Matthew Lawrence Lynch

Dry powder precursors of cubic liquid crystalline nanoparticles (cubosomes

Cubosomes are dispersed nanostructured particles of cubic phase liquid crystal that have stimulated significant research interest because of their potential for application in controlled-release and drug delivery. Despite the interest, cubosomes can be difficult to fabricate and stabilize with current methods. Most of the current work is limited to liquid phase processes involving high shear dispersion of bulk cubic liquid crystalline material into sub-micron particles, limiting application flexibility. In this work, two types of dry powder cubosome precursors are produced by spray-drying: (1) starch-encapsulated monoolein is produced by spray-drying a dispersion of cubic liquid crystalline particles in an aqueous starch solution and (2) dextran-encapsulated monoolein is produced by spray-drying an emulsion formed by the ethanol–dextran–monoolein–water system. The encapsulants are used to decrease powder cohesion during drying and to act as a soluble colloidal stabilizer upon hydration of the powders. Both powders are shown to form (on average) 0.6 μm colloidally-stable cubosomes upon addition to water. However, the starch powders have a broader particle size distribution than the dextran powders because of the relative ease of spraying emulsions versus dispersions. The developed processes enable the production of nanostructured cubosomes by end-users rather than just specialized researchers and allow tailoring of the surface state of the cubosomes for broader application.

Enhanced loading of water-soluble actives into bicontinuous cubic phase liquid crystals using cationic surfactants

Over the past few years, bicontinuous cubic phase liquid crystals have been investigated for their applicability to controlled delivery of active ingredients. These liquid crystals have a unique structure of interpenetrating channels of water and lipid that provides compatibility with water-soluble, lipid-soluble, and amphiphilic active ingredients. Actives tend to be stable in the matrix and the structure provides control over their release. However, loading of water-soluble actives is difficult. It is especially problematic for cubic phase liquid crystal dispersions (cubosomes) given the large fraction of bulk water present. The inherent problem reflects the preference of the water-soluble actives to associate with water rather than with the liquid crystals. Ideally, the properties of the liquid crystal can be tailored to enhance the association of the liquid crystal with the active, thereby increasing loading. It is found that the inclusion of surfactant into the liquid crystal can provide this function. This work illustrates the enhanced loading of negatively charged, water-soluble active ketoprofen by the inclusion of positively charged surfactants into the liquid crystal. Loading differences resulting from the inclusion of dioctadecyl dimethyl ammonium chloride (DODMAC) and dioctadecyl ammonium chloride (DOAC) into the liquid crystal demonstrate that the magnitude of the enhancement is dependent on the surfactant concentration and the steric nature of its head group. The upper limit of the enhancement is explored by the inclusion of di(canola ethyl ester) dimethyl ammonium chloride (DEEDAC) formulated to greater than 20 wt% and demonstrates an order-of-magnitude enhancement over previous reports. This work provides a practical demonstration of functionalizing cubic phase liquid crystals and lays the framework for future work.

Bicontinuous liquid crystals

Preface Introduction Acknowledgments Bicontinuous Cubic Liquid Crystalline Materials: A Historical Perspective and Modern Assessment Kare Larsson Intermediate Phases Michael C. Holmes and Marc S. Leaver Cubic Phases and Human Skin: Theory and Practice Steven Hoath and Lars Norlen The Relationship between Bicontinuous Inverted Cubic Phases and Membrane Fusion D.P. Siegel Aspects of the Differential Geometry and Topology of Bicontinuous Liquid-Crystalline Phases Robert W. Corkery Novel L3 Phases and Their Macroscopic Properties R. Beck and H. Hoffmann Bicontinuous Cubic Phases of Lipids with Entrapped Proteins: Structural Features and Bioanalytical Applications Valdemaras Razumas NMR Characterization of Cubic and Sponge Phases Olle Soderman and Bjorn Lindman Synthesis of Controlled-Porosity Ceramics Using Bicontinuous Liquid Crystals Stephen E. Rankin Controlled Release from Cubic Liquid-Crystalline Particles (Cubosomes) Ben J. Boyd Membrane Protein Crystallization in Lipidic Bicontinuous Liquid Crystals Martin Caffrey Application of Monoglyceride-Based Liquid Crystals as Extended-Release Drug Delivery Systems Chin-Ming Chang and Roland Bodmeier Cubic Liquid-Crystalline Particles as Protein and Insoluble Drug Delivery Systems Hesson Chung, Seo Young Jeong, and Ick Chan Kwon Bicontinuous Liquid Crystalline Mesophases-Solubilization Reactivity and Interfacial Reactions Nissim Garti Applications of Lipidic Cubic Phases in Structural Biology Ehud M. Landau The Controlled Release of Drugs from Cubic Phases of Glyceryl Monooleate Jaehwi Lee and Ian W. Kellaway Index

Correlation of Amine Number and pDNA Binding Mechanism for Trehalose-Based Polycations

