Abstract：
Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
摘要：
基于脂质的药物输送系统在满足关键医疗需求方面具有巨大的前景。从癌症和神经退行性疾病到传染病。通过封装活性药物成分-从小分子药物到蛋白质和核酸-这些纳米载体增强治疗功效和安全性。然而,他们的商业成功面临障碍，例如缺乏系统的设计方法以及与可扩展性和可重复性相关的问题。这项工作旨在通过结合分子动力学模拟和热力学建模技术来提供对药物-磷脂相互作用的见解。特别是,我们已经将药物-磷脂系统的结构特性与载药脂质体纳米制剂的物理化学性能联系起来。我们考虑了两种典型的药物，非洛地平（FEL）和萘普生（NPX），和一个模型氢化大豆磷脂酰胆碱（HSPC）双层膜。分子动力学模拟揭示了磷脂双层内的哪些区域最受药物分子青睐。NPX倾向于驻留在水-磷脂界面处,并且特征在于双层膜渗透的较低自由能屏障。同时,FEL优选位于磷脂的疏水尾部内,并且特征在于膜渗透的较高自由能屏障。Flory-Huggins热力学模型,小角度X射线散射，动态光散射,TEM,这些脂质体纳米制剂的药物释放研究证实了这种药物-磷脂结构的差异。萘普生-磷脂系统具有较低的渗透自由能障，更高的药物与双层的混溶性，更大的脂质体纳米颗粒尺寸，和更快的药物在水介质中的释放比非洛地平。我们建议，分子动力学和热力学方法的这种结合可能为设计和开发用于未满足医疗应用的基于脂质的纳米载体提供新工具。
