Monoolein cubic phase including in situ ionically gelled alginate and its salt-responsive release property

Salt-responsive monoolein (MO) cubic phase was prepared by in situ ionically gelling alginate contained in its water channels. On the TEM micrographs, bilayers, and water channels, characteristic of MO cubic phase were observed, and alginate and CaCl₂ had little effect on the structure. According to the differential scanning calorimetric thermogram, the cubic-to-hexagonal phase transition temperature of the cubic phase containing CaCl₂ solution was 46.8°C and it was much lower than that of the cubic phase containing distilled water, 60.5°C. The transition temperature was not significantly affected by alginate. The phase transition temperatures measured by the calorimetric analysis were in accordance with those determined by polarized optical microscopy. An initial burst release of dye (i.e., amaranth) was observed when the gelled alginate was not contained in the water channel of the cubic phase. A sustained release was obtained with the cubic phase containing the gelled alginate. The release of dye loaded in the cubic phase containing the gelled alginate was significantly promoted when the cubic phase came into contact with PBS (10?mM, pH 7.4), possibly because the multivalent cation (Ca²⁺) bound to alginate chains could be replaced by the monovalent cation (Na⁺).     

In vitro skin permeation of cubosomes containing water soluble extracts of Korean barberry

The monoolein (MO) cubic phases containing water soluble extract (WSE) from Berberis koreana (Korean barberry) were prepared by hydrating the molten MO with aqueous solutions of WSE (0.5, 1.0, and 1.5%). The phase transition temperature of cubic phase containing WSE (∼70°C) was almost the same as that of WSE-free MO cubic phase that indicates that WSE was immobilized in the water channels of the cubic phase and did not affect its structure. The release of WSE from the cubic phase fits the first order process. The cubosomes were obtained by micronizing the cubic phase in a sonicator using Pluronic F127 as a dispersant. The cubosomes were stable in size at the ethanol concentration ≲16%. When compared with WSE solution in phosphate-buffered saline (10 mM, pH 7.4), in vitro skin permeation of WSE in the cubosomes was enhanced by about two times.     

Monoolein cubic phases containing hydrogen peroxide

Monoolein (MO) cubic phases were prepared by hydrating MO using distilled water or 12 wt.% H₂O₂ solution so that the content of aqueous phase in the cubic phase is 30 wt.%. The thermal transition of the isotropic cubic phase to reversed hexagonal phase was observed on a polarizing photomicroscope and the transition temperature was found to be around 65 °C on a differential scanning calorimeter (DSC). Small-angle X-ray scattering (SAXS) patterns indicated the cubic phases had diamond surfaces. The cubic phase released H₂O₂ into an aqueous phase in a saturation manner so that approx. 50% of total loaded H₂O₂ release in the first 10 h and thereafter relatively slow was observed over 40 h. The cubic phase was stable at 45 °C for 56 days before it broke down into an oily phase and an aqueous phase in 70 days. According to ¹H NMR spectrum, glycerol moiety and ---CH₂=CH₂--- of the oily phase were detected less in number than those of intact MO. Therefore, the hydrolysis and the oxidation of MO would be responsible for the breakdown of the cubic phase. The tensile adhesive forces of the cubic phases were higher than a skin-adhesive patch prepared using polyacrylate. The cubic phase containing H₂O₂ could be used as a topical disinfected gel for a wounded skin.     

Monoolein cubic phase containing disulfide proteinoid and its reduction-responsive release property

Monoolein (MO) cubic phase, which can release its payload in answering to reducing condition, was prepared by including a disulfide proteinoid composed of Asp, DL-leucine (Leu), and dithiodipropionic acid (DTPA) in its water channel. On the TEM micrograph, the cubic phase could accommodate the proteinoid with no change in its bilayer structure. The phase transition temperature of the cubic phase was about 58.7°C, and it was little affected by the proteinoid. The release degree of allura red loaded in the cubic phase was higher at a higher dithiothreitol (DTT) concentration. The proteinoid would be broken down by the reducing agent, facilitating the release.     

