Polypseudorotaxane-based supramolecular hydrogels consisting of cyclodextrins and Pluronics as stabilizing agents for antibody drugs.

Recently, antibody drugs have been used worldwide, and based on worldwide sales, 7 of the top 10 pharmaceutical products in 2019 were antibody-based drugs. However, antibody drugs often form aggregates upon thermal and shaking stresses with few efficient stabilizing agents against both stresses. Herein, we developed polypseudorotaxane (PpRX) hydrogels consisting of cyclodextrins (CyDs) and polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG block copolymers (Pluronics F108, F87, F68, and L44), and evaluated their utility as antibody stabilizing agents. α- and γ-CyDs formed PpRX hydrogels with Pluronics, where CyD/F108 gels showed remarkable stabilizing effects for human immunoglobulin G (IgG) against both thermal and shaking stresses beyond CyD/PEG gels or generic gels. The effects were probably due to the interaction between IgG and the free PPG block of Pluronic F108, resulting in the strong IgG retention in the gels. These findings suggest the great potential of CyD/Pluronic gels as pharmaceutical materials for antibody formulations.

Effect of the Crystallization Process of Surfactant Bilayer Lamellar Structures on the Elongation of High-Aspect-Ratio Gold Nanorods.

The growth mechanism of an "in-gel synthesis method", that is, the effects of composition and structure of the lamellar gel phase below the Krafft temperature of surfactant solutions on the growth of long gold nanorods, was investigated. We changed the alkyl chain length of surfactant molecules to investigate the effect of surfactant self-assembly on the elongation of gold nanorods systematically; eight mixed solutions of alkyltrimethylammonium bromide (C nTAB; n = 2-16; n = even) with C18TAB were used for investigation. The Krafft temperature, self-assembly of surfactant molecules, and the crystallization process of each mixture were observed by differential scanning calorimetry, wide-angle X-ray scattering, visual inspection, and small-angle X-ray scattering. Gold nanorods were synthesized in these eight surfactant mixtures. These observations demonstrated that when the surfactant Lß phase sustains for a long time, the space of the water layer is also kept large enough for the seeds to take up Au ions bound to surfactant micelles. In this case, the seeds can form long nanorods between bilayers. We conclude that not only the stability of the lamellar gel phase but also co-existence of Au-ion carriers, that is, surfactant micelles, is essential for the elongation of long gold nanorods.

Effects of Oscillatory Shear on the Orientation of the Inverse Bicontinuous Cubic Phase in a Nonionic Surfactant/Water System.

The bicontinuous inverse cubic phase (V2 phase) formed in amphiphilic systems consists of bilayer networks with a long-range order. We have investigated effects of oscillatory shear on the orientation of the V2 phase with space group Ia3d formed in a nonionic surfactant (C12E2)/water system by using simultaneous measurements of rheology/small-angle X-ray scattering. It is shown that grain refining occurs by applying the large amplitude oscillatory shear (LAOS) with a strain amplitude (γ0) of ∼20, which gives the ratio of the loss modulus (G″) to the storage modulus (G') (G″/G' = tan δ) of ∼100. On the other hand, orientation of the cubic lattice occurs when the small amplitude (γ0 ≈ 0.0004) oscillatory shear (SAOS) in the linear regime is applied to the sample just after the LAOS. Interestingly, the orientation is strongly enhanced by the "medium amplitude" (γ0 ≈ 0.05) oscillatory shear ("MAOS") after the SAOS. When the MAOS is applied before applying the LAOS, orientation to a particular direction is not observed, indicating that the grain refining process by the LAOS is necessary for the orientation during the MAOS. The results of additional experiments show that the shear sequence "LAOS-MAOS" is effective for the orientation of the cubic lattice. When the LAOS and MAOS are applied to the sample alternatively, grain refining and orientation occur during the LAOS and MAOS, respectively, indicating reversibility of the orientation. It is shown that (i) the degree of the orientation is dependent on γ0 and the frequency (ω) of the MAOS and (ii) relatively higher orientation can be obtained for the combination of γ0 and ω, which gives tan δ = 2-3. The lattice constant does not change throughout all the shearing processes and is equal to that before shearing within the experimental errors, indicating that the shear melting does not occur. These results suggest a possibility to control the orientation of the cubic lattice only by changing the conditions of oscillatory shear without using the epitaxial transition from other anisotropic phases, such as the hexagonal and lamellar phases.

