Coarse grained simulations of local anesthetics encapsulated into a liposome.
Coarse grained simulations of local anesthetics encapsulated into a liposome.
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封装在脂质体中的局部麻醉剂的粗粒度模拟。
DOI：
10.1021/jp909148n
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
G. Giupponi
中科院分区：
文献类型：
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作者：
M. Pickholz;G. Giupponi
我们研究了一种广泛应用于牙科的胺酰胺局麻药——丙胺卡因（PLC）的单层脂质体包封。我们扩展了最近开发的粗粒度模型，以访问与问题相关的时间和长度尺度。分子动力学（MD）模拟了PLC的不同质子化状态，捕捉到了PLC-囊泡相互作用的重要特征。我们发现所有中性PLC分子（nPLC）以不对称的双峰密度分布迅速扩散到囊泡的疏水区域，nPLC分子在内部和外部囊泡单层之间跳跃。最初放置在水中的质子化PLC分子（plplc）只在外部单层上发现，与水相的交换率很高，无法进入脂质体的内部。尽管PLC尾部和带相反电荷的脂质头基团之间的静电相互作用是结构化的，但疏水性是PLC在脂质体内吸收药物的驱动力。我们的模拟还表明，当pPLC分布在脂质膜内时，大部分的pPLC仍然被困在脂质体的内部水相中。这表明在低pH条件下脂质体- plc复合物以及因此产生的药效很大程度上取决于制备过程。
We investigated the encapsulation of prilocaine (PLC), an aminoamide local anesthetic widely used in dentistry, into a small unilamellar liposome. We extended a recently developed coarse grained model to access the problem relevant time and length scales. Molecular dynamics (MD) simulations for different protonation states of the PLC captured important features of the PLC-vesicle interactions. We found that all neutral PLC molecules (nPLC) rapidly diffuse into the hydrophobic region of the vesicle adopting an asymmetric bimodal density distribution, with nPLC molecules jumping between the internal and external vesicle monolayers. Protonated PLC molecules (pPLC) initially placed in water were instead only found on the external monolayer, with a high rate of exchange with the water phase and no access to the inner part of the liposome. Although electrostatic interaction between pPLC tails and oppositely charged lipid head groups is shown to be structured, hydrophobicity is the driving force of PLC drug absorption within the liposome. Our simulations also show that a major percentage of pPLC remains trapped within the interior water phase of the liposome when starting from a configuration with pPLC distributed within the lipid membrane. This suggests that at low pH liposome-PLC complexes and therefore drug efficacy can strongly depend on the preparation procedure.