Evidence for the presence of clofazimine and its distribution in the healthy mouse brain

Baijnath, Sooraj; Naiker, Suhashni; Shobo, Adeola; Moodley, Chivonne; Adamson, John; Ngcobo, Bongani; Bester, Linda A.; Singh, Sima; Kruger, Hendrik G.; Naicker, Tricia; Govender, Thavendran

doi:10.1007/s10735-015-9634-3

Cited by 27 publications

(16 citation statements)

References 14 publications

(17 reference statements)

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“…Matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) is a label‐free technique, which offers the advantage of determining the distribution of parent drug and metabolites simultaneously . We have recently shown that a combination of liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) with MALDI MSI provides better correlation than PET imaging technique . The aim of this study was to establish methods for the preclinical evaluation and localization of fluoroquinolones in the rat brain by using LC‐MS/MS and MALDI MSI as sensitive tools for its determination.…”

Section: Introductionsupporting

confidence: 84%

MALDI MSI and LC‐MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones

Shobo

Baijnath

Bratkowska

et al. 2015

Drug Testing and Analysis

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Fluoroquinolones are broad-spectrum antibiotics with efficacy against a wide range of pathogenic microbes associated with respiratory and meningeal infections. The potential toxicity of this class of chemical agents is a source of major concern and is becoming a global issue. The aim of this study was to develop a method for the brain distribution and the pharmacokinetic profile of gatifloxacin in healthy Sprague-Dawley rats, via Multicenter matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). We developed a sensitive LC-MS/MS method to quantify gatifloxacin in plasma, lung, and brain homogenates. A pharmacokinetic profile was observed where there is a double peak pattern; a sharp initial increase in the concentration soon after dosing followed by a steady decline until another increase in concentration after a longer period post dosing in all three biological samples was observed. The imaging results showed the drug gradually entering the brain via the blood brain barrier and into the cortical regions from 15 to 240 min post dose. As time elapses, the drug leaves the brain following the same path as it followed on its entry and finally concentrates at the cortex. Copyright © 2015 John Wiley& Sons, Ltd.

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Section: Introductionsupporting

confidence: 84%

MALDI MSI and LC‐MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones

Shobo

Baijnath

Bratkowska

et al. 2015

Drug Testing and Analysis

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“…The application of MSI to investigate small‐molecule spatial distribution was first demonstrated in 2003 following imaging of two anti‐cancer drugs, SCH 226 374 and compound A, in rat brain . Since then, a wide range of small molecules have been mapped using MSI in various biological tissues . MSI of antiretroviral drugs in various biological tissues has been done; however, there are no MSI‐related studies showing the spatial distribution of elvitegravir in biological tissues, and few studies have demonstrated the use of MSI to map tenofovir in situ .…”

Section: Resultsmentioning

confidence: 99%

“…The matrix solution was prepared by dissolving CHCA in 50% acetonitrile, 0.1% trifluoroacetic acid to make up a final concentration of 7 mg/mL. For matrix and ISTD application, a previously described standardized ImagePrep (Bruker Daltonics, Bremen, Germany) five‐cycle method was used, each cycle consisting of three steps including spraying, incubation and drying . An automated ImagePrep spraying equipment uniformly deposited the matrix onto the tissue in a form of an aerosol.…”

Section: Methodsmentioning

confidence: 99%

“…For matrix and ISTD application, a previously described standardized ImagePrep (Bruker Daltonics, Bremen, Germany) five-cycle method was used, each cycle consisting of three steps including spraying, incubation and drying. 13,14,17 An automated ImagePrep spraying equipment uniformly deposited the matrix onto the tissue in a form of an aerosol. An aerosol was generated by a vibrating spray generator producing tiny droplets with an average droplet size of ca 20 μm.…”

Section: Sample Preparation For Maldi-msimentioning

confidence: 99%

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Spatial distribution of elvitegravir and tenofovir in rat brain tissue: Application of matrix‐assisted laser desorption/ionization mass spectrometry imaging and liquid chromatography/tandem mass spectrometry

Ntshangase

Mdanda

Naicker

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale The complexity of central nervous system (CNS) drug delivery is the main obstacle with the blood–brain barrier (BBB) known to restrict access of most pharmaceutical drugs into the brain. Mass spectrometry imaging (MSI) offers possibilities for studying drug deposition into the CNS. Methods The deposition and spatial distribution of the two antiretroviral drugs elvitegravir and tenofovir in the brain were investigated in healthy female Sprague–Dawley rats following a single intraperitoneal administration (50 mg/kg). This was achieved by the utilization of quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) and matrix‐assisted laser desorption/ionization (MALDI) MSI. Results LC/MS/MS showed that elvitegravir has better BBB penetration, reaching maximum concentration in the brain (Cmaxbrain) of 976.5 ng/g. In contrast, tenofovir displayed relatively lower BBB penetration, reaching Cmaxbrain of 54.5 ng/g. MALDI‐MSI showed the heterogeneous distribution of both drugs in various brain regions including the cerebral cortex. Conclusions LC/MS/MS and MALDI‐MSI provided valuable information about the relative concentration and the spatial distribution of the two common antiretroviral drugs. This study has also shown the capability of MALDI‐MSI for direct visualization of pharmaceutical drugs in situ.

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“…We show that clofazimine exhibits minimal penetration of the blood-brain barrier, and its low solubility and high lipophilicity are also barriers to translation for brain tumors. There has been conflicting evidence for whether clofazimine is able to penetrate the brain; while some studies have reported no detectable levels in the brain (Baik et al, 2013;Holdiness, 1989), other studies detected a level of 156 ng/mL of clofazimine in the brain of mice treated with 25 mg/kg of the drug (Baijnath et al, 2015) and an effect on Kv1.3 channels in the brain in animals treated with 50 mg/kg clofazimine after traumatic brain injury (Reeves et al, 2016). In contrast, using the equivalent of the maximum tolerated human dose (2.44 mg/kg in mice), we were unable to detect clofazimine in the brain using mass spectrometry or the ability for it to cross the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Development of a Cx46 targeting strategy for cancer stem cells

Mulkearns-Hubert

Torre-Healy

Silver

et al. 2018

Preprint

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Conflicts of interest: None to declare Summary (150 words)Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

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Evidence for the presence of clofazimine and its distribution in the healthy mouse brain

Cited by 27 publications

References 14 publications

MALDI MSI and LC‐MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones

MALDI MSI and LC‐MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones

Spatial distribution of elvitegravir and tenofovir in rat brain tissue: Application of matrix‐assisted laser desorption/ionization mass spectrometry imaging and liquid chromatography/tandem mass spectrometry

Development of a Cx46 targeting strategy for cancer stem cells

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