Pressure-Induced Transition of Bilayers in a Nonionic Surfactant Solution.

Pressure effects on the bilayers of polyoxyethylene type nonionic surfactant in water have been investigated by means of small- and wide-angle X-ray scattering. It has been found that the Krafft transition from the micellar phase to the lamellar gel phase (Lß) is induced by pressure. By further pressurizing, the lamellar structural parameters, such as the repeat distance d and Caillé parameter η, discontinuously decrease after taking a maximum. All the SAXS and WAXS results revealed that the Lß phase is transformed into the higher-ordered lamellar crystal phase (Lc). On the basis of these observations, we have made the T-C and T-P phase diagrams.

Mesoscopic simulation of phase behaviors and structures in an amphiphile-solvent system.

We have performed a three-dimensional simulation of mesoscopic structures in a mixture of AB amphiphilic molecule and C solvent by employing the density-functional theory under the conditions that (i) the size of the AB is much larger than C and (ii) the affinity between A and B is much larger than the affinity between B and C. First, we have calculated the free energy of five periodic structures, i.e., the lamellar phase, hexagonally packed cylinders, body-centered-cubic spheres, face-centered-cubic spheres, and gyroid phase for different sets of the concentration of AB (ϕ[over ¯]_{AB}) and the χ parameter (χ_{AC}). By comparing the free energies for these structures, the χ_{AC}-ϕ[over ¯]_{AB} phase diagram has been obtained. In addition to these periodic structures, it has been shown that nonperiodic structures such as spherical and rodlike micelles can be obtained although they might be metastable phase.

Electrolyte effect on lamellar domain morphology in a nonionic surfactant solution below the Krafft temperature.

In our previous papers, we have studied the lamellar domain morphology in aqueous solutions of nonionic surfactants C16E6 and C16E7 below the Krafft temperature. In this study, electrolyte effects on lamellar domain morphology have been investigated by means of DSC, confocal microscope, small/wide-angle X-ray scattering (SAXS/WAXS). It has been found that vesicles in C16E7 solution are transformed to network structures by adding chaotropic ion Cl(-), F(-) and CH3COO(-), whereas the network structures in C16E6 solution are gradually changed to the vesicles with increasing kosmotropic ion SCN(-) concentration. Especially, we focused on the SCN(-) ion effects on the C16E6 system, and found that the characteristic morphology of cylinder-like domains were formed in a certain specific concentration range. In the SAXS observation in nm scale, we have also found that the repeat distance of lamellar structures in the C16E6/NaSCN solution is anomalously swollen when adding 1.2-2 mol/kg NaSCN, where the cylinder-like domains are formed. We have concluded that the cylindrical vesicles could be explained by the osmotic pressure difference due to the addition of NaSCN.

Effects of surfactant concentration on formation of high-aspect-ratio gold nanorods.

The effects of surfactant concentration in a growth solution on the elongation of gold nanorods were examined. Gold nanorods were synthesized in solutions with different concentrations of hexadecyltrimethylammonium bromide (HTAB): 100, 200, 300, 400, 500, and 600 mM. The nanorods grown in a solution with higher surfactant concentrations were longer (aspect ratio ~30) than those grown in that with lower concentrations (aspect ratio <10). The self-assembled surfactant structures in the solutions were analyzed using viscosity measurement and small-angle X-ray scattering. These results showed a decrease in the inter-micellar distance with increasing surfactant concentration. Taking the chemical equilibrium for the complex formation between Au ions and HTAB micelles into account, we found that the free Au ion concentration decreases accompanied with the increase in the surfactant concentration. This decrease in the free Au ion concentration suppresses undesirable secondary nucleation of gold crystals in a growth solution, resulting in gold nanorod elongation.

