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Formation of Bilayer Membrane and Niosomes by Double-Tailed Polyglyceryl-Type Nonionic Surfactant Kenji Aramaki,*,† Junya Yamada,† Yoshitomo Tsukijima,† Tetsuya Maehara,‡ Daisuke Aburano,‡ Yuichi Sakanishi,‡ and Kyuhei Kitao‡ †

Graduate School of Environment and Information Sciences, Yokohama National University, Tokiwadai 79-7, Hodogaya-ku, Yokohama 240-8501, Japan ‡ R&D Center, Organic Chemical Products Company, DAICEL Corporation, 1239 Shinzaike, Aboshi-ku, Himeji-shi, 671-1283, Japan ABSTRACT: Vesicles with synthetic nonionic surfactants are called niosomes or NSVs, and these have been the focus of attention as an alternative to phospholipid liposomes as drug carriers. Especially it is demanded to discover novel niosomal systems with polyol-type nonionic surfactants from the viewpoint of environmental aspects. In this paper, a novel series of double-tailed nonionic surfactants, polyglyceryl dialkyl ethers, (C12)2Gn (n = 2.3, 5.4, 9.4, and 13.8), was synthesized, and its aqueous phase behavior and niosome formation were studied. Because of its double-tailed molecular structure, a lamellar liquid crystalline phase was dominant in the binary phase diagrams for different polyglyceryl chain lengths. The single lamellar liquid crystalline phase region was expanded as the polymerization degree in the hydrophilic moiety increased. Small-angle X-ray scattering spectra revealed the lamellar structure for the (C12)2G2.3 was extremely loose. Molecular packing in the lamellar phase was analyzed except for the (C12)2G2.3 system by using a geometrical model of the lamellar phase. The effective cross-sectional area per molecule at the interface increased extensively as dilution for the (C12)2G13.8 system but remained almost unchanged for the (C12)2G5.4 system. From the molecular parameters, water-holding ability in the lamellar phase was evaluated, and the results indicated strong hydration ability of the long polyglyceryl chain. In a dilute region, micron-sized giant niosomes and small niosomes of about 100 nm were formulated by vortex mixing and ultrasonication, respectively. The multilamellar structure of the small niosomes was confirmed by transmission electron microscopy. Cholesterol addition in the present surfactant lamellar phase induced the phase transition to the liquid ordered phase, which is the same phenomenon in a phospholipid−cholesterol mixture. The stability of niosomes with/without cholesterol was monitored by the niosome size change. In both cases, the niosomes were stable for at least 100 days.

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INTRODUCTION A cell membrane is a lipid bilayer formed mainly by phospholipids. Phospholipids are natural amphiphilic molecules and have a molecular structure with a single large hydrophilic head and double hydrophobic acyl tails. Such a double-tailed molecular structure enables the formation of a flexible bilayer structure. As a mimic of the cell membrane, liposomes can be prepared by phospholipids and have been extensively used as model biological membranes and drug delivery carriers. Apart from phospholipid liposomes, vesicles can be formed by synthetic surfactant molecules. Since the report of the synthetic bilayer membrane composed of a cationic dialkyldimethylammonium salt by Kunitake and Okahata,1 vesicle formation by various synthetic surfactant molecules has been reported. Among the vesicles with synthetic surfactant molecules, nonionic vesicles, which are called niosomes or NSVs, have been the focus of attention as an alternative to phospholipid liposomes as drug carriers since niosomes can be formulated at relatively lower cost and high purity in comparison with liposomes and generally have better chemical stability and possibilities of surface modification.2 Because of © XXXX American Chemical Society

their nonionic nature, niosomes have low toxicity and can be applied to biological systems. Several poly(oxyethylene)-type surfactants have been employed for niosome formulation3−8 as well as polyol-type surfactants.9−14 Especially the latter type has benefits of environmental aspects such as higher biodegradability and use of naturally renewable resources. Therefore, it is justified to discover novel niosomal systems with polyol-type nonionic surfactants and study those characteristics that can help future applications. In this paper, the formation of a bilayer structure with high water-holding ability and niosome formulation by novel doubletailed nonionic amphiphiles, polyglyceryl dialkyl ethers, is reported. Polyglyceryl alkyl ethers or polyglycerol fatty acid esters have been studied with respect to phase behavior and self-assembly.15−18 Thanks to the relatively strong intermolecular interaction among hydroxyl groups, polyglycerol-type surfactants have low monomeric solubility in oil and can Received: July 3, 2015 Revised: August 19, 2015

