The development of improved methods to allow the low energy production of cubic phase forming nanoparticles (cubosomes) is highly desired. The lamellar to hexagonal and cubic phase change of these lipid nanoparticles has previously been induced via the lowering of pH and the addition of calcium ions to anionic lipid nanoparticles. We have developed a method to produce low polydispersity cubosomes without the requirement of high energy input such as shear, sonication or homogenization under physiological conditions. We have found that the simple addition of phosphate buffered saline solution to aqueous dispersions of cationic liposome vesicles made with phytantriol results in the spontaneous formation of cubosomes after vortex mixing. This finding demonstrates the potential of utilizing this technique to incorporate shear and temperature sensitive compounds into cubosomes under extremely mild conditions for biomedical and nanotechnological applications.
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