Synthesis and Activity of a Novel Autotaxin Inhibitor–Icodextrin Conjugate

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.

自分泌运动因子（Autotaxin）是一种细胞外磷脂酶D，可催化溶血磷脂酰胆碱（LPC）水解生成具有生物活性的脂质溶血磷脂酸（LPA）。自分泌运动因子已被证实参与多种与癌症相关的病理过程。腹腔给予自分泌运动因子抑制剂或可使卵巢癌患者获益；然而，已知低分子量化合物会从腹腔快速清除。艾考糊精（Icodextrin）是一种已应用于临床的聚合物，因其可从腹腔缓慢清除。本文报道了将自分泌运动因子抑制剂HA155与艾考糊精偶联的研究。该偶联物可抑制自分泌运动因子活性，其半数抑制浓度（IC50）为0.86±0.13 μg·mL⁻¹，且能抑制细胞迁移。将抑制剂与艾考糊精偶联可提升其溶解度、降低其膜通透性，并改善其在小鼠体内的腹腔滞留性。上述结果表明，艾考糊精作为共价结合型药物递送平台的首次应用，有望用于卵巢癌的治疗。