Effect of tris(hydroxymethyl) aminomethane on the phase behavior of poly(ethylene imine)/cinnamic acid conjugate and the release property of cubic phase containing the conjugate

The upper critical solution temperature (UCST) of poly(ethylene imine)/cinnamic acid (PEI/CA) conjugate decreased as the tris(hydroxymethyl) aminomethane (THMAM) concentration increased. On the optical micrographs of PEI/CA mixture solutions at 25°C, the microspheres were found when the THMAM concentration was 0?mM and 100?mM, but hardly found at 200?mM. Monoolein (MO) cubic phase containing PEI, CA, and THMAM exhibited a bilayer structure on the TEM micrograph. The release degree of methylene blue loaded in the cubic phase was not strongly dependent on THMAM concentration at 25°C and 37°C, but strongly dependent on the concentration at 50°C.     

Thermo- and UV Photo-Triggerable Monoolein Cubic Phase Bearing Poly(Hydroxyethyl Acrylate-co-Coumaryl Acrylate-co-Octadecyl Acrylate)

Thermo- and UV photo-triggerable monoolein (MO) cubic phases were developed by incorporating poly(hydroxyethyl acrylate-co-coumaryl acrylate-co-octadecyl acrylate) (P(HEA-CA-ODA)) in the cubic phases. P(HEA-CA-ODA)s, for which the HEA/CA/ODA molar ratio was 98.6:0:1.4, 96.7:2.0:1.3, 96.2:2.6:1.2, 95:3.8:1.2, and 92.8:6.1:1.1, calculated on the ¹H NMR spectra, were prepared by a free radical reaction. The air–water interfacial tension was inversely proportional to the CA content of the copolymer. The copolymers for which the CA content was 2.6%, 3.8%, and 6.1% exhibited their phase transition temperature in an aqueous solution in the temperature range from 25°C to 40°C. As the CA content was more, the temperature sensitivity was higher and the phase transition temperature was lower. The UV light (254 nm, 6 W)-induced dimerization degree of CA was proportional to its content in the copolymers. The release of fluorescein isothiocyanate-dextran from cubic phases containing P(HEA/CA/ODA)s was promoted by UV light irradiation, possibly due to the photo-induced collapse of the copolymer chains. The release from cubic phases incorporating copolymers, for which the CA content was 3.8% and 6.1%, was enhanced by increasing the releasing medium temperature from 23°C to 37°C, possibly due to the thermal collapse of the copolymer chains.     

Tripolyphosphate-responsive release property of monoolein cubic phase containing sodium dodecyl sulfate and oligo chitosan

Tripolyphosphate (TPP)-responsive MO cubic phase was prepared by immobilizing oligo chitosan in the water channel through its electrostatic attraction with sodium dodecyl sulfate (SDS). The phase transition temperature (PTT) increased with increasing the content of SDS. The PTT of cubic phase whose SDS content was 0%, 0.21%, 0.42%, 0.84%, and 1.68%, determined by polarized microscopy, was about 69.5°C, 72°C, 75°C, 80.5°C, and 95°C, respectively. The PTT did not markedly deviate from that determined by differential scanning calorimetry. The release degree for 72 h of dye (i.e., amaranth and methylene blue) was dependent on the pH value of release medium (pH 3.0 and pH 7.0). Moreover, the release degree significantly increased when the TPP concentration in the release medium increased to 0.4% (w/v). Oligo chitosan was electrostatically complexed with TPP and the complexation took place extensively at the oligo chitosan/TTP mass ratio of 1:0.125 and 1:0.25 and at the oligo chitosan concentration of 1.6% (w/v), evidenced by optical spectroscopy and scanning electron microscopy. It was thought that the complexation was responsible for the TPP concentration-dependent release.     

Glucose-Responsive Monoolein Cubic Phase Containing Glucose Oxidase

Glucose-responsive monoolein (MO) cubic phase was prepared by immobilizing proteinoid composed of Asp and Leu (PAL) and hydrophobically modified glucose oxidase (HmGOD) onto the MO bilayers. The hydrodynamic mean diameter of PAL aggregate in aqueous solution decreased with increasing the pH value. The number of pamitic acid residue per one molecule of HmGOD was determined to be 6.3 by a calorimetric method. HmGOD could acidify glucose solution in a few hours, possibly because it converted glucose to gluconic acid. PAL- and HmGOD-immobilized MO cubic phase was prepared by hydrating MO melt with the mixture aqueous solution of PAL and HmGOD. The cubic phase exhibited its phase transition around 62.5°C, determined by polarizing microscopy. The release of carboxylic fluorescein (CF) from the cubic phase was suppressed when the pH value of release medium decreased, possibly because PAL can aggregate more at a lower pH value. The release was suppressed when glucose concentration increased, possibly because the release medium can be more acidified and PAL will be more aggregated at a higher glucose concentration. The cubic phase could be used as a drug carrier which releases its content in a sustained manner when the glucose concentration is abnormally high.     

