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A prodrug strategy for the in vivo imaging of aldehyde dehydrogenase activity

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)561-570
JournalRSC Chemical Biology
Issue number5
Early online date11 Mar 2022
Accepted/In press4 Mar 2022
E-pub ahead of print11 Mar 2022
Published1 May 2022

Bibliographical note

Funding Information: This study was funded through a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (107610/Z/15/Z) and a Wellcome Trust Senior Research Fellowship (220221/Z/20/Z) to THW. As this research was funded by the Wellcome Trust and for the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: THW has received commercial funding from GlaxoSmithKline and Life Molecular Imaging. The other authors have no conflicts of interest to declare. Publisher Copyright: © 2022 The Author(s).

King's Authors


Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments. Here, we have designed a prodrug radiotracer for the non-invasive imaging of aldehyde dehydrogenase 1A1 (ALDH1A1) activity. Elevated ALDH1A1 activity is a marker of drug-resistant cancer cells, modelled here with matched cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells. The aromatic aldehyde of our prodrug radiotracer was intracellularly liberated by esterase cleavage of the geminal diacetate and specifically trapped by ALDH through its conversion to the charged carboxylic acid. Through this mechanism of action, ALDH-specific retention of our prodrug radiotracer in the drug-resistant tumour cells was twice as high as the drug-sensitive cells. Acylal masking of the aldehyde afforded a modest protection from oxidation in the blood, which was substantially improved in carrier-added experiments. In vivo positron emission tomography imaging of tumour-bearing mice produced high tumour-to-background images and radiotracer uptake in high ALDH-expressing organs but was unable to differentiate between drug-sensitive and drug-resistant tumours. Alternative strategies to protect the labile aldehyde are currently under investigation.

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