Re-entrant lamellar/onion transition with varying temperature under shear flow.

We have found for the first time the reentrant lamellar/onion (lamellar-onion-lamellar) transition with varying temperature under constant shear rate by using simultaneous measurements of shear stress and small-angle X-ray scattering (Rheo-SAXS) for a nonionic surfactant (C(14)E(5))/water system, which exhibits the lamellar phase in a wide temperature range from 15-75 °C. The onion state exists in a closed region in the temperature-concentration diagram at a constant shear rate. Temperature dependence of the lamellar repeat distance (d) at rest has also been measured at several concentrations. It is shown that the increase of d with increasing temperature is necessary for the existence of the lower transition. We have investigated the change in the lamellar orientation in the lamellar-to-onion and onion-to-lamellar transition processes near the upper and lower transition temperatures. For all four kinds of transition processes, the following change in the lamellar orientation is observed; lamellar state (oriented to the velocity gradient direction) ↔ further enhancement of the orientation to the velocity gradient direction ↔ enhancement of the orientation to the neutral direction ↔ onion state.

Microscopic investigation on morphologies of bilayer gel structure in the mixed polyoxyethylene-type nonionic surfactant systems.

We investigated morphologies of lamellar domains below the Krafft temperature in the mixed polyoxyethylene-type nonionic surfactant, a C(16)E(6)/C(16)E(7)/water system, by using optical microscopy, confocal microscopy, small/wide-angle X-ray scattering, and small-angle neutron scattering. We have found that the morphology discontinuously changes from network structures of lamellar domains to spherical vesicles with increasing mole fraction of C(16)E(7), via the coexistence region of vesicles and network structures of lamellar domains.

3D structure of lamellar domains in a surfactant solution below the Krafft temperature.

We have studied the 3D structure of lamellar domains in aqueous solutions of nonionic surfactant C(16)E(6) and C(16)E(7) below the Krafft temperature by means of confocal microscopy. A new morphology of lamellar domains has been found in the C(16)E(6) system, which is the network of lamellar domains. In the C(16)E(7) system, we have confirmed that the spherical vesicles have a hollow including excess water. Furthermore, we have investigated the initial formation process of lamellar domains in those two systems. It has been found that initial lamellar domains of both systems are tiny and plate-like and that the domains are gradually curved in the C(16)E(7) system, while in the C(16)E(6) system, they spread to fuse together and form networks.

Transition processes from the lamellar to the onion state with increasing temperature under shear flow in a nonionic surfactant/water system studied by Rheo-SAXS.

In a previous paper, we reported for the first time the lamellar-to-onion transition with increasing temperature at around 67 °C under a constant shear rate (0.3-10 s(-1)) in a nonionic surfactant C(16)E(7)/water system. In this study, the first temperature-shear rate diagram has been constructed in a wider range of shear rate (0.05-30 s(-1)) than in our previous study based on the temperature dependence of the shear stress at constant shear rate. The results suggest that the critical temperature above which the transition begins does not depend on the shear rate very much, although it takes a very shallow minimum. Then we have performed simultaneous measurements of small-angle X-ray scattering/shear stress (rheo-SAXS) with a stepwise increase in temperature of 0.1 K per 15 min at a constant shear rate of 3 s(-1) near the transition temperature. When the temperature exceeds 67 °C, just before the increase in the shear stress, the intensity of the Bragg peak for the velocity gradient direction (approximately proportional to the number of lamellae with their normal along this direction) is suddenly increased. As the temperature increases by 0.2 K, the shear stress begins to increase. At the same time, the peak intensity in the velocity gradient direction rapidly decreases and instead the intensity in the neutral direction increases. As the temperature increases further, the intensities in both the neutral and gradient directions decrease whereas the intensity in the flow direction increases, corresponding to the formation of onions. We have also performed rheo-SAXS experiments with a stepwise increase in shear rate at 72 °C. The sequence of the change in the intensity in each direction is almost the same in the temperature scan experiments at constant shear rate, suggesting that the transition mechanisms along these two paths are similar. The abrupt enhancement of the lamellar orientation with the layer normal along the velocity gradient direction just before the transition is the first finding and strongly supports the coherent buckling mechanism in the lamellar-to-onion transition proposed by Zilman and Granek (Zilman, A. G.; Granek, R. Eur. Phys. J. B 1999, 11, 593).

