Development of acidic phospholipid containing immobilized artificial membrane column to predict drug-induced phospholipidosis potency.
Development of acidic phospholipid containing immobilized artificial membrane column to predict drug-induced phospholipidosis potency.
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DOI：
10.1016/j.chroma.2021.462147
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
Jincai Wang;Xianglong Zhao;Dongsheng Xu;Liang Lai;J. Crommen;Jialiang Guo;Zhengjin Jiang
中科院分区：
文献类型：
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作者：
Jincai Wang;Xianglong Zhao;Dongsheng Xu;Liang Lai;J. Crommen;Jialiang Guo;Zhengjin Jiang
药物诱导的磷脂沉积症 (DIPLD) 是监管机构和制药公司在药物发现方面的一大担忧。许多研究指出，带负电荷的溶酶体内脂质在DIPLD的形成中发挥着重要作用。为了更好地模拟这种带负电荷的脂质表面，通过12-甲基丙烯酰正十二烷基磷酸胆碱（MDPC）和12-甲基丙烯酰正十二烷基磷酸（MDPA）的原位共聚制备了一种新型固定化人工膜（IAM）柱。通过引入 MDPA，所得整体柱的表面可以在较宽的 pH 范围内保持带负电荷。通过扫描电子显微镜、元素分析和纳米高效液相色谱实验对所得整体IAM柱的理化性质和色谱性能进行了表征。 ζ 电位和保留机制研究的结果表明，由于酸性条件下带负电的 MDPA 的存在，疏水和静电相互作用对阳离子分析物的保留有很大贡献。为了更好地评估药物的 DIPLD 效力，对整体柱中 MDPC 和 MDPA 之间的摩尔比进行了仔细优化。结果表明，聚(MDPC70PA30-co-EDMA)柱在61种药物的定性分析中具有最佳的预测性，仅出现两个假阳性（多奈哌齐、氟卡尼）。
Drug-induced phospholipidosis (DIPLD) represents a big concern for both regulatory authorities and pharmaceutical companies in drug discovery. Many researches pointed out that the negatively charged intralysosomal lipids play an important role in the formation of DIPLD. To better mimic this negatively charged lipid surface, a novel immobilized artificial membrane (IAM) column was prepared via in situ copolymerization of 12-methacryloyl n-dodecylphosphocholine (MDPC) and 12-methacryloyl n-dodecylphosphoric acid (MDPA). By introducing MDPA, the surface of the resulting monolithic column can be maintained negatively charged over a broad pH range. Scanning electron microscopy, elemental analysis and nano-HPLC experiments were carried out to characterize the physicochemical properties and chromatographic performance of the obtained monolithic IAM column. The results of ζ-potential and retention mechanism studies indicate that both hydrophobic and electrostatic interactions contribute greatly to the retention of cation analytes owing to the existence of the negatively charged MDPA under acidic conditions. To better assess the DIPLD potency of drug, the molar ratio between MDPC and MDPA in the monolithic column was carefully optimized. The results show that the poly(MDPC70PA30-co-EDMA) column has the best predictability with only two false-positives (donepezil, flecainide) in qualitative analysis of 61 drugs.