Low-pH-induced transformation of bilayer membrane into bicontinuous cubic phase in dioleoylphosphatidylserine/monoolein membranes

Cubic biomembranes, nonbilayer membranes with connections in three-dimensional space that have a cubic symmetry, have been observed in various cells. Interconversion between the bilayer liquid-crystalline (L(alpha)) phase and cubic phases attracted much attention in terms of both biological and physicochemical aspects. Herein we report the pH effect on the phase and structure of dioleoylphosphatidylserine (DOPS)/monoolein (MO) membranes under a physiological ion concentration condition, which was revealed by small-angle X-ray scattering (SAXS) measurement. At neutral pH, DOPS/MO membranes containing high concentrations of DOPS were in the L(alpha) phase. First, the pH effect on the phase and structure of the multilamellar vesicles (MLVs) of the DOPS/MO membranes preformed at neutral pH was investigated by adding various low-pH buffers into the MLV suspension. For 20%-DOPS/80%-MO MLVs, at and below pH 2.9, a transition from the L(alpha) to cubic (Q(224)) phase occurred within 1 h. This phase transition was reversible; a subsequent increase in pH to a neutral one in the membrane suspension transformed the cubic phase into the original L(alpha) phase. Second, we found that a decrease in pH transformed large unilamellar vesicles of DOPS/MO membranes into the cubic phase under similar conditions. We have proposed the mechanism of the low-pH-induced phase transition and also made a quantitative analysis on the critical pH of the phase transition. This finding is the first demonstration that a change in pH can induce a reversible phase transition between the L(alpha) and cubic phases of lipid membranes within 1 h.     

Synthesis,characterization, and evaluation of enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels for colon‐specific drug delivery

The enzymatically degradable poly(N‐isopropylacrylamide‐co‐acrylic acid) hydrogels were prepared using 4,4^′‐bis(methacryloylamino)azobenzene (BMAAB) as the crosslinker. It was found that the incorporated N‐isopropylacrylamide (NIPAAm) monomer did not change the enzymatic degradation of hydrogel, but remarkably enhanced the loading of protein drug. The hydrogels exhibited a phase transition temperature between 4°C (refrigerator temperature) and 37°C (human body temperature). Bovine serum albumin (BSA) as a model drug was loaded into the hydrogels by soaking the gels in a pH 7.4 buffer solution at 4°C, where the hydrogel was in a swollen status. The high swelling of hydrogels at 4°C enhanced the loading of BSA (loading capability, ca. 144.5 mg BSA/g gel). The drug was released gradually in the pH 7.4 buffer solution at 37°C, where the hydrogel was in a shrunken state. In contrast, the enzymatic degradation of hydrogels resulted in complete release of BSA in pH 7.4 buffer solution containing the cecal suspension at 37°C (cumulative release: ca. 100 mg BSA/g gel after 4 days). Copyright © 2008 John Wiley & Sons, Ltd.     

pH-Dependent Release from Monoolein Cubic Phase Containing Hydrophobically Modified Chitosan

Monoolein (MO) cubic phase incorporating hydrophobically modified chosan (Hm chitosan) was prepared to obtain a pH-dependent release. Following calorimetric study, Hm chitosan had little effect on the crystal structure of MO cubic phase under acidic condition where Hm chitosan is readily soluble. At a higher pH (e.g., pH 9.0), however, the crystal structure of MO cubic phase was disturbed, possibly due to the insolubilization of Hm chitosan at the alkali condition. Whether the dye included in the cubic phase is anionic (amaranth) or cationic (methylene blue), the release from the cubic phase was suppressed as the pH of release medium increased. The structural change of cubic phase caused by the insolubilization of Hm chitosan, or the blockage of the water channel of the cubic phase by precipitated Hm chitosan would be responsible for the suppressed released.     