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Small-Angle X-ray Scattering (SAXS). SAXS measurements were performed on a Kratky-type camera (SAXSess, Anton Paar, Austria) with a PW3830 laboratory X-ray generator (Philips, Netherlands). It has a long fine focus sealed glass X-ray tube (Cu Kα wavelength of 0.1542 nm). The apparatus was operated at 40 kV and 50 mA, and the X-ray beam was irradiated on samples for 10 min. Samples were encapsulated in a quartz capillary (1 mm thick) specially designed for the SAXSess camera. Differential Scanning Calorimetry (DSC). DSC measurements were performed on a DSC 6200 instrument (Seiko Instruments, Japan). Samples were packed in aluminum pans and then tightly sealed. DSC traces were recorded at a heating rate of 10 °C/min. The effect of the heating rate ranging from 1 to 20 °C on the phase transition temperature was not so significant. It was less than 3 °C. Density Measurement and Lipophilic Volume Calculation. Density measurements at 30 °C were performed on a DSA-5000 density meter (Anton Paar, Austria). Density values of methanol solutions of each surfactant at different concentrations were measured. The density was linearly changed by the composition. Extrapolated density values at 100% surfactant composition were determined as the density of each pure surfactant at 30 °C. The density values obtained were 0.9913, 1.0247, and 1.0622 for n = 5.4, 9.4, and 13.8, respectively. Those density values and the lipophilic part (two lauryl chains) volume, 421.8 nm3, which was estimated by Tanford’s equation,26 were used to evaluate molecular parameters described in the later section Transmission Electron Microscopy (TEM). The morphological analysis of niosomes was carried out by transmission electron microscopy (TEM), using a H-7600 (Hitachi, Japan) unit working at an accelerating voltage of 100 kV. The negative staining method was used with 2% phosphotungstic acid. Dynamic Light Scattering (DLS). Diameters of niosomes prepared by ultrasonication were measured by the dynamic light scattering (DLS) method. DLS measurement was performed with a DLS-7000 (Otsuka Electronics, Japan). The DLS apparatus consists of a goniometer, 75 mW Ar ion laser (λ) 488 nm, and a multiple tau digital real-time correlator (ALV-5000/EPP, Germany). Intensity of light was measured at 90°. Correlation functions were analyzed by the cumulant method.

effectively be adsorbed onto water−oil interfaces, which is a better feature than the poly(oxyethylene)-type emulsifier with relatively high monomeric solubility in oil. This feature also allows the formation of nonionic reverse micelles in oils.19−22 The phase behavior of aqueous polyglycerol fatty acid esters was reported by Kunieda et al.23−25 They showed that the phase behavior was similar to general surfactant systems, in which a sphere−rod−planar shape transition took place depending on surfactant HLB or the critical packing parameter, due to a graft-copolymer type molecular structure. Therefore, we employed a molecular structure resembling that of phospholipids, i.e., one head and double tails. With this molecular structure, we can expect effective formation of the flat synthetic bilayer membranes.

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MATERIALS AND METHODS

Materials. Polyglyceryl dialkyl ethers were synthesized by the following procedure. Dodecyl glycidyl ether (150 g, 0.70 mol) was added dropwise to a stirred solution of dodecyl alcohol (1043 g, 6.1 mol) and SnCl4 (1.82 g, 9.6 mmol) for 1 h at 80 °C under nitrogen gas. Then distilled water was added to quench the reaction. Potassium carbonate (9.67 g, 0.070 mol) was added into the solution to remove residual water. The solution was diluted with n-heptane (259 g, 2.6 mol), and the solid body in the obtained slurry was removed by filtration. Residual n-heptane was removed in vacuo. Unreacted dodecyl alcohol was removed at 200 °C, 2 mmHg to obtain didodecyl monoglycerol (287.9 g). Note that the didodecyl monoglycerol contains 1,3-form (94.9%) and 1,2-form (5.1%). 28% methanol solution of sodium methoxide (23.7 g) was added to didodecyl monoglycerol (45.1 g, 0.11 mol). Methanol was removed from the solution for 10 h at 100 °C, 2 mmHg. Glycidol (77.9 g, 1.1 mol) was added dropwise for 10 h to a stirred solution. After the solution was neutralized with 85% phosphoric acid aqueous solution (8.1 g, 0.097 mol), the slurry was attenuated with methanol (150 g) and filtrated. Methanol was removed in vacuo at 2 mmHg to obtain didodecyl polyglycerol (123 g) as shown by the illustrated structure in Scheme 1. We obtained four different averated polymerization degrees of the polyglycerol chain, n = 2.3, 5.4, 9.4, and 13.8, for (C12)2Gn.

