventricular injection (intraventricular injection mouse model; IVM) of HER2-positive breast cancer (MDA-MB-361-luc-BR2/BR3) or T790M-EGFR-positive lung cancer (NCI-H1975-luc) cells. After a single oral administration, epertinib and lapatinib concentrations in brain metastatic regions were analyzed by quantitative imaging mass spectrometry. In the NCI-H1975 lung cancer IVM, the concentration of epertinib in brain metastasis was comparable to that of lapatinib. However, in the MDA-MB-361 breast cancer IVM, the concentration of epertinib in brain metastasis was >10 times higher than that of lapatinib. Furthermore, the epertinib tumor-to-normal brain ratio was ~4 times higher than that of lapatinib. Blood-tumor barrier (BTB) permeability was assessed in each brain metastatic region. In the lung cancer model, fluorescently labeled dextran was more highly detected in brain metastatic regions than in brain parenchyma. However, in breast cancer models, dextran fluorescence intensity in brain metastatic regions and brain parenchyma were comparable, suggesting that the BTB remained largely intact. Epertinib would be promised as a therapeutic agent for HER2-positive breast cancer with brain metastasis.

Toward Higher Sensitivity in Quantitative MALDI Imaging Mass Spectrometry of CNS Drugs Using a Nonpolar Matrix

“…[28][29][30][31][32] One of the most promising applications for MSI is the measurement of the spatial distribution of xenobiotics in CNS tissue. 33 A number of studies have described CNS spatial distribution of different drugs, 34,35,[44][45][46][36][37][38][39][40][41][42][43] narcotics, 47-49 neurotoxin 50 and positron emission 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 tomography (PET) ligands. 51 Two recent studies reported more sophisticated uses of MALDI-MSI, including studying drug-drug interactions and their impact on the BBB permeability, 52 and amyloid-binding molecules in an experimental model of Alzheimer's disease.…”

“…Consequently, despite the aforementioned physicochemical properties of CNS drugs (small lipophilic molecules with low polar surface area and limited 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 hydrogen bonding 5-7 ), virtually all MALDI-MSI studies of these pharmaceuticals use the two most common polar and acidic matrices, α-cyano-4-hydroxycinnamic acid (CHCA) 36,39,44,48,50,51,59,74 and 2,5-dihydroxybenzoic acid (DHB). 35,38,49,52,53,[39][40][41][42][43][45][46][47] In this study, we successfully applied the nonpolar DCTB (2-[(2E)-3-(4-tertbutylphenyl)-2-methylprop-2-enylidene]malononitrile) matrix for high sensitivity imaging of CNS drugs in mouse brain sections. DCTB has been frequently used as an electron-transfer matrix.…”

Mass Spectrometry Imaging of Neurotransmitters

“…MSI has been applied to quantitative analysis of drugs [90,91], metabolites [92], and biomarkers in tissue [93] using pneumatic sprayers and sublimation techniques described in this chapter. Nearly all of these demonstrations have utilized organic acid matrices such as DHB, CHCA, and trihydroxyacetophenone (THAP), with one research group utilizing TiO 2 NPs [94,95].…”

“…Specific examples with clinical relevancy are briefly described here. First, epertinib and lapatinib were quantified in a metastatic brain cancer mouse model using stable isotope labeling, and with liquid chromatography (LC)-MS validation [91]. The topical drugs roflumilast, tofacitinib, ruxolitinib, and LEO 29102 were examined in human skin explants to determine drug penetration and evaluate lipid markers [90].…”

Modelling the structural and reactivity landscapes of tucatinib with special reference to its wavefunction-dependent properties and screening for potential antiviral activity

“…Breast cancer is one of the most common type of neoplasm found in women and it is divided basically into different subtypes, viz., Luminal A, Luminal B, HER2-enriched, Basallike and the human epidermal growth factor receptor-2enriched (HER2-E) is indicated by the overexpression of growth factor receptor-related genes and cell cycle-related genes along with low presence of oestrogen-related and basal-related genes [1][2][3]. Always, there is a risk of metastatic spread to other interorgans like lungs, brain and bone [4,5].…”