Fisher, N, Edwards, MG, Hemming, R, Allin, SM, Wallis, JD, Bulman Page, PC, Mckenzie, MJ, Jones, SM, Elsegood, MRJ, King-Underwood, J and Richardson, A ORCID: 0000-0003-1825-3375 (2018) Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate. Journal of Medicinal Chemistry. ISSN 1520-4804

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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.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via American Chemical Society at http://doi.org/10.1021/acs.jmedchem.8b00935 - please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > R Medicine (General)
Related URLs:
Depositing User: Symplectic
Date Deposited: 23 Aug 2018 13:33
Last Modified: 23 Aug 2018 13:37
URI: http://eprints.keele.ac.uk/id/eprint/5242

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