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RESULTS AND DISCUSSION Phase Behavior of Aqueous (C12)2Gn Systems. Figure 1 shows composition−temperature phase diagrams of the binary systems with water and (C12)2Gn. W, Lα, Om, and S indicate water, lamellar liquid crystalline, reverse micellar, and solid phase, respectively. All the systems show a solid phase below 20 °C, which is unusual for poly(oxyethylene)-type nonionic surfactants with a dodecyl chain.27 This could happen due to tight packing of hydrophobic tails of the present double-tailed surfactant systems. Above the solid melting temperature, a single lamellar phase region existed at relatively high surfactant concentration. An excess water phase was separated from Lα in lower surfactant composition and the two-phase equilibrium (Lα + W) continues to the dilute region. The Lα was confirmed by visual observation under crossed polarizers and small-angle X-ray scattering (SAXS). Figure 2 shows the SAXS spectra of the Lα phase for aqueous (C12)2Gn systems at different surfactant concentrations. For n = 5.4, 9.4, and 13.8, a set of Bragg peaks for the 1:2 spacing ratio was observed. For n = 2.3, no clear diffraction peaks were observed even at a high surfactant concentration, and only the observation of birefringence is proof of the Lα. The fluidity of the Lα samples for n = 2.3 was apparently high compared to others. There is a possibility of a reverse hexagonal phase, but it is denied by the apparent high fluidity which is not possible for such a two-dimensionally ordered phase. Judging from both SAXS and apparent fluidity,

Scheme 1. Molecular Structure of (C12)2Gn

The molecular structure of the (C12)2Gn was characterized by 1H NMR. (C12)2G2.3: 1H NMR (δ ppm, d-DMSO): 0.87−0.92 (t, 6H), 1.27 (s, 32H), 1.40−1.57 (m, 8H), and 3.20−3.98 (m, 23H). (C12)2G5.4: 1H NMR (δ ppm, d-DMSO): 0.87−0.92 (t, 6H), 1.27 (s, 32H), 1.40−1.57 (m, 8H), and 3.20−3.98 (m, 42H). (C12)2G9.4: 1H NMR (δ ppm, d-DMSO): 0.87−0.92 (t, 6H), 1.27 (s, 32H), 1.40− 1.57 (m, 8H), and 3.20−3.98 (m, 65H). (C12)2G13.8: 1H NMR (δ ppm, d-DMSO): 0.87−0.92 (t, 6H), 1.27 (s, 32H), 1.40−1.57 (m, 8H), and 3.20−3.98 (m, 92H). Sample Preparation and Determination of Phase State. The predetermined amounts of surfactant and water were weighed into screw-capped glass test tubes and mixed by a vortex mixer or ultrasonication (20 kHz, 50 W). After mixing, the samples were stored in a temperature-controlled water bath at a constant temperature. Phase states above the solid melting temperature were determined by visual inspection using crossed polarized plates and small-angle X-ray scattering (SAXS) experiments. Solid melting temperatures were determined by differential scanning calorimetry (DSC). B

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Figure 1. Composition−temperature phase diagrams of the water/(C12)2Gn systems for n = 2.3, 5.4, 9.4, and 13.8. W, Lα, Om, and S indicate water, lamellar liquid crystalline, reverse micellar, and solid phase, respectively.

