Micelle Formation Process Research Articles

Doxorubicin-Loaded Unimolecular Micelle-Stabilized Gold Nanoparticles as a Theranostic Nanoplatform for Tumor-Targeted Chemotherapy and Computed Tomography Imaging.

Current research is mainly trending toward addressing the development of multifunctional nanocarriers that could precisely reach disease sites, release drugs in a controlled-manner, and act as an imaging agent for both diagnosis and targeted therapy. In this study, a pH-sensitive theranostic nanoplatform as a promising dual-functional nanovector for tumor therapy and computed tomography (CT) imaging was developed. The 21-arm star-like triblock polymer of β-cyclodextrin-{poly(ε-caprolactone)-poly(2-aminoethyl methacrylate)-poly[poly(ethylene glycol) methyl ether methacrylate]}21 [β-CD-(PCL-PAEMA-PPEGMA)21] with stable unimolecular micelles formed in aqueous solution was first synthesized by combined ROP with ARGET ATRP techniques and then was used as a template for fabricating gold nanoparticles (AuNPs) with uniform sizes and excellent colloidal stability in situ followed by the encapsulation of doxorubicin (DOX) with maximum entrapment efficiency up to 60% to generate the final product β-CD-(PCL-PAEMA-PPEGMA)21/AuNPs/DOX. Furthermore, dissipative particle dynamics (DPD) simulations revealed further details of the formation process of unimolecular micelles and the morphologies and distributions of AuNPs and DOX. Almost 80% of DOX was released in 120 h in an acidic tumoral environment in an in vitro drug release experiment, and the experiments both in vitro and in vivo demonstrated the fact that β-CD-(PCL-PAEMA-PPEGMA)21/AuNPs/DOX exhibited similar antitumor efficacy to free DOX and effective CT imaging performance. Therefore, we believe this structurally stable unimolecular micelle-based nanoplatform synergistically integrated with anticancer drug delivery and CT imaging capabilities hold great promise for future cancer theranostics.

Polyion complex micelle formation from double-hydrophilic block copolymers composed of charged and non-charged segments in aqueous media

Polymeric micelles are representative self-assembly structures of block copolymers and have widely been investigated from both fundamental and applied aspects. In 1995, we discovered polyion complex (PIC) micelles formed from a pair of oppositely charged block copolymers with poly(ethylene glycol) segments through electrostatic interactions in aqueous media, which expanded the concept of polymeric micelle formation in selective solvents. Hereafter, extensive studies have been carried out on PIC micelles, for example, fundamental characterizations as a novel class of self-assembly systems and applications as nanocarrier systems for the delivery of charged molecules with therapeutic efficacies, including nucleic acids and proteins. This review mainly focuses on physicochemical studies on the formation of PIC micelles, particularly the critical molecular factors that have a role to determine the self-assembly scheme of charged block copolymers for micelle structures. This review focuses on the physicochemical characterization of polyion complex (PIC) micelles, particularly addressing the critical molecular factors to determine the self-assembly scheme of double-hydrophilic block copolymers composed of charged and non-charged segments into micelle structures. The process of PIC micelle formation provides new insights on the block copolymer self-assembly in thermodynamically equilibrium condition in aqueous medium, such as chain length recognition and transition from uPIC, which is the PIC of smallest neutralizing unit, to PIC micelle structures.

Experimental Investigation of Change in the Contrast between Flotation Properties of Calcic Minerals

The interaction of fatty acid sodium oleate collector and higher isoalcohols in a liquid phase and on surface of separated scheelite and calcite minerals is investigated. The research findings on monophase calcite and scheelite are presented with their X-ray patterns and IR spectra. The experimental data show the contribution of the intermolecular interactions in combinations of differently ionizable oxyhydryl collectors to the increased contrast between floatabilities of scheelite and calcite. The IR spectroscopy states that the maximum strength of the intermolecular hydrogen bridges between oleate and isoalcohols in the range of 300–3200 cm–1 fits with the molar ratio of 2. Isoalcohols in the surface layer of scheelite neutralize hydrophilic behavior of oleate micellas by means of generation of heteromolecular associates through hydrogen bridges, loosen the hydrated layer and enhance air bubble attachability; adhesion of isoalcohol drops improves floatability of scheelite; higher isoalcohols reduce flotation activity of calcite. The maximum contrast in flotation properties is observed in slimes at respective oleate concentrations fitting the micelle formation process.

PH-responsive unimolecular micelle-gold nanoparticles-drug nanohybrid system for cancer theranostics.