Glycopolymers with repeat units comprised of the disaccharide trehalose and an oligoamine of increasing amine have been previously synthesized by our group and shown to efficiently deliver pDNA (plasmid DNA) to HeLa cells while remaining relatively nontoxic. Complexes formed between the most amine-dense of these polycations and pDNA were also found to be relatively stable in serum and have low aggregation, which is desirable for in vivo gene delivery. To lend insight into these interesting results, this study was aimed at investigating the binding strength and mechanism of interaction between these macromolecules, via isothermal titration calorimetry (ITC) and ethidium bromide exclusion assays. The size of these pDNA-polymer complexes, or polyplexes, at various states of formation was determined through light scattering and zeta-potential measurements. Varying degrees of pDNA secondary structure change occurred upon interaction with the polymers, as evidenced by circular dichroism spectra through increasing molar ratios of polymer amine to DNA phosphate, and Fourier transform infrared (FT-IR) results demonstrated stronger electrostatic binding with the phosphate backbone with the least amine-dense of the series. It was concluded that, depending on the number of secondary amines in the repeat unit, these polymers interact with pDNA via different mechanisms with varying extents of electrostatic interaction and hydrogen bonding. These differing mechanisms may affect the ability of trehalose to serve as a deterrent against aggregation in serum conditions and lend insight into the roles of polymer-pDNA binding during the complex transfection process.

Amide Spacing Influences pDNA Binding of Poly(amidoamine)s

Previously, a series of three poly(amidoamine)s was designed and synthesized by polymerizing oxylate, succinate, or adipate groups with pentaethylenehexamine. These resulting polymers (named O4, S4, and A4, respectively) were created as models to poly(glycoamidoamine) nucleic acid delivery agents to understand how the absence of hydroxyl groups and changes in the amide bond spacing affect polymer degradation, plasmid DNA (pDNA) encapsulation, toxicity, and transfection efficiency in vitro. To understand differences in the biological properties quantitatively, we investigated the mechanism of interaction between these macromolecules and pDNA to reveal differences in pDNA binding affinity and complexation as a function of structure. Herein, several analytical techniques such as dynamic light scattering, circular dichroism, thermal gravimetric analysis, isothermal titration calorimetry (ITC), and ethidium bromide exclusion assays were used to examine the pDNA binding strength of O4, S4, and A4, and the results are compared with the previous series of poly(glycoamidoamine)s. It was found that the length of the amide bond spacer in these nonhydroxylated analogs did affect the pDNA binding affinity to a small degree (binding affinity order A4 > S4 > O4). The increase in binding affinity with longer methylene spacer was not due to hydrophobic interactions but likely from optimization in electrostatic interactions and hydrogen bond formation. Even though O4 was revealed to have the lowest pDNA binding affinity of the nonhydroxylated series, this polymer yields the highest cellular transfection efficiency, which is likely an effect of the faster hydrolysis rate.

Calorimetric Study of the Adsorption of Poly(ethylene oxide) and Poly(vinyl pyrrolidone) onto Cationic Nanoparticles

The adsorption of two polymers, poly(ethylene oxide) (PEO) and poly(vinyl pyrrolidone) PVP, onto cationic nanoparticles suspended in both water and a buffer solution is studied via isothermal titration calorimetry (ITC). These are model systems studied previously to understand polymer-induced phase separation and bridging flocculation in the protein limit. ITC measurements provide critical information for rationalizing the effects of polymer type and added buffer solution on the loss of stability of nanoparticle-polymer solutions. For PEO, weak segmental adsorption energies of approximately 0.2k(B)T for PEO in water and buffer are consistent with depletion phase separation. For PVP in water, segmental adsorption energies on the order of approximately 1.6k(B)T support the observed bridging flocculation, whereas a weaker adsorption energy of approximately 0.7k(B)T for PVP in buffer is consistent with depletion phase separation. Multilayer adsorption is observed in buffer solutions, which corroborates a measured increase in the hydrodynamic size of the polymer-nanoparticle complexes with added buffer. The entropy of adsorption is calculated from equilibrium constants determined by combining ITC and adsorption isotherms.

Nanovesicle formation and microstructure in aqueous ditallowethylesterdimethylammonium chloride (DEEDMAC) solutions

HYPOTHESIS Surfactant vesicles composed of ditallowethylesterdimethylammonium chloride (DEEDMAC), a cationic double tail surfactant, are commonly present in personal care industrial formulations such as fabric softeners. There is significant interest in formulating vesicle dispersions, investigation of stability, characterization of their structure and flow properties due to the biodegradable nature of DEEDMAC. EXPERIMENTS We investigate the formation and structure of unilamellar nanovesicles having a shell made of DEEDMAC and a core containing water. We use bright field optical microscopy to elucidate the formation mechanism, and a combination of small angle neutron scattering (SANS), cryogenic transmission electron microscopy (cryo-TEM), viscometry, densitometry, dynamic light scattering (DLS), small angle X-ray scattering (SAXS) and zeta potential measurements to determine the nanostructure of well-defined surfactant nanovesicles (∼15 nm diameter). FINDINGS We report methods for the determination of volume fraction of nanovesicles and vesicle density, which are crucial for quantitative estimation of nanovesicle performance in practical applications and for predicting vesicle stability. The nanovesicle volume fraction can be obtained directly from the intrinsic viscosity and density. The robust method presented here is simple and effective as confirmed by quantitative agreement of the results with independent SANS measurements.