Figure 2. SAXS spectra at 30 °C for the water/(C12)2Gn systems at different surfactant compositions are plotted.

for smaller n could easily be fluctuated by the thermal energy, leading to reduced periodicity of the lamellar structure. At a low surfactant concentration, a broad peak is overlapped with the sharp Bragg peaks, which is significant for n = 5.4. This broad peak could come from the form factor of the bilayers whose thickness is on a nanometers scale. Kato et al. reported a huge decrease in the interlayer spacing of a nonionic surfactant

the Lα phase of the (C12)2G2.3 system has a loosely ordered structure. The bilayer bending elasticity becomes generally lower with the decreasing bilayer thickness;28−30 therefore, it decreased as n decreased. Also, the hydration force31 that stabilizes the bilayer stack is reduced due to the smaller number of water molecules of hydration. Consequently, thinner bilayers C

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Langmuir lamellar phase under shear.32 Such a water-squeezing effect could have also happened in the present system for a part of the lamellar phase. The Griffin’s HLB number (NHLB) was calculated from the molecular structure as NHLB = 3.7, 8.6, 11.8, and 13.8 for n = 2.3, 5.4, 9.4, and 13.8, respectively. NHLB = 3.7 is highly hydrophobic for general single-head and single-tail surfactants, and L α is usually not formed. In spite of the high hydrophobicity of (C12)2G2.3, the (C12)2G2.3 molecules are ordered in a lamellar structure due to its double-tailed molecular structure. For n = 5.4, the Lα region expands to a lower surfactant concentration than n = 2.3. The Lα region expands to an even lower concentration and higher temperature for n = 9.4, and it dominates the phase diagram for n = 13.8. At high concentration, an isotropic phase (Om) appeared, which is similar to poly(oxyethylene)-type surfactant systems. Water-Swelling Ability of Lα Phase. The interlayer spacing, d, was calculated by the formula d = 2π/q1, where q1 indicates the q value for the first-order SAXS peak. The d is the sum of the bilayer and the water layer thicknesses, and therefore, molecular parameters can be evaluated using a lamellar model.33 The hydrophobic layer thickness, 2dL, is described by the equation dL =

dϕL 2

(1)

where ϕL indicates the volume fraction of the hydrophobic part of surfactant in the system. The ϕL was estimated by VL/(VW + VS), where VL, VW, and VS are the volume of surfactant hydrophobic part, water, and surfactant in a sample, respectively. Since we prepared samples by weight basis, VW and VS were calculated by density values for these compounds. The surfactant density was measured as described in the Materials and Methods section. The VL was calculated by using the Tanford’s equation,26 which is described in the Materials and Methods section. The molecular occupied area, aS, is described by the equation v aS = L dL (2)

Figure 3. Interlayer spacing (a), half thickness of hydrophobic bilayer (b), and effective cross-sectional area at interface (c) are plotted against the surfactant concentration in the (C12)2Gn systems for n = 5.4 (circles), 9.8 (triangles), and 13.8 (squares).

where vL indicates the volume of the hydrophobic part of a surfactant molecule. Figure 3 is a plot of d, dL, and aS for the (C12)2Gn systems for n = 5.4, 9.8, and 13.8. The dL increased (the aS decreased because of the relation of eq 2) as the surfactant concentration increased for all the systems, which is a common trend in other nonionic surfactant systems34−36 and can be easily understood by less hydration of polyglycerol chains at higher surfactant concentration. The slope of variation in Figure 3b,c is pronounced for longer polyglycerol chain length, indicating a larger number of water molecules of hydration on longer polyglycerol chains. The swelling or solubilization capacity of water in the Lα phase can be evaluated by the amount of water per surfactant molecule. It was estimated as vw by the equation (3)

Figure 4. Values of vw are plotted as a function of the surfactant concentration in the (C12)2Gn systems for n = 5.4 (circles), 9.8 (triangles), and 13.8 (squares).

where dW is the thickness of the water layer and vh is the volume of the surfactant headgroup. Figure 4 is a plot of the vw values as a function of the surfactant concentration. The vw increases with surfactant dilution and reached 2.9, 4.1, and 5.3

nm3 for n = 5.4, 9.8, and 13.8 at WS = 0.3, respectively. Considering also the result of the molecular occupied area, it

d a vw = W S − v h 2

D

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Figure 5. Optical micrograph of myelin figures observed after 2 min (a) and of niosomes prepared by vortex mixing (b) in the water/(C12)2G9.4 system at 1 wt %.

