Effect of fatty acid ester structure on cytotoxicity of self-emulsified nanoemulsion and transport of nanoemulsion droplets

Abstract

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.