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

Hugh Sparks, Hiroshi Kondo, Steven Hooper, Ian Munro, Gordon Kennedy, Christopher Dunsby (), Paul French () and Erik Sahai ()
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Hugh Sparks: The Francis Crick Institute
Hiroshi Kondo: The Francis Crick Institute
Steven Hooper: The Francis Crick Institute
Ian Munro: South Kensington Campus
Gordon Kennedy: South Kensington Campus
Christopher Dunsby: South Kensington Campus
Paul French: South Kensington Campus
Erik Sahai: The Francis Crick Institute

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04820-6

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