shows that the water swelling ability for the longest polyglycerol surfactant is superior. Preparation and Stability of Niosomes. Vesicles have been the focus of attention for many decades as a model biological membrane and nano or micro delivery vehicle for functional molecules and biomolecules. Since vesicles are formed by closed bilayers, they are therefore formed as a lamellar structure in water. In the present double-tailed surfactant system, two-phase equilibrium of water and Lα phases are found, and therefore vesicle formulation can be expected in the two-phase region. Our first experiment regarding niosome formulation was the observation of the Myelin figures which have been observed as precursors of vesicle formation for lecithin touched with water.37 A concentrated lamellar liquid crystal of the (C12)2G9.4 system was sandwiched between a slide glass and a cover glass. Then water was penetrated from the edge of the cover glass, followed by optical microscopic observation. When we observed around the region at which the water and lamellar liquid crystal were contacted, the optical micrograph of Figure 5a was observed. Myelin figures were clearly observed after 2 min for this particular sample, and it suggests niosome formation in the diluted lamellar samples. Next, we prepared samples at 1 wt % surfactant concentration by the method described in the Materials and Methods section. Figure 5b is an optical micrograph in the same system at 1 wt % surfactant concentration with a few minutes vortex mixing. Giant niosomes can be seen as spherical objects that have a micrometer scale. The size of niosomes is generally dependent on agitation power. In fact, small-sized niosomes can be obtained by ultrasonication with 20 kHz. Figure 6 is a negativestained TEM observation of the water/(C12)2G9.4 system at 1 wt %. Multilamellar-type niosomes with a diameter of several tens of nanometers can be seen in the TEM photo. Cholesterol is often added to liposomes to stiffen the bilayer membrane,38 and cholesterol based liposomes can be used as drug carriers.39 Cholesterol also added to niosomes to expect the similar functions as used for liposomes.2,40,41 Mixing of cholesterol induces niosome formation with relatively hydrophilic nonionic surfactants. Niosomes with cholesterol do not only increase the stability but also increase the entrapment efficiency.42 Adding cholesterol induces structural change of the phospholipid bilayer. An intermediate structure between a crystalline and a liquid crystalline state is called a liquid ordered phase (LO),43 which is the structure in the lipid raft in biological cell membranes.44 Figure 7a shows a DSC thermogram of the

Figure 6. Negative-stained TEM observation of the water/(C12)2G9.4 system is shown. The sample at concentration was 1 wt % and was prepared by ultrasonication. The bar indicates 100 nm. Multilamellartype niosomes with diameters of several tens of nanometers are indicated by arrows.

water/(C12)2G9.4 system at 60 wt % water. The mole fraction of cholesterol in a mixture of (C12)2G9.4 and cholesterol mixture, X, is indicated in the figure. At X = 0, a large endothermic peak for the major transition is observed at 21.5 °C. The major transition took place due to melting of hydrocarbon chains of the surfactant molecules. As X increased, the major transition peak was shifted to 17−18 °C and the peak area decreased. At X = 0.34, the major transition peak disappeared. Figure 7b shows the heat of the major transition. The Q value decreased almost linearly against X and reached zero at around X = 0.28, indicating the LO phase formation45,46 above X = 0.28. LO formation is also supported by the WAXS spectra at 10 °C as shown in Figure 8. A sharp WAXS peak for an α-type crystalline structure (d ≈ 0.42 nm) that has a hexagonal subcell structure was found at X = 0. The peak intensity decreased as X increased. The sharp WAXS peak completely disappeared above X = 0.34. The orderliness of alkyl chain packing in the LO phase is the degree between a crystalline and a liquid crystalline state47,48 since the rigid hydrophobic moiety of cholesterol disturbs subcell lattice structures of a crystalline state whereas it is intercalated and induces a trans conformation of alkyl chains.49 Therefore, loosening of the orderliness proved by the WAXS spectra indicates the LO formation above X = 0.34. We also prepared niosomes in the system with cholesterol by using ultrasonication. The niosome size at 25 °C was measured by DLS for samples at X = 0, 0.15, and 0.40. In all the compositions, the niosome size was small but slightly larger for the cholesterol-added system as is shown in Figure 9. A similar E

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Figure 7. DSC spectra (a) and heat of transition Q (b) in the water/(C12)2G9.4 system at 60 wt % of water are shown. The major transition temperatures for each X are also indicated.