甘油单油酸脂/水立方液晶体系流变性质的研究

Monoglyceride (MO) can form various liquid crystalline phases spontaneously in the presence of various amount of water at room temperature. The appropriate compositions from binary phase diagram of MO/H2O were selected to form cubic phases. The selected systems were studied at different salt concentrations and pH value using rheological methods. There was a weak effect of salt on viscoelastic properties of cubic phases formed from MO/H2O system. Hexagonal phase was formed when pH value was decreased or increased. The viscoelasticity of cubic phases was different from that of hexagonal liquid crystals. Rheological properties of MO/H2O cubic phases were stable at pH and salt concentration similar to physiological condition.     

Monoolein cubic phase containing azobenzene and its UV/visible light irradiation-dependent release property

Monoolein (MO) cubic phase, whose MO/azobenzene mass ratios were 1:0, 1:0.0025, 1:0.005, and 1:0.025, was prepared by a melt-hydration method. According to the polarized optical micrographs and the differential thermograms, the phase transition temperature of the cubic phase was lower as the content of azobenzene was higher, and it decreased upon the subsequent irradiation of UV light for 1 hour and visible light for 1 hour. The photoirradiation significantly promoted the release of methylene blue (a water-soluble dye) loaded in the cubic phase only when the MO/azobenzene mass ratio was 1:0.025. The photoirradiation could promote the release of Nile red (an oil-soluble dye) even when the MO/azobenzene mass ratio was less than 1:0.025. The higher photo-susceptibility of Nile red release was possibly because the dye would be intercalated in the MO lipid matrix and the photoirradiation could affect the lipid matrix property.     

Phase Behavior of a Designed Cyclopropyl Analogue of Monoolein: Implications for Low‐Temperature Membrane Protein Crystallization

Lipidic cubic phases (LCPs) are used in areas ranging from membrane biology to biodevices. Because some membrane proteins are notoriously unstable at room temperature, and available LCPs undergo transformation to lamellar phases at low temperatures, development of stable low‐temperature LCPs for biophysical studies of membrane proteins is called for. Monodihydrosterculin (MDS) is a designer lipid based on monoolein (MO) with a configurationally restricted cyclopropyl ring replacing the olefin. Small‐angle X‐ray scattering (SAXS) analyses revealed a phase diagram for MDS lacking the high‐temperature, highly curved reverse hexagonal phase typical for MO, and extending the cubic phase boundary to lower temperature, thereby establishing the relationship between lipid molecular structure and mesophase behavior. The use of MDS as a new material for LCP‐based membrane protein crystallization at low temperature was demonstrated by crystallizing bacteriorhodopsin at 20 °C as well as 4 °C.     

Self-assembled liposomes from electrosprayed polymer-based microparticles

Composite poly(N-isopropylacrylamide) (PNIPAAm)/phosphatidylcholine (PC) microparticles were prepared by electrospraying. PC-based liposomes were subsequently generated upon the addition of water. The microparticles have an average diameter of ca. 1 μm, while the liposomes produced were found to have much smaller diameters of ca. 225–280 nm. The liposomes had zeta potentials of ?44 to ?50 mV, consistent with the formation of a stable suspension. Upon heat treatment, the liposomes exhibit phase transitions due to the influence of PNIPAAm. The liposomes containing 33 % PC have a phase transition temperature of approximately 36 °C, close to physiological conditions. The model drug ketoprofen could be loaded into electrosprayed microparticles and subsequently incorporated into self-assembled liposomes, with an entrapment efficiency for the latter process of ca. 75 %. Sustained drug release regulated by temperature was observed from these drug-loaded materials. At 25 °C, only 45 % of the total drug loading was released after 110 hours, while at 37 °C drug release approached 90 % over the same time period. The self-assembled liposomes reported here, therefore, have great potential as drug delivery devices.     

Calorimetric Investigation of Conversion to The Most Stable Subgel Phase of Phosphatidylethanolamine-water System

The conversion of either the gel or the liquid crystal phase to the most stable subgel phase in dimyristoylphosphatidylethanolamine (DMPE)-water system at a water content of 25 mass% was studied by differential scanning calorimetry and isothermal calorimetry. The calorimetric experiments were performed for two samples depending on whether the thermal treatment of cooling to -60°C was adopted or not. In DSC of varying heating rate, exothermic peaks due to the partial conversion were observed at either temperatures just below the gel-to-liquid crystal phase transition at 50°C or temperatures where the liquid crystal phase is present as a metastable state. The enthalpies of conversion for both the gel and the liquid crystal phase were measured directly by the isothermal calorimetries at 47 and 53°C, respectively, where the exothermic peaks were observed by DSC and were compared with the enthalpy difference between the gel and subgel phases and that between the liquid crystal and subgel phases. This revised version was published online in July 2006 with corrections to the Cover Date.     

