The interactions of drugs with biological and liposomal membranes

这项拟议的工作旨在建立定量的生物物理规则，描述药物和其他小分子与生物膜和脂膜的相互作用。由于几乎所有药物都必须与膜相互作用，它们可能与膜受体结合，通过改变膜的性质发挥作用，或者需要跨膜才能到达靶点，因此这些都是基本的兴趣。此外，人工膜(脂质体)装载了药物，用于靶向给药和优化释放。我们计划确定和模拟膜和添加剂的哪些关键性质和如何控制添加剂的摄取、通过膜的渗透以及添加剂引起的膜性质的变化。研究结果将揭示药物相关分子(如抗菌肽、渗透促进剂、麻醉剂)的作用机理，并将为药物和药物制剂(包括脂质体给药载体)的有效性、选择性和药代动力学的优化提供规则。为了实现这一目标，我们计划应用一些新开发的生物物理技术，如压力微扰量热法、滴定量热法和荧光光谱分析的新方法以及现有的方法。

The proposed work aims at establishing quantitative biophysical rules describing the interaction of drugs and other small molecules with biological and liposomal membranes. These are of fundamental interest since virtually all drugs have to interact with membranes; they may bind to membrane receptors, act by changing membrane properties, or need to cross membranes to reach their target. Furthermore, artificial membranes (liposomes) are loaded with drugs for targeted drug delivery and optimized release.We plan to determine and model which and how key properties of the membrane and the additive govern the uptake of the additive, its permeation through the membrane, and changes of membrane properties induced by the additive. The results will shed light on the mechanisms of action of pharmaceutically relevant molecules (e.g., antibiotic peptides, penetration enhancers, anaesthetics) and they will provide rules for the optimization of drugs and drug formulations (including liposomal drug delivery vehicles) regarding their efficacy, selectivity, and pharmacokinetics.To achieve this goal, we plan to apply a number of newly developed, biophysical techniques such as pressure perturbation calorimetry and new assays for titration calorimetry and fluorescence spectroscopy along with established methods.