Understanding the photothermal heating effect in non-lamellar liquid crystalline systems, and the design of new mixed lipid systems for photothermal on-demand drug delivery.

Lipid-based liquid crystalline systems are showing potential as stimuli-responsive nanomaterials, and NIR-responsive gold nanoparticles have been demonstrated to provide control of transitions in non-lamellar phases. In this study, we focus on a deeper understanding of the photothermal response of both lamellar and non-lamellar phases, and new systems formed by alternative lipid systems not previously reported, by linking the photothermal heating to the bulk thermal properties of the materials. Dynamic photothermal studies were performed using NIR laser irradiation and monitoring the structural response using time resolved small angle X-ray scattering for the bulk phases and hexosomes. In addition, cryoFESEM and cryoTEM were used to visualise and assess the effect of GNR incorporation into hexagonal phase nanostructures. The ability of the systems to respond to photothermal heating was correlated with the thermal phase behaviour and heat capacities of the different structures. Access to alternative phase transitions in these systems and understanding the likely photothermal response will facilitate different modes of application of these hybrid nanomaterials for on-demand drug delivery applications.

Disposition and association of the steric stabilizer Pluronic® F127 in lyotropic liquid crystalline nanostructured particle dispersions.

Liquid crystalline nanostructured particles, such as cubosomes and hexosomes, are most often colloidally stabilised using the tri-block co-polymer Pluronic® F127. Although the effect of F127 on the internal particle nanostructure has been well studied, the associative aspects of F127 with cubosomes and hexosomes are poorly understood. In this study the quantitative association of F127 with phytantriol-based cubosomes and hexosomes was investigated. The amount of free F127 in the dispersions was determined using pressure ultra-filtration. The percentage of F127 associated with the particles plateaued with increasing F127 concentration above the critical aggregation concentration. Hence the free concentration of F127 in the dispersion medium was proposed as a key factor governing association below the CMC, and partitioning of F127 between micelles and particles occurred above the CMC. The association of F127 with the particles was irreversible on dilution. The F127 associated with both the external and internal surfaces of the phytantriol cubosomes. The effects of lipid and F127 concentration, lipid type, dilution of the dispersions and internal nanostructure were also elucidated. A greater amount of F127 was associated with cubosomes comprised of glyceryl monooleate (GMO) than those prepared using phytantriol. Hexosomes prepared using a mixture of phytantriol and vitamin E acetate (vitEA) had a greater amount of F127 associated with them than phytantriol cubosomes. Hexosomes prepared using selachyl alcohol had less F127 associated with them than phytantriol:vitEA-based hexosomes and GMO-based cubosomes. This indicated that both the lipid from which the particles are composed and the particle internal nanostructure have an influence on the association of F127 with lyotropic liquid crystalline nanostructured particles.

Transfer of lipid and phase reorganisation in self-assembled liquid crystal nanostructured particles based on phytantriol.

The internal structure of dispersed liquid crystal nanostructured particles of the V(2) and H(2) phases, termed cubosomes and hexosomes respectively, is integral to their application in the pharmaceutical, agricultural and food industries. However the nanostructure is susceptible to change upon incorporation of other lipids and hence it is important to understand the potential for interparticle lipid transfer for such particles when they encounter a particle of dissimilar lipid content. Using time resolved synchrotron small angle X-ray scattering, we have investigated the transfer of material between cubosomes composed of phytantriol with three different particle types of dissimilar composition, (i) hexosomes and (ii) emulsified microemulsion composed of phytantriol and vitamin E acetate, and (iii) cubosomes prepared from glycerol monooleate. It was found that material was transferred between the different dispersed nanostructured particles, with the transfer being caused by compositional ripening. Somewhat counter-intuitively the transfer was bidirectional with phytantriol being more rapidly transferred than the minor component vitamin E acetate. The greater lipophilicity of vitamin E acetate supports previous studies suggesting greater mobility for the less lipophilic components, regardless of the more efficient transfer route to achieve uniform composition. When particles comprising lipids with similar lipophilicities were mixed, the transfer was limited and did not achieve completion; a phase change between cubic nanostructures required to achieve complete mixing provides an apparent barrier to further compositional ripening. The conclusions from this study provide additional support to lipid transfer mechanisms, and highlight some subtleties in using dissimilar lipid mixtures in e.g. food applications.

Nonequilibrium effects in self-assembled mesophase materials: unexpected supercooling effects for cubosomes and hexosomes.

Polar lipids often exhibit equilibrium liquid crystalline structures in excess water, such as the bicontinuous cubic phases (Q(II)) at low temperatures and inverse hexagonal phase (H(II)) at higher temperatures. In this study, the equilibrium and nonequilibrium phase behavior of glyceryl monooleate (GMO) and phytantriol (PHYT) systems in excess water were investigated using both continuous heating and cooling cycles, and rapid temperature changes. Evolution of the phase structure was followed using small-angle X-ray scattering (SAXS). During cooling, not only was supercooling of the liquid crystalline systems by up to 25 degrees C observed, but evidence for nonequilibrium phase structures (not present on heating; such as the gyroid cubic phase only present at low water content in equilibrium) was also apparent. The nonequilibrium phases were surprisingly stable, with return to equilibrium structure for dispersed submicrometer sized particle systems taking more than 13 h in some cases. Inhibition of phase nucleation was the key to greater supercooling effects observed for the dispersed particles compared to the bulk systems. These findings highlight the need for continued study into the nonequilibrium phase structures for these types of systems, as this may influence performance in applications such as drug delivery.

Liquid crystalline coated drug particles as a potential route to long acting intravitreal steroids.

The aim of this study was to investigate the potential for coating drug particles with liquid crystalline lipids with a view to modifying drug dissolution behaviour in the particle form. Firstly, dissolution of a simple salicylic acid layer on a microscope slide, as a model system was shown to be hindered by the liquid crystal layer and was sensitive to the type of liquid crystal nanostructure present. Particles of sodium salicylate (hydrophilic) and triamcinolone acetonide (hydrophobic) were produced, and lipids applied to the drug surface using either mechanofusion or co-spray drying approaches. The coated sodium salicylate particles dissolved extremely rapidly. Triamcinolone acetonide particles on the other hand dissolved very slowly compared to uncoated triamcinolone acetonide particles, which indicated that the coating was in fact intact, and that drug solubility in the aqueous channels likely controlled the transport of drug into the dissolution medium. Whilst more investigation is required, these initial studies demonstrate a potentially useful strategy for controlling drug dissolution for applications such as intravitreal steroid injections.