Vesicle growth and deformation in a surfactant solution below the Krafft temperature.

We have studied vesicle growth and deformation in aqueous solutions of nonionic surfactant C(16)E(7) below the Krafft temperature by means of an optical microscope. It has been found that vesicles become larger by fusing together, and that the growth rate is slower than that of the unilamellar vesicle or emulsion systems due to the multilamellar structures of shells in a vesicle. The deformation of the vesicles depends on the temperature quench depth, and we found the transformation from spherical vesicles to string-like domains at a certain quench-temperature. From the small angle X-ray scattering and confocal microscope experiments, it can be deduced that the deformation of vesicles would be induced by osmotic pressure due to the micellar concentration difference between inside and outside of vesicles.

Lamellar-to-onion transition with increasing temperature under shear flow in a nonionic surfactant/water system.

Simultaneous measurements of small-angle light scattering/shear stress (Rheo-SALS) and small-angle X-ray scattering/shear stress (Rheo-SAXS) have been performed in the lamellar phase of the C(16)E(7)/D(2)O system. As the temperature is increased and exceeds 67 degrees C at constant shear rates (at 1 and 3 s(-1)), the shear stress increases abruptly and a four-lobe pattern is observed in the depolarized SALS. These results suggest that the lamellar-to-onion transition occurs with increasing temperature, which has not yet been reported. The diameter of onions obtained from the depolarized SALS pattern at 3 s(-1) increases with increasing temperature. The transition is reversible against the change in temperature. The Rheo-SALS measurements have also been made with a stepwise increase in shear rate at constant temperature. The results are consistent with the above temperature-scan experiments at constant shear rate, suggesting that the transition does not depend on the path. The variation of the SAXS pattern at 3 s(-1) indicates that the orientation of lamellae becomes isotropic as the temperature is increased from 67 to 69 degrees C, which also supports the lamellar-to-onion transition. The transition temperature at constant shear rate (at 3 s(-1)) increases rapidly with a slight increase in surfactant concentration. From this, together with the SAXS results at rest in our previous study, we deduce that an increase in the water-layer thickness is necessary for the lamellar-to-onion transition with increasing temperature.

Formation process of bilayer gel structure in a nonionic surfactant solution.

We investigated the structure and formation process of lamellar domains below the Krafft temperature in two nonionic surfactants, the C(16)E(7)/water and C(16)E(6)/water systems, using an optical microscope and small-angle X-ray scattering. We found that vesicles and long leek-like lamellar domain structures are formed in the C(16)E(7) and C(16)E(6) systems, respectively. This large difference between the lamellar domain structures of the systems can be explained by the elastic properties of bilayers in the structural formation process.

Pressure effects on bending elasticities of surfactant monolayers in a ternary microemulsion composed of aerosol-OTD2O/decane.

