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.