Developing polymeric nanoplatforms as integrated theranostic vehicles for improving cancer diagnostics and therapy is an emerging field of much importance. This article aims to develop an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging. Specific emphases is on structure-properties relationship. There is a sea of literature on polymeric drug nanocarriers, and a couple of polymer-stabilized gold nanoparticles (GNPs) systems for cancer diagnosis are also known. However, to our knowledge, there has been no report on polymeric unimolecular micelles capable of dual loading of GNPs without external reducing agents and anticancer drugs for cancer diagnosis and treatment. To this end, the target of the current work was to develop an in situ formed nanocarrier, which actively dual wrapped CT contrast agent GNPs and hydrophobic anticancer drug doxorubicin (DOX), achieving high CT imaging and antitumor efficacy under in vitro and in vivo acid tumor condition. Meanwhile, by taking advantage of dissipative particle dynamics (DPD) simulation, we further obtained the formation process and mechanism of unimolecular micelles, and detailed distributions and microstructures of GNPs and DOX on unimolecular micelles. Taken together, our results here provide insight and guidance for the design of more effective nanocarriers for cancer theranostic application.

Interaction of surfactants with block-copolymer systems in the presence of Hofmeister anions

The interactions of block copolymers poly (ethylene oxide butylene oxide), E58B7 and E58B11 with anionic surfactant sodium dodecyl sulfate and cationic surfactant cetyltrimethylammonium bromide were studied by using different techniques such as surface tension, conductivity, and dynamic light scattering. The effect of salts in the Hofmeister series on polymer–surfactant systems was also investigated. The interactions were found to be dependent on both surfactant and polymer concentrations. The results were utilized to compute different thermodynamic parameters including enthalpy of micellization (ΔHm), entropy of micellization (ΔSm), free energy of adsorption (ΔGads) and free energy of micellization (ΔGmic). For diblock-copolymer surfactant systems the negative value of (ΔGmic) shows that the process of micelle formation is thermodynamically favorable. The solubilization in surfactant micelles altered the physicochemical properties of the block copolymer. The value of critical aggregation concentration decreases with the addition of Hofmeister anions, and the decrease is more pronounced for sodium fluoride as compared to sodium iodide.

Kinetics of Photocontrollable Micelles: Light-Induced Self-Assembly and Disassembly of Azobenzene-Based Surfactants Revealed by TR-SAXS.

The kinetics of micelles involving photosensitive surfactants is still not well understood. In this work, we unravel the mechanistic pathways involved in the micelle formation and dissolution of photocontrollable micelles. We focus on the fast self-assembly processes of photosensitive cationic azobenzene-containing surfactants (AzoTMA) that display a change in hydrophobicity induced by a reversible cis-trans conformational transition upon exposure to light. By combining both in situ time-resolved small-angle X-ray scattering (SAXS) and light scattering, we characterized the detailed structure and phase behavior of AzoTMA in mixtures of water and dimethylformamide (DMF). Time-resolved synchrotron SAXS with monochromatic light as a trigger enabled us to observe the nonequilibrium formation and dissolution process of micelles (demicellization) directly on the nanoscale with a time resolution starting from milliseconds. The structural results show that in pure water UV-light illumination leads to a 12% reduction of the aggregation number of the micelles and more than a 50% increase in the critical micelle concentration (CMC). Close to the CMC, adjusted by the addition of DMF, UV light illumination leads to a complete dissolution of the micelles, while shining blue light reverses the process and leads to the reformation of micelles. The UV-triggered dissolution follows a two-step mechanism; the first and rapid (second time scale) release of unimers is followed by a slower decomposition of the micelles (over tens of seconds) as a result of an increase in temperature due to optical absorption. Similarly, the reverse process, i.e., micelle formation, occurs rapidly upon photoconversion to trans conformers under blue light, and micelles are disrupted at long exposure time due to the optical absorption and corresponding increase in temperature. Interestingly, the coexistence of unimers with regular micelles is found at all times, and no other transient assemblies could be detected by SAXS.

Effects of Carbon Numbers and Concentration of Alkanol Cosurfactants on the CMC and Thermodynamic Properties of Span80 in N,N-Dimethylformamide Solvent by Microcalorimetry

The power–time curves of the micelle formation process were determined for nonionic surfactants (Span80) in N,N-dimethylformamide solvent with alkanol (n-heptanol, n-octanol, n-nonanol, n-decanol) by titration microcalorimetry. The critical micelle concentration (CMC), aggregation number (n) and thermodynamic functions (ΔrHmθ, ΔrGmθ, ΔrSmθ) were obtained at different alkanol cosurfactants and concentrations. