Although the cytotoxic and permeation enhancing activities of some fatty acid esters (FAEs) have been studied individually, there lacks systemic studies on how their molecular structures can affect these activities and how the activities would change when FAEs form micelles or nanoemulsion droplets. Therefore, this study aims to address these issues by investigating the cytotoxic and permeation enhancing effects of twenty-six FAEs in lipid droplets on Madin-Darby Canine Kidney (MDCK) cell monolayer. The effect of FAEs on the cytotoxicity and the transport of nanoemulsion droplets depends on how easy the FAE monomers can diffuse out of the droplets and perturbate into the cellular membrane, which determined by the critical structures of FAEs including hydrophilic head size, chain length, number of chains, and number of double bond(s) in the chain. The less the intermolecular attraction, the easier the monomer to diffuse out of the lipid droplets and the more interaction with the cell monolayer. Fatty acid monoester (FAME) with less intermolecular attraction than di- and tri-esters had more cytotoxic and higher permeation enhancing effects. Among the FAMEs, the cytotoxicity and permeation enhancing effects were in the order: medium-chain with small hydrophilic head (propylene glycol and glycol) > long-chain with two double bonds > medium-chain with large head (sorbitan, polyethylene glycol, sucrose, and PEGylated sorbitan) ≈ long-chain with single double bond > saturated long-chain, which are consistent with the intermolecular attraction force (low-high). However, the more kinks in the monomer’s tail caused by the double bond, the less the monomer can perturbate into the cell membrane, resulting in less cytotoxicity and permeation enhancement. In conclusion, the FAEs with less intermolecular attraction and straight chain have more cytotoxic and permeation enhancing effects when formulated in nanoemulsion.

尽管已经单独研究了某些脂肪酸酯（FAE）的细胞毒性和渗透增强活性，但仍缺乏系统的研究来研究它们的分子结构如何影响这些活性以及当FAE形成胶束或纳米乳液液滴时活性将如何改变。因此，本研究旨在通过研究26种FAE在脂滴中对Madin-Darby犬肾脏（MDCK）细胞单层的细胞毒性和渗透增强作用来解决这些问题。FAE对纳米乳剂液滴的细胞毒性和运输的影响取决于FAE单体从液滴中扩散出来并扰动进入细胞膜的难易程度，这取决于FAE的关键结构，包括亲水头尺寸，链长，数量链的数量以及链中双键的数量。分子间吸引力越小，单体越容易从脂质液滴中扩散出来，并且与细胞单层的相互作用越多。分子间吸引力小于二酯和三酯的脂肪酸单酯（FAME）具有更高的细胞毒性和更高的渗透增强作用。在FAME中，细胞毒性和渗透增强作用的顺序为：亲水性头较小的中链（丙二醇和乙二醇）>具有两个双键的长链>大头部的中链（脱水山梨醇，聚乙二醇，蔗糖）和PEG化脱水山梨糖醇）≈具有单双键的长链>饱和的长链，这与分子间引力（低-高）一致。但是，双键导致的单体尾巴扭结越多，单体可以干扰细胞膜的分子越少，导致细胞毒性和渗透增强的作用就越小。总之，当以纳米乳液配制时，分子间吸引力和直链较少的FAE具有更高的细胞毒性和渗透增强作用。