Figure 9. Change in niosome diameter at 25 °C with time for X = 0 (circles), 0.15 (squares), and 0.4 (triangles).

highly frequent vibration in a sample, and local temperature became high even if the sample bottle was in a water bath. Therefore, at X = 0, the bilayer in the Lα state was dispersed to formulate niosomes. At X = 0.4, the major transition temperature disappeared, and therefore the dispersion took place for the bilayer in the LO state. Since the LO has higher bending elasticity than the Lα, niosomes that have a larger size could have been obtained at X = 0.4. Figure 9 shows the change in niosome diameter over time. The niosome size was almost unchanged even after 100 days for all the compositions, indicating niosomes of the present double-tailed nonionic surfactant were stable. Figure 10 shows the effect of an anionic surfactant, sodium dodecyl sulfate (SDS) addition on niosome stability. The SDS is known to strongly disturb bilayer membrane. The niosome diameter was significantly affected by the SDS addition for the cholesterol-free system (X = 0) while less affected at X = 0.4,

Figure 8. WAXS spectra at 10 °C in the water/(C12)2G9.4 system at 60 wt % of water.

observation was reported by Manosroi et al. as larger niosome size with cholesterol addition.42 As shown before, the structure of the bilayer in niosomes at 25 °C was a crystalline state at X = 0 and a liquid ordered state at X = 0.4. At X = 0.15, the bilayer structure could be a mixture of crystalline and liquid ordered domains, which is inferred in the literature50 reporting the direct observation of a microphase separation in the phospholipid bilayer. The initial size of niosomes can be influenced by the difference in the bending rigidity of the bilayers under the same dispersion power. Ultrasonication gave F

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(2) Marianecci, C.; Di Marzio, L.; Rinaldi, F.; Celia, C.; Paolino, D.; Alhaique, F.; Esposito, S.; Carafa, M. Niosomes from 80s to present: The state of the art. Adv. Colloid Interface Sci. 2014, 205, 187−206. (3) Kunieda, H.; Nakamura, K.; Davis, H. T.; Evans, D. F. Formation of vesicles and microemulsions in a water/tetraethylene glycol dodecyl ether/dodecane system. Langmuir 1991, 7, 1915−1919. (4) Olsson, U.; Nakamura, K.; Kunieda, H.; Strey, R. Normal and Reverse Vesicles with Nonionic Surfactant: Solvent Diffusion and Permeability. Langmuir 1996, 12, 3045−3054. (5) Harvey, R. D.; Heenan, R. K.; Barlow, D. J.; Lawrence, M. J. The effect of electrolyte on the morphology of vesicles composed of the dialkyl polyoxyethylene ether surfactant 2C18E12. Chem. Phys. Lipids 2005, 133, 27−36. (6) Tavano, L.; Alfano, P.; Muzzalupo, R.; de Cindio, B. Niosomes vs microemulsions: new carriers for topical delivery of Capsaicin. Colloids Surf., B 2011, 87, 333−339. (7) Mandal, S.; Banerjee, C.; Ghosh, S.; Kuchlyan, J.; Sarkar, N. Modulation of the Photophysical Properties of Curcumin in Nonionic Surfactant (Tween-20) Forming Micelles and Niosomes: A Comparative Study of Different Microenvironments. J. Phys. Chem. B 2013, 117, 6957−6968. (8) Ahmad, N.; Ramsch, R.; Esquena, J.; Solans, C.; Tajuddin, H. A.; Hashim, R. Physicochemical Characterization of Natural-like Branched-Chain Glycosides toward Formation of Hexosomes and Vesicles. Langmuir 2012, 28, 2395−2403. (9) Aripin, N. F. K.; Hashim, R.; Heidelberg, T.; Kweon, D.-K.; Park, H. J. Effect of vesicle’s membrane packing behaviour on skin penetration of model lipophilic drug. J. Microencapsulation 2013, 30, 265−273. (10) Salim, M.; Abou-Zied, O. K.; Kulathunga, H. U.; Baskaran, A.; Kuppusamy, U. R.; Hashim, R. Alkyl mono- and di-glucoside sugar vesicles as potential drug delivery vehicles: detecting drug release using fluorescence. RSC Adv. 2015, 5, 55536−55543. (11) Oskolkova, M. Z.; Norrman, E.; Olsson, U. Study of the micelleto-vesicle transition and smallest possible vesicle size by temperaturejumps. J. Colloid Interface Sci. 2013, 396, 173−177. (12) Patel, J.; Ketkar, S.; Patil, S.; Fearnley, J.; Mahadik, K. R.; Paradkar, A. R. Potentiating antimicrobial efficacy of propolis through niosomal-based system for administration. Integr. Med. Res. 2015, 4, 94−101. (13) Valdés , K.; Morilla, M. J.; Romero, E.; Cháv ez, J. Physicochemical characterization and cytotoxic studies of nonionic surfactant vesicles using sucrose esters as oral delivery systems. Colloids Surf., B 2014, 117, 1−6. (14) Wilkhu, J. S.; Ouyang, D.; Kirchmeier, M. J.; Anderson, D. E.; Perrie, Y. Investigating the role of cholesterol in the formation of nonionic surfactant based bilayer vesicles: Thermal analysis and molecular dynamics. Int. J. Pharm. 2014, 461, 331−341. (15) Shrestha, L. K.; Saito, E.; Shrestha, R. G.; Kato, H.; Takase, Y.; Aramaki, K. Foam Stabilized by Dispersed Surfactant Solid and Lamellar Liquid Crystal in Aqueous Systems of Diglycerol Fatty Acid Esters. Colloids Surf., A 2007, 293, 262−271. (16) Shrestha, L. K.; Sato, T.; Aramaki, K. Phase Behavior and SelfOrganized Structures of Diglycerol Monolaurate in Different Nonpolar Organic Solvents. Langmuir 2007, 23, 6606−6613. (17) Matsumoto, Y.; Alam, Md.M.; Aramaki, K. Phase Behavior, Formation, and Rheology of Cubic and Hexagonal Phase Based Gel Emulsions in water/tetraglyceryl lauryl ether/oil systems. Colloids Surf., A 2009, 341, 27−32. (18) Shrestha, R. G.; Shrestha, L. K.; Solans, C.; Gonzalez, C.; Aramaki, K. Nonaqueous foam with outstanding stability in diglycerol monomyristate/olive oil system. Colloids Surf., A 2010, 353, 157−165. (19) Shrestha, L. K.; Dulle, M.; Glatter, O.; Aramaki, K. Structure of Polyglycerol Oleic Acid Ester Nonionic Surfactant Reverse Micelles in Decane: Growth Control by Headgroup Size. Langmuir 2010, 26, 7015−7024. (20) Shrestha, L. K.; Shrestha, R. G.; Aramaki, K. Intrinsic Parameters for the Structure Control of Nonionic Reverse Micelles in Styrene: SAXS and Rheometry Studies. Langmuir 2011, 27, 5862−5873.

