jm8b00935_si_001.pdf (1.62 MB)
Synthesis and Activity of a Novel Autotaxin Inhibitor–Icodextrin Conjugate
journal contribution
posted on 2018-07-30, 00:00 authored by Natalie Fisher, Michael G. Edwards, Ryan Hemming, Steven M. Allin, John D. Wallis, Philip C. Bulman Page, Michael J. Mckenzie, Stefanie M Jones, Mark R. J. Elsegood, John King-Underwood, Alan RichardsonAutotaxin
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.
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membrane permeabilityextracellular phospholipase Dmass compoundsautotaxin inhibitorIntraperitoneal administrationcell migrationautotaxin inhibitor HA 155covalently-bonded drug delivery platformicodextrinintraperitoneal retentionIC 50lysophosphatidyl cholineLPCreport conjugationLPAautotaxin activitybioactive lipid lysophosphatidic acidAutotaxincavity
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