Pressure effects on the bending elasticities of surfactant monolayers have been investigated in a microemulsion system composed of aerosol-OT (AOT), D2O, and deuterated decane by means of small angle neutron scattering, neutron spin echo (NSE), and dynamic light scattering (DLS). In this system, a water-in-oil droplet structure, at ambient temperature and pressure, decomposes into two phases, under both increasing temperature and pressure. The authors' previous study showed that the bending modulus kappa of monolayers slightly decreased with increasing temperature, while it increased with increasing pressure. Temperature and pressure dependencies of kappa were explained in terms of a microscopic model, which takes into account the interactions between surfactant molecules. In this paper, the authors present the temperature and pressure dependencies of kappa obtained by the analysis combined with DLS and NSE experiments. The values of the bending modulus and mean displacement of the second-order droplet deformation are reasonable. It was further confirmed that an increase in the attractive interaction between hydrocarbon tails of AOT molecules with increasing pressure could be the origin of the pressure-induced phase transition.

Micelle structures in aqueous solutions of glucose-based surfactants having an isoprenoid-type hydrophobic chain.

Surfactant self-diffusion coefficients have been measured on a binary system of 1-O-beta-3,7-dimethyloctyl-D-maltopyranoside (beta-Mal(2)(Ger))/water and a mixed surfactant system of beta-Mal(2)(Ger)/1-O-beta-3,7-dimethyloctyl-D-glucopyranoside (beta-Glc(Ger))/water at 25 degrees C. For comparison, measurements have also been made on 1-O-beta-decyl-D-maltopyranoside (beta-Mal(2)C(10))/water and beta-Mal(2)C(10)/1-O-beta-decyl-D-glucopyranoside (beta-GlcC(10))/water. The hydrodynamic radius of beta-Mal(2)(Ger) micelles obtained from the micellar diffusion coefficient is around 3 nm and nearly equal to that of beta-GlcC(10) micelles within experimental error. In the mixed surfactant systems, the hydrodynamic radii for both systems increase with increasing X(G) (the mole fraction of beta-Glc(Ger) or beta-GlcC(10) in the total mixed solute) above X(G) congruent with 0.4 when the total surfactant concentration is kept constant at 2 wt%. The R(H) of beta-Glc(Ger)/Mal(2)(Ger) micelles increases more rapidly than beta-GlcC(10)/beta-Mal(2)C(10) micelles, and then phase separation occurs at X(G) congruent with 0.65. On the other hand, the R(H) of beta-GlcC(10)/beta-Mal(2)C(10) micelles continues to increase until the phase separation occurs at X(G) congruent with 0.92. Measurements have also been performed as a function of total surfactant concentration at constant X(G) (=0.6). The CMC of the beta-Glc(Ger)/Mal(2)(Ger) system is larger than that of the beta-GlcC(10)/beta-Mal(2)C(10) system as expected from the results of the pure surfactant systems published previously. The R(H) increases with increasing total surfactant concentration for both systems. At higher concentrations, the R(H) of beta-Glc(Ger)/Mal(2)(Ger) micelles increases more rapidly than beta-GlcC(10)/beta-Mal(2)C(10) micelles. These results can be explained by the fact that the geranyl and decyl chains have the same volume but different chain lengths.

Anomalous decrease in lamellar spacing by shear flow in a nonionic surfactant/water system.

We study the effects of shear flow on the structure of a lamellar phase in a C16E7 [hepta(oxyethylene glycol)-n-hexadecyl ether]/water system (40-55 wt % of C16E7) at 70 degrees C using small-angle neutron scattering in the range of shear rate of 10(-3)-30 s(-1). At the shear rate 0.1-1 s(-1), the repeat distance (d) is decreased significantly (down to about 40% of d at rest in the most significant case) and discontinuously with increasing shear rate. With the further increase in the shear rate, d increases through a sharp minimum (referred to as d*). Such a shear rate dependence of d is obtained for all the principal orientations of lamellae. As the concentration of C16E7 decreases from 55 to 40 wt %, d increases from 6.5 to 8.5 nm at rest whereas d* remains almost constant (approximately equal to 5 nm). Moreover, d* is found to be almost equal to the thickness of bilayers obtained from the line shape analysis of small-angle X-ray scattering at rest. The results strongly suggest that the water layer is excluded by shear flow and that the lamellar phase segregates into surfactant-rich and water-rich regions, although these regions do not reach macroscopic size.