Design and manufacturing of monodisperse and malleable phytantriol-based cubosomes for drug delivery applications

Abstract

In this study, we report the detailed characterization of phytantriol-based cubosomes submitted to stressing processes, such as lyophilization and extrusion. Lyophilization (or freeze-drying) of nanoparticles systems can be challenging with respect to preserving physicochemical properties and the biological activities of the materials. Extrusion can be used to prevent agglutination, sedimentation and Ostwald ripening or droplet coalescence, resulting in homogeneous size distribution of the formulation and smaller particle size. Samples in both ultra pure water and PBS buffer were analyzed by SAXS, DLS, NTA and electron microscopy. It was found that cubosomes hold their morphological features when lyophilized with a minor change in particle size, a decrease of 3.5% in ultra pure water and an increase of 16% in PBS buffer, as well as an increase in particle polydispersion. Regarding nanoparticle concentration, there is a considerable decrease from 4.09± 0.66 x 1012 particles/mL to 1.76± 0.66 x 1012 particles/mL in ultrapure water and from 6.67± 0.84 x 1012 particles/mL to 1.43± 0.34 x 1012 particles/mL in PBS buffer. When extruded, the cubic structure is preserved. Curiously, particle size is not affected by the pore size of the extrusion filter, as compared to liposomes, for instance. On this ground, cubosomes show great malleability even when undergoing extrusion in a 50 nm pore size filter, presenting average size of 185± 2 nm compared to 237± 5 nm of the control sample in ultra pure water and 277± 3 nm compared to 229± 1 nm in PBS buffer. Polydispersion is not affected by this process. Regarding concentration, for both systems, there is an increase from 4.09± 0.66 x 1012 particles/mL to 7.88± 0.66 x 1012 particles/mL in ultra pure water and from 6.67± 0.84 x 1012 particles/mL to 8.54± 0.15 x 1012 particles/mL in PBS buffer, indicating that larger particles are broken into smaller ones, in a rearranging process. Finally, it was shown that cubosomes are very malleable once they can undergo stressing processes without alterations in particle size or morphology. We believe that these results can improve our understanding of the cubosome structure, and can even bring new possibilities of applications due to its high malleability.