Irena Krodkiewska

Protic Ionic Liquids: Physicochemical Properties and Behavior as Amphiphile Self-Assembly Solvents

The physicochemical properties of 22 protic ionic liquids (PILs) and 6 protic molten salts, and the self-assembly behavior of 3 amphiphiles in the PILs, are reported. Structure-property relationships have been explored for the PILs, including the effect of increasing the substitution of ammonium cations and the presence of methoxy and hydroxyl moieties in the cation. Anion choices included the formate, pivalate, trifluoroacetate, nitrate, and hydrogen sulfate anions. This series of PILs had a diverse range of physicochemical properties, with ionic conductivities up to 51.10 mS/cm, viscosities down to 5.4 mPa.s, surface tensions between 38.3 and 82.1 mN/m, and densities between 0.990 and 1.558 g/cm3. PILs were designed with various levels of solvent cohesiveness, as quantified by the Gordon parameter. Fourteen PILs were found to promote the self-assembly of amphiphiles. High-throughput polarized optical microscopy was used to identify lamellar, hexagonal, and bicontinuous cubic amphiphile self-assembly phases. The presence and extent of amphiphile self-assembly have been discussed in terms of the Gordon parameter.

Protic Ionic Liquids and Ionicity

Protic ionic liquids (PILs) are a subset of ionic liquids formed by the equimolar mixing of a Bronsted acid and a Bronsted base. PILs have been categorized as poor ionic liquids. However, the issue of assessing the ionicity of PILs is still a matter of debate. In this work we studied some physicochemical properties of three chosen PILs, namely, ethanolammonium acetate (EOAA), 2-methylbutylammonium formate (2MBAF), and pentylammonium formate (PeAF), at the initial equimolar (stoichiometric) acid/base ratio and in the presence of excess acid and base. DSC phase-transition studies along with NMR, IR, and Raman spectroscopy were performed on the chosen PILs. The results are discussed in terms of the degree of ionization (extent of proton transfer from the Bronsted acid to Bronsted base), and the possibility of the formation of polar 1:1 complexes and larger aggregates in the neat stoichiometric PILs.

Soft ordered mesoporous materials from nonionic isoprenoid-type monoethanolamide amphiphiles self-assembled in water

The thermal and lyotropic liquid crystalline phase behaviour of a series of amide and monoethanolamide amphiphiles with isoprenoid-type hydrocarbon chains has been investigated. The amphiphilic nature of these molecules combined with their ability to form nanostructured self-assemblies makes them ideal candidates as delivery vehicles of bioactive molecules. For both families of molecules, increased branching in the hydrophobic chain, associated with increasing chain length, results in a decreased melting point. The melting points of the amides are significantly higher than their monoethanolamide homologues. Interestingly, both hexahydrofarnesoyl (H-farnesoyl) and phytanoyl monoethanolamide exhibit a glass transition temperature at around −72 °C to −74 °C. H-Farnesoyl and phytanoyl monoethanolamide form lyotropic liquid crystalline phases in water, whilst H-farnesoyl and phytanoyl amide form a spontaneous emulsion at the amphiphile–water interface. In particular, at room temperature H-farnesoyl and phytanoyl monoethanolamide form the Schwarz diamond (QIID) and the Schoen gyroid (QIIG) bicontinuous cubic phases which are retained down to temperatures as low as 1 °C. Furthermore, phytanoyl monoethanolamide displays a QIID, QIIG and inverse hexagonal phase (HII) at physiological temperature. Both phytanoyl and H-farnesoyl monoethanolamide form mesoporous cubic phases at room temperature that are easily dispersed into cubosomes. The robust nature of the nanostructured phase formation of these two monoethanolamides over a wide range of temperatures makes them ideal candidates for a variety of applications.

Ordered Nanostructured Amphiphile Self-Assembly Materials from Endogenous Nonionic Unsaturated Monoethanolamide Lipids in Water

The self-assembly, solid state and lyotropic liquid crystalline phase behavior of a series of endogenous n-acylethanolamides (NAEs) with differing degrees of unsaturation, viz., oleoyl monoethanolamide, linoleoyl monoethanolamide, and linolenoyl monoethanolamide, have been examined. The studied molecules are known to possess inherent biological function. Both the monoethanolamide headgroup and the unsaturated hydrophobe are found to be important in dictating the self-assembly behavior of these molecules. In addition, all three molecules form lyotropic liquid crystalline phases in water, including the inverse bicontinuous cubic diamond (Q(II)(D)) and gyroid (Q(II)(G)) phases. The ability of the NAEs to form inverse cubic phases and to be dispersed into ordered nanostructured colloidal particles, cubosomes, in excess water, combined with their endogenous nature and natural medicinal properties, makes this new class of soft mesoporous amphiphile self-assembly materials suitable candidates for investigation in a variety of advanced multifunctional applications, including encapsulation and controlled release of therapeutic agents and incorporation of medical imaging agents.

