Consideration of metabolite efflux in radiolabelled choline kinetics
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore may confound uptake of choline radiotracer
[
18F]fluoromethyl-[1,2-
2H4]-choline ([
18 F]-D4-FCH). The aim of this study was to investigate how hypoxia affects choline radiotracer dynamics. Three underlying mechanisms by which hypoxia
could potentially alter the uptake of the choline radiotracer, [
18 F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and efflux of [18 F]-D4-FCH and its phosphorylated product [
18F]-D4-FCHP. Effects of hypoxia on [18 F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer, MDA-MB-231 cells. Mechanisms of radiotracer efflux were assessed by cell uptake and immunofluorescence in vitro, and examined in vivo (N=24). Mathematical modelling methodology was further developed to verify efflux hypothesis using [18 F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (N=17). We report a novel finding involving export of phosphorylated
[18F]-D4-FCH, [18 F]-D4-FCHP, via HIF-1α-responsive efflux transporters including ABCB4 when HIF-1α level is augmented. This is supported by graphical analysis of human data with a compartmental model (M2T6k+k5) that accounts for efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting consideration of efflux in modelling of radiotracer dynamics.
[
18F]fluoromethyl-[1,2-
2H4]-choline ([
18 F]-D4-FCH). The aim of this study was to investigate how hypoxia affects choline radiotracer dynamics. Three underlying mechanisms by which hypoxia
could potentially alter the uptake of the choline radiotracer, [
18 F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and efflux of [18 F]-D4-FCH and its phosphorylated product [
18F]-D4-FCHP. Effects of hypoxia on [18 F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer, MDA-MB-231 cells. Mechanisms of radiotracer efflux were assessed by cell uptake and immunofluorescence in vitro, and examined in vivo (N=24). Mathematical modelling methodology was further developed to verify efflux hypothesis using [18 F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (N=17). We report a novel finding involving export of phosphorylated
[18F]-D4-FCH, [18 F]-D4-FCHP, via HIF-1α-responsive efflux transporters including ABCB4 when HIF-1α level is augmented. This is supported by graphical analysis of human data with a compartmental model (M2T6k+k5) that accounts for efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting consideration of efflux in modelling of radiotracer dynamics.
Date Issued
2021-08-12
Date Acceptance
2021-08-06
Citation
Pharmaceutics, 2021, 13 (8), pp.1-18
ISSN
1999-4923
Publisher
MDPI AG
Start Page
1
End Page
18
Journal / Book Title
Pharmaceutics
Volume
13
Issue
8
Copyright Statement
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Cancer Research UK
Identifier
https://www.mdpi.com/1999-4923/13/8/1246
Grant Number
16584
Subjects
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
choline kinase
hypoxia
efflux
POSITRON-EMISSION-TOMOGRAPHY
BINDING CASSETTE TRANSPORTERS
PROSTATE-CANCER
KINASE ALPHA
MALIGNANT-TRANSFORMATION
PHOSPHOLIPID-METABOLISM
MULTIDRUG-RESISTANCE
TRANSFER CONSTANTS
HYPOXIA
EXPRESSION
choline kinase
efflux
hypoxia
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2021-08-12