SM Allin
Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate
Allin, SM; Wallis, JD; Bulman Page, PC; Mckenzie, MJ; Jones, SM; Elsegood, MRJ; King-Underwood, J; Richardson, A; Fisher, N; Edwards, MG; Hemming, R
Authors
JD Wallis
PC Bulman Page
MJ Mckenzie
SM Jones
MRJ Elsegood
J King-Underwood
Alan Richardson a.richardson1@keele.ac.uk
N Fisher
Michael Edwards m.g.edwards@keele.ac.uk
R Hemming
Abstract
Autotaxin is an extracellular phospholipase D that catalyzes the hydrolysis of lysophosphatidyl choline (LPC) to generate the bioactive lipid lysophosphatidic acid (LPA). Autotaxin has been implicated in many pathological processes relevant to cancer. Intraperitoneal administration of an autotaxin inhibitor may benefit patients with ovarian cancer; however, low molecular mass compounds are known to be rapidly cleared from the peritoneal cavity. Icodextrin is a polymer that is already in clinical use because it is slowly eliminated from the peritoneal cavity. Herein we report conjugation of the autotaxin inhibitor HA155 to icodextrin. The conjugate inhibits autotaxin activity (IC50 = 0.86 ± 0.13 µg mL-1) and reduces cell migration. Conjugation of the inhibitor increased its solubility, decreased its membrane permeability, and improved its intraperitoneal retention in mice. These observations demonstrate the first application of icodextrin as a covalently-bonded drug delivery platform with potential use in the treatment of ovarian cancer.
Citation
Allin, S., Wallis, J., Bulman Page, P., Mckenzie, M., Jones, S., Elsegood, M., …Hemming, R. (2018). Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate. Journal of Medicinal Chemistry, 7942-7951. https://doi.org/10.1021/acs.jmedchem.8b00935
Acceptance Date | Jun 12, 2018 |
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Publication Date | Aug 15, 2018 |
Journal | Journal of Medicinal Chemistry |
Print ISSN | 0022-2623 |
Publisher | American Chemical Society |
Pages | 7942-7951 |
DOI | https://doi.org/10.1021/acs.jmedchem.8b00935 |
Publisher URL | http://doi.org/10.1021/acs.jmedchem.8b00935 |
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