Abstract
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.
Highlights
Aldehyde dehydrogenases (ALDHs) are a family of NAD(P)dependant enzymes that catalyse the oxidation of aldehydes to carboxylic acids.[1]
aldehyde dehydrogenase 1A1 (ALDH1A1) is known to exhibit esterase activity[23] and we envisaged that following passive diffusion into the cell, the diacetate would be cleaved to furnish [18F]1
A nucleophilic aromatic substitution (SNAr) was performed on N-(4-(1,3-dioxolan-2-yl) benzyl)-N-ethyl-6-chloronicotinamide 4 with [18F]KF/K222 in dimethyl sulfoxide (DMSO) at 150 1C for 25 min followed by an acid mediated acetal-cleavage step to furnish [18F]1 in 44 Æ 7% radiochemical yield (RCY; n = 5; for further details see Fig. S1 and S2, Electronic supplementary information (ESI)†)
Summary
Aldehyde dehydrogenases (ALDHs) are a family of NAD(P)dependant enzymes that catalyse the oxidation of aldehydes to carboxylic acids.[1]. Endogenous aldehydes can be produced as a result of metabolism of amino acids, alcohols, lipids and vitamins, while exogenous aldehydes can derive from the metabolism of cytotoxic drugs and environmental factors.[2–6]. Tumour recurrence arises from drug-resistant tumour cells able to repopulate the tumour niche and seed new lesions. These cells have been termed cancer stem cells (CSCs), and are characterised by high ALDH1A1 expression, alongside other biomarkers such as CD133 and CD44.10,11 A programme of transcriptional, metabolic, and immunosurveillance pathways further contribute to therapy resistance.[12]. Inhibition of ALDH1A1 in animal models of ovarian cancer has proven an attractive therapeutic strategy for CSC depletion and the prevention of recurrence.[15]
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