Cargo-Free Nanoparticles Containing Cationic Lipids Induce Reactive Oxygen Species and Cell Death in HepG2 Cells

Abstract

These effects were dependent on the lipid concentration, surface density of cationic lipids, and particle size of NPs. However, neutral NPs consisting of 1,2-dioleoyl-3-phosphocholine did not elicit the effective ROS generation or cell death regardless of the lipid concentration and particle size. The present study suggests that DOTAP-and DOTMA-NPs are able to induce cancer cell death through production of ROS in the absence of any therapeutic cancer reagents. These results also provide a rational background for the design of delivery systems using cationic lipid-based NP formulations.

Diacylglycerol in Cationic Nanoparticles Stimulates Oxidative Stress‐Mediated Death of Cancer Cells

“…To test this possibility, DOPE was incorporated into cargo‐free cNP up to 30 mol% at the expense of DOTAP and the DOPE‐cNP were treated with cells. However, ROS levels were somewhat lower than those observed after treatment with DOPE‐free cNP (results not shown), which was already suggested previously (Yun et al, ). Although the overall results in this study did not provide any evidence that explained the contrasting effect of DOPE on ROS induction, this discrepancy may be attributable to the different potency of DAG and DOPE in the promotion of the nonlamellar phase in membranes.…”

“…Therefore, these results indicate that cationic lipid‐induced ROS generation in cells is closely related to cell viability, and that DAG in cNP enhances the ROS‐mediated cell death. In addition, these results suggested that although a positive charge in cNP is important in ROS production and death of cancer cells (Yun et al, ), other factors such as specific lipid compositions and/or the physicochemical properties of cNP are also involved in cytotoxicity, as mentioned above. Similar to the results shown in Fig.…”

“…These results implied that DAG per se may induce cell injury through DAG-induced ROS generation. However, previous results suggested that DOTAP-based or other cationic lipid-based NP themselves elicited effective cell death via ROS production even in the absence of DAG in the NP (Yun et al, 2016). Moreover, few studies have provided evidence for a direct relation between DAG and ROS generation.…”

“…Moreover, cationic liposomes containing DOTAP or stearylamine have been suggested to induce ROS and subsequent cell death and/or cellular toxicity (Aramaki et al, 2000;Dokka et al, 2000;Iwaoka et al, 2006). Previously, it was reported that cargo-free NP based on cationic lipids induce ROS generation and cell death in HepG2 cells (Yun et al, 2016), which was confirmed by Sadhu et al (2017). Recently, it was also suggested that cationic peptides (such as 6K) encapsulated into cNP synergistically caused cancer cell death through the ROS generation (Yun et al, 2019).…”

Edaravone, a cytoprotective drug, enhances transgene expression mediated by lipoplexes in HepG2 cells and mice

“…Compared with viral vectors, transfection efficiency (TE) of cationic liposomes is low and clinically insufficient. One reason for this is reactive oxygen species (ROS) generation, which induces cytotoxicity (Yun et al, 2016) and affects intracellular signaling pathways (Mikhed et al, 2015). It has been suggested that the cytotoxicity of cationic carriers, especially 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)based cationic liposomes, is caused by ROS generation.…”