Gaining an increased understanding of the toxicity of new lipid nanoparticle formulations such as the class of cubic and hexagonal phase forming nanomaterials called cubosomes™ and hexosomes™ is crucial for their development as therapeutic agents. Surprisingly, the literature on the in vitro and in vivo toxicity of cubic and hexagonal phase forming lipid nanoparticles is negligible, despite a rapidly growing number of publications on their potential use in various therapeutic applications. In this work we have developed methods to study the in vitro cytotoxicity of two chemically distinct cubic phase nanoparticle dispersions using the lipids glycerol monooleate and phytantriol respectively. We have found that the toxicity of phytantriol cubosomes is considerably greater than that of glycerol monooleate cubosomes.The increased toxicity of phytantriol appears to result from its greater ability to disrupt the cellular membrane (haemolytic activity) and oxidative stress. This finding has significant impact and can provide useful guidelines for those conducting further research on the use of cubic phase forming lipids for therapeutic and diagnostic applications both in vitro and in vivo. † Electronic supplementary information (ESI) available. See

Monoolein forms self-assembled nanoparticles with various internally ordered nanostructures, including the lyotropic liquid crystalline inverse hexagonal and inverse bicontinuous cubic phases. This study investigated the influence of a saturated fatty acid, capric acid (decanoic acid), on the formation of different lyotropic liquid crystalline phases in monoolein-based systems. The nanoparticles were characterized by synchrotron small angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering, and zeta potential measurements. The addition of capric acid to monoolein triggered concentration dependent phase changes with the sequence evolving from an inverse primitive cubic phase to inverse double-diamond cubic, inverse hexagonal (H II ), and emulsified microemulsions. SAXS and cryo-TEM revealed the formation of both single phase and mixed phases within a nanoparticle. To understand the cytotoxicity effects of the different nanoparticles, cellular cytotoxicity and hemolysis assays were performed. Nanoparticles in emulsion and hexagonal phases were found to be less toxic than cubic phase nanoparticles. The hemolysis assays followed the same trend with cubic phase dispersions causing the highest level of hemoglobin release. In summary, this study showed that the internal lyotropic liquid crystal mesophase structure of self-assembled nanoparticles needs careful consideration in the design of drug delivery vehicles. ; Tel: +61 3 9925 4265 † Electronic supplementary information (ESI) available. See