Figure 10. Effect of SDS addition on niosome diameter for X = 0 (circles) and 0.4 (triangles).

indicating cholesterol enhanced robustness of the bilayer membrane of the niosome.

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CONCLUSIONS Polyglyceryl dialkyl ethers, (C12)2Gn, are a novel nonionic double-tailed surfactant series and have a similar molecular structure to phospholipids. As expected from the molecular structure, (C12)2Gn formed a lamellar liquid crystalline phase in water and especially over wide composition and temperature ranges for higher n values. The water-swelling ability of the lamellar liquid crystalline phase was estimated by small-angle Xray scattering (SAXS) measurement. Because of the strong hydration ability of the polyglycerol chain, (C12)2Gn with n = 13.8 showed extensive water-swelling ability. In a dilute composition, niosomes (nonionic surfactant vesicles) were formulated. The size of the niosomes was tuned by agitation methods. Giant niosomes were obtained by vortex mixing and small-sized and multilamellar types of less than 100 nm were obtained by ultrasonication. The stability of small-sized niosomes was relatively high, which is a promising feature for future applications as nanocapsules. The cholesterol effect on the bilayer structure of (C12)2Gn was studied by differential scanning calorimetry (DSC) and wide-angle X-ray scattering measurements. The liquid-ordered phase (LO), which has intermediate membrane fluidity between crystalline and liquid crystalline phases, was formed by mixing cholesterol in the aqueous (C12)2G9.4 system. This result indicates that the LO formation is not limited in phospholipid systems but is also possible in general synthetic bilayer membrane systems. This report shows that the polyglycerol dilauryl ether, (C12)2Gn, is a good building block of nano- or microcapsules constructed by synthetic bilayer membranes and has promising applications for functionalized biomimetic soft matter.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (K.A.). Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Kunitake, T.; Okahata, Y. A totally synthetic bilayer membrane. J. Am. Chem. Soc. 1977, 99, 3860−3861. G

DOI: 10.1021/acs.langmuir.5b02454 Langmuir XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.langmuir.5b02454 Langmuir XXXX, XXX, XXX−XXX