Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy
File(s)
Published version
Author(s)
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.
Date Issued
2018-07-09
Date Acceptance
2018-05-24
Citation
Nature Communications, 2018, 9 (7)
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
9
Issue
7
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/
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/
Sponsor
Engineering & Physical Science Research Council (EPSRC)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29985394
PII: 10.1038/s41467-018-04820-6
Grant Number
EP/F040202/1
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CANCER
RESISTANCE
MICROSCOPY
EVOLUTION
MICROENVIRONMENT
Animals
Antibiotics, Antineoplastic
Cell Line, Tumor
Chromatin
Doxorubicin
Drug Delivery Systems
Fluorescence
Humans
Mice, Nude
Microscopy, Confocal
Neoplasms
Xenograft Model Antitumor Assays
Cell Line, Tumor
Chromatin
Animals
Humans
Mice, Nude
Neoplasms
Doxorubicin
Antibiotics, Antineoplastic
Microscopy, Confocal
Drug Delivery Systems
Xenograft Model Antitumor Assays
Fluorescence
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN 2662