Ionic strength/temperature-induced gelation of aqueous poly(N-isopropylacrylamide-co-vinylimidazole) solution

A high molecular weight copolymer of N-isopropylacrylamide (NiPAAm) and vinyl imidazole (VI) was synthesized and its phase transition behavior in aqueous solutions (5 wt%) by simultaneous changes of ionic strength and temperature was investigated. At low ionic strengths, the copolymer solution showed two phases (clear and opaque solutions), which were freely mobile, as increasing temperatures up to 65°C due to repulsion interaction of positive charges developed by basic imidazole group on the polymer aggregates. However, at the physiological condition (I=0.15, T=37°C), four distinctive phases (clear solution, opaque solution, gel and shrunken gel) were observed because of charge shielding effect by added salts. The gel state was stable and maintained from 32°C to 55°C. In particular, the phase transition from opaque solution to gel rapidly occurred by the change in ionic strength (from ∼ 0 to 0.15) at 37°C. This characteristic can be utilized as a liquid embolic agent.     

Thermosensitive phase behavior and drug release of in situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels

In situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels were prepared by precipitation polymerization in the presence of various amounts of N,N′-methlenebisacrylamide as a crosslinker. The diameters of microgels were in the range of 200–300 nm with narrow distributions as determined by photo correlation spectroscopy. The equilibrium swelling ratio and thermosensitive properties of the microgels increased with decreasing crosslinker content. The volume phase transition of microgels dispersions at high concentrations were investigated by phase diagrams. The microgels dispersions experienced four phases when the temperature was increased: semitranslucent swollen gel, clear flowable suspension, cloud flowable suspension, and white shrunken gel. The related phase transition temperatures were influenced by crosslinker content and the concentration of the microgel dispersions. Herein, the gelation temperature was changed by more than 20 °C, shrinking temperatures were slightly changed by about 3 °C, and cloud point temperatures showed almost no change. The three phase transition temperatures of microgels dispersed in phosphate-buffered saline solutions were lower than that in water. As drug carriers, the release rates of bleomycin from bleomycin-loaded microgel dispersions exhibited diffusion control at human body temperature.     

蔗糖对MO/水立方液晶体系流变性质的影响

主要研究了蔗糖对甘油单油酸脂(monoolein, MO)/水立方液晶体系的流变学性质及其相行为的影响. 根据体系流变性质的变化和偏光显微镜照片, 得出随着蔗糖含量的增加, MO/水体系发生了由反相立方液晶到反相六角状液晶的相转变. 蔗糖与MO分子通过氢键相互作用, 减弱了两亲分子间的静电斥力. 当蔗糖含量增加到一临界值时, 体系的立方结构被破坏, 继续增加蔗糖的含量, 体系就会形成新的反相六角状液晶.     

Thermal behavior of the composite xerogels of zirconium oxyhydroxide and silicic acid

Gels were prepared via sol?Cgel method by addition of zirconium oxychloride solution into sodium metasilicate (SZ) and sodium metasilicate solution into zirconium oxychloride (ZS) at varying final pH. Si/Zr molar ratio equaled 1/1. Synthesized gels were dried with calcium chloride until they reached a constant mass. SEM and nitrogen adsorption analysis have shown that SZ gels have surface area 175?C200?m^2?g^?1, consist of 20?C30?nm grains. ZS samples have surface area about 1?m^2?g^?1, consist of grains smaller than 10?nm. Thermal and X-ray phase analysis have shown that transition of amorphous ZrO₂ to crystalline form shifts from 430 to 850?C870?°C for SZ gels. Unlike zirconia gels phase transitions that proceed in order: ??amorphous (430?°C)??tetragonal (800?°C)??monoclinic (1,000?°C) phases??, the monoclinic phase in ZS gels appears immediately after transition from amorphous to crystalline state; the tetragonal phase in SZ samples is stable until 1,000?°C.