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Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy

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Title: Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy
Authors: Sparks, H
Kondo, H
Hooper, S
Munro, I
Kennedy, G
Dunsby, C
French, P
Sahai, E
Item Type: Journal Article
Abstract: We present an approach to quantify drug-target engagement using in vivo fluorescence endomicroscopy, validated with in vitro measurements. Doxorubicin binding to chromatin changes the fluorescence lifetime of histone-GFP fusions that we measure in vivo at single-cell resolution using a confocal laparo/endomicroscope. We measure both intra- and inter-tumor heterogeneity in doxorubicin chromatin engagement in a model of peritoneal metastasis of ovarian cancer, revealing striking variation in the efficacy of doxorubicin-chromatin binding depending on intra-peritoneal or intravenous delivery. Further, we observe significant variations in doxorubicin-chromatin binding between different metastases in the same mouse and between different regions of the same metastasis. The quantitative nature of fluorescence lifetime imaging enables direct comparison of drug-target engagement for different drug delivery routes and between in vitro and in vivo experiments. This uncovers different rates of cell killing for the same level of doxorubicin binding in vitro and in vivo.
Issue Date: 9-Jul-2018
Date of Acceptance: 24-May-2018
URI: http://hdl.handle.net/10044/1/60955
DOI: https://dx.doi.org/10.1038/s41467-018-04820-6
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Issue: 1
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article ’ s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Keywords: MD Multidisciplinary
Publication Status: Published
Conference Place: England
Article Number: 2662
Appears in Collections:Physics
Faculty of Natural Sciences