Monodisperse nonionic phytanyl ethylene oxide surfactants: high throughput lyotropic liquid crystalline phase determination and the formation of liposomes, hexosomes and cubosomes

The phase behaviour (both neat and lyotropic) and toxicity of eight new ethylene oxide amphiphiles (EO = 1 to 8) with a single phytanyl chain (3,7,11,15 tetramethylhexadecyl) is reported. There is a discontinuity at EO > 4 where the neat and lyotropic behaviour exhibit a tipping point which is qualitatively rationalised in terms of the molecular geometry of the surfactant. Below four EO units the behaviour of the neat surfactants show only a glass transition, Tg ∼ −90 °C. Above four EO units crystallisation (Tcrys) and crystal-isotropic liquid (Tm) transitions are also observed. These increase monotonically with the hydrophilicity of the surfactant; consistent with the greater cohesiveness of the molecules due to van der Waals interactions. The increase in hydrophilicity corresponds to a decrease in curvature of the surfactant layer towards water. However, the exaggerated splay of the phytanyl chain is effective in promoting various self-assembled structures with inverse cubic and hexagonal phases preferred below ambient temperatures for EO < 4, and these are stable to dilution. Variation of the EO head group length promotes an interesting diversity of cubic phases, with an inverse micellar cubic phase (Fd3m) present for EO = 2 and the bicontinuous gyroid cubic (Ia3d) and double diamond cubic (Pn3m) phases present at higher ethoxylation. DIT-NIR microspectroscopy provided a high throughput, low volume, fast equilibrating method for obtaining the approximate partial temperature-composition phase diagrams of the binary systems with water. The toxicity of colloidal dispersions of these amphiphiles was assayed against normal breast epithelial (HMEpiC) and breast cancer (MCF7) cell lines. The IC50 of the EO amphiphiles was similar in both cell lines with moderate toxicity ranging from ∼80–110 μM in an in vitro cell viability assay.

Submicron Dispersions of Hexosomes Based on Novel Glycerate Surfactants

Glycerate-based surfactants are a new class of swelling amphiphiles which swell to a finite degree with water. Among this class of surfactants, oleyl (cis-octadec-9-enyl) glycerate is very similar in structure to a well characterized mesophase-forming lipid, glyceryl monooleate (GMO). Despite the similar structural characteristics, a subtle change in connectivity of the ester bond substantially alters the binary surfactant-water phase behaviour. Whereas the phase behaviour of GMO is diverse and dominated by cubic phases, the phase behaviour of oleyl glycerate and a terpenoid analogue phytanyl (3,7,11,15-tetramethyl-hexadecane) glycerate is much simplified. Both exhibit an inverse hexagonal phase (H-II), which is stable to dilution with excess water, and an inverse micellar phase (L-II) at ambient temperatures. The inverse hexagonal phases formed by oleyl glycerate and phytanyl glycerate have been characterized using SAXS. Analogous to GMO cubosomes, the inverse hexagonal phase of phytanyl glycerate has been dispersed to form hexagonally facetted particles, termed hexosomes, whose structure has been verified using cryo-TEM.

Endogenous nonionic saturated monoethanolamide lipids: solid state, lyotropic liquid crystalline, and solid lipid nanoparticle dispersion behavior.

The n-acylethanolamides (NAEs) are a family of naturally occurring monoethanolamide containing lipids that display a variety of interesting biological properties. In this study, some physicochemical properties of a series of saturated monoethanolamide lipids with increasing hydrocarbon chain length (lauroyl, myristoyl, palmitoyl, and stearoyl) have been investigated. Temperature induced phase transitions for these NAEs indicate that both the monoethanolamide headgroups and the unsaturated hydrophobic tails play a role in the melting behavior of these lipids. All four lipids examined demonstrate the presence of at least three different polymorphic crystal forms. Transitions in crystal structure can be induced via heating and visualized with polarized optical microscopy. At room and physiological temperature, the four NAEs are solid lamellar crystalline materials. All four molecules form lyotropic liquid crystalline phases in water, albeit at relatively high temperatures, including the lamellar liquid crystalline phase and at least two isotropic phases. Lamellar crystalline palmitoyl monoethanolamide was dispersed as solid lipid nanoparticles (SLNs). The cytotoxicity of these SLNs toward human mammary epithelial cells (HMEpiC) and the MCF7 breast cancer cell line was assessed at physiological temperature. The palmitoyl monoethanolamide SLNs showed little to no toxicity to the HMEpiC even at a concentration of 30 microM. At concentrations above 3 microM, the HMEpiC population was reduced by less than 15%, while the MCF7 population was reduced by approximately 20-30%. The endogenous nature and natural medicinal properties make this series of lipids ideal candidates for further investigation as solid lipid nanoparticle drug delivery systems.

