2134/35246
Natalie Fisher
Natalie
Fisher
Michael G. Edwards
Michael G.
Edwards
Ryan Hemming
Ryan
Hemming
Steven M. Allin
Steven M.
Allin
John D. Wallis
John D.
Wallis
Philip C. Bulman Page
Philip C. Bulman
Page
Michael J. McKenzie
Michael J.
McKenzie
Stefanie M. Jones
Stefanie M.
Jones
Mark Elsegood
Mark
Elsegood
John King-Underwood
John
King-Underwood
Alan Richardson
Alan
Richardson
Synthesis and activity of a novel Autotaxin inhibitor-Icodextrin conjugate
Loughborough University
2018
untagged
Chemical Sciences not elsewhere classified
Organic Chemistry
2018-10-09 10:22:43
Journal contribution
https://repository.lboro.ac.uk/articles/journal_contribution/Synthesis_and_activity_of_a_novel_Autotaxin_inhibitor-Icodextrin_conjugate/9391880
© Copyright 2018 American Chemical Society. Autotaxin is an extracellular phospholipase D that catalyses 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 HA-155 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.