从分子动力学模拟中了解聚乙二醇化如何降低 pH 敏感脂质体的功效,Molecular Pharmaceutics

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从分子动力学模拟中了解聚乙二醇化如何降低 pH 敏感脂质体的功效
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-06-06 , DOI: 10.1021/acs.molpharmaceut.1c00122
Mohammad Mahmoudzadeh ₁ , Aniket Magarkar ₂ , Artturi Koivuniemi ₁ , Tomasz Róg ₃ , Alex Bunker ₃

Affiliation

基于脂质体的药物递送系统由用胆固醇半琥珀酸 (CHMS) 稳定的 DOPE 组成，作为一种药物递送机制，当阴离子形式 (CHSa) 在降低的 pH 值下质子化 (CHS) 时，pH 触发释放。聚乙二醇化已知会降低这种 pH 敏感性。在这份手稿中，我们着手使用具有全原子分辨率的模型进行分子动力学 (MD) 模拟，以深入了解为什么将聚乙二醇 (PEG) 掺入 DOPE-CHMS 脂质体会降低其 pH 敏感性；我们还解决了两个额外的问题：（1）CHSa 如何在生理 pH 值为 7 时将 DOPE 双层稳定为层状构象。4？(2) 在酸性 pH 下从 CHSa 到 CHS 的变化如何触发 DOPE 双层的不稳定？我们发现 (A) CHSa 通过增加双层表面的亲水性来稳定 DOPE 脂质膜，(B) 当 CHSa 通过降低 pH 值变为 CHS 时，DOPE 双层由于双层亲水性的降低和面积的减少而变得不稳定每个脂质，和 (C) PEG 将 DOPE 双层稳定到层状相中，从而通过渗透到双层中增加每个脂质的面积来降低脂质体的 pH 敏感性，这是我们的主要关注点。

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Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations

Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE–CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

更新日期：2021-07-05

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