Monodisperse nonionic isoprenoid-type hexahydrofarnesyl ethylene oxide surfactants: High throughput lyotropic liquid crystalline phase determination

The neat and lyotropic phase behavior of eight new ethylene oxide amphiphiles (EO = 1-8) with a hexahydrofarnesyl chain (3,7,11-trimethyldodecyl) and narrow polydispersity (>98.5% purity) is reported. Below five EO units the behavior of the neat surfactants show only a glass transition, Tg ∼ -90 °C. Above four EO units, crystallization (Tcrys) and crystal-isotropic liquid (Tm) transitions are also observed that increase with degree of ethoxylation of the surfactant headgroup. The lyotropic liquid crystalline phase behavior spans a complex spectrum of surfactant-water interfacial curvatures. Specifically, inverse phases are present below ambient temperatures for EO < 4, with HFarn(EO)2 exhibiting an inverse hexagonal (H(II)) phase stable to dilution. The phase diagram of HFarn(EO)3 displays both the gyroid (Ia3d) and double diamond (Pn3m) inverse bicontinuous cubic phases, with the latter being thermodynamically stable in excess water within the physiological regime. There is a strong preference for planar bilayer structures at intermediate headgroup ethoxylation, with the crossover to normal phases occurring at HFarn(EO)(7-8) which exhibits normal hexagonal (H(I)) and cubic (Q(I)) phases at ambient temperatures. The toxicity of colloidal dispersions of these EO amphiphiles was assayed against normal breast epithelial (HMEpiC) and breast cancer (MCF7) cell lines. The IC50 of the EO amphiphiles was similar in both cell lines with moderate toxicity ranging from ca. <5 to 140 μM in an in vitro cell viability assay. Observations are qualitatively rationalized in terms of the molecular geometry of the surfactant. The physicochemical behavior of the HFarnesyl ethylene oxide amphiphiles is compared to other ethylene oxide surfactants.

Synthesis of unsymmetrically 4-substituted 2,2′-bipyridines

Abstract Pyridin-2-nitrile oxide was generated in situ and reacted with 2-substituted but-1-ene-4-ols to give 5-substituted 5-(2-hydroxyethyl)-3-(pyrid-2-yl)-Δ 2 -isoxazolines. The isoxazolines were reductively ring-opened with LiAlH 4 to give 2-(3-substituted-1-amino-3,5-dihydroxypentyl)-pyridines, which were subjected to Dess-Martin oxidation with concomitant dehydration to give 4-substituted 2,2′-bipyridines.

Anandamide and analogous endocannabinoids: a lipid self-assembly study

Anandamide, the endogenous agonist of the cannabinoid receptors, has been widely studied for its interesting biological and medicinal properties and is recognized as a highly significant lipid signaling molecule within the nervous system. Few studies have, however, examined the effect of the physical conformation of anandamide on its function. The study presented herein has focused on characterizing the self-assembly behaviour of anandamide and four other endocannabinoid analogues of anandamide, viz., 2-arachidonyl glycerol, arachidonyl dopamine, 2-arachidonyl glycerol ether (noladin ether), and o-arachidonyl ethanolamide (virodhamine). Molecular modeling of the five endocannabinoid lipids indicates that the highly unsaturated arachidonyl chain has a preference for a U or J shaped conformation. Thermal phase studies of the neat amphiphiles showed that a glass transition was observed for all of the endocannabinoids at ∼ −110 °C with the exception of anandamide, with a second glass transition occurring for 2-arachidonyl glycerol, 2-arachidonyl glycerol ether, and virodhamine (−86 °C, −95 °C, −46 °C respectively). Both anandamide and arachidonyl dopamine displayed a crystal-isotropic melting point (−4.8 and −20.4 °C respectively), while a liquid crystal-isotropic melting transition was seen for 2-arachidonyl glycerol (−40.7 °C) and 2-arachidonyl glycerol ether (−71.2 °C). No additional transitions were observed for virodhamine. Small angle X-ray scattering and cross polarized optical microscopy studies as a function of temperature indicated that in the presence of excess water, both 2-arachidonyl glycerol and anandamide form co-existing QIIG (gyroid) and QIID (diamond) bicontinuous cubic phases from 0 °C to ∼20 °C, which are kinetically stable over a period of weeks but may not represent true thermodynamic equilibrium. Similarly, 2-arachidonyl glycerol ether acquired an inverse hexagonal (HII) phase in excess water from 0 °C to 40 °C, while virodhamine and arachidonyl dopamine exist as an isotropic L2 phase, even at very low temperatures. Due to their preferential conformation and lipid self-assembly behaviour, all five endocannabinoids constitute high curvature lipids that can impart membrane stress within a cell membrane which has been linked to a number of membrane and membrane protein associated processes.