A novel mixed phospholipid functionalized monolithic column for early screening of drug induced phospholipidosis risk.

Chromatography, High Pressure Liquid/instrumentation; Drug Evaluation, Preclinical; Hydrophobic and Hydrophilic Interactions; Microscopy, Electron, Scanning; Phospholipids/chemistry; Polymerization; Spectroscopy, Fourier Transform Infrared; Drug-induced phospholipidosis; Immobilized artificial membrane; Mixed phospholipid; Monolithic columns

Abstract :

[en] Drug-induced phospholipidosis (PLD) is characterized by the excessive accumulation of phospholipids, resulting in multilamellar vesicle structure within lysosomes. In the present study, a novel mixed phospholipid functionalized monolithic column was developed for the first time through a facile one-step co-polymerization approach. The phospholipid composition of the monolith can be adjusted quantitatively and accurately to mimic the mixed phospholipid environment of different biomembranes on a solid matrix. The mixed phospholipid functionalized monolith as a promising immobilized artificial membrane technique was used to study drug-phospholipid interaction. Scanning electron microscopy, elemental analysis, FT-IR spectra, zeta-potential analysis and micro-HPLC were carried out to characterize the physicochemical properties and separation performance of the monolith. Mechanism studies revealed that both hydrophobic and electrostatic interactions play an important role in the retention of analytes. The ratio of their contributions to retention can be easily manipulated by adjusting the composition of the mixed phospholipids, in order to better mimic the interaction between drugs and cell membrane. The obtained mixed phospholipid functionalized monolithic columns were applied to the screening of drug-induced PLD potency. Data from 79 drugs on the market demonstrated that the chromatographic hydrophobicity index referring to the mixed phospholipid functionalized monolith at pH 7.4 (CHI IAM7.4) for the selected drugs were highly correlated with the drug-induced PLD potency data obtained from other in vivo or in vitro assays. Moreover, the effect of the acidic phospholipid phosphatidylserine proportion on prediction accuracy was also investigated. The monolith containing 20% phosphatidylserine and 80% phosphatidylcholine exhibited the best prediction ability for the drug-induced PLD potency of the tested compounds. This research has led to the successful development of a novel and facile approach to prepare a mixed phospholipids functionalized monolith, which offers a reliable, cost-effective and high-throughput screening tool for early prediction of the PLD potency of drug candidates.

Research center :

Centre Interfacultaire de Recherche du Médicament - CIRM

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Zhao, Xianglong

Chen, Weijia

Liu, Zhenghua

Guo, Jialiang

Zhou, Zhengyin

Crommen, Jacques ; Université de Liège > Département de pharmacie > Département de pharmacie

Moaddel, Ruin

Jiang, Zhengjin

Language :

English

Title :

A novel mixed phospholipid functionalized monolithic column for early screening of drug induced phospholipidosis risk.

Publication date :

2014

Journal title :

Journal of Chromatography. A

ISSN :

0021-9673

eISSN :

1873-3778

Publisher :

Elsevier, Amsterdam, Netherlands

Volume :

1367

Pages :

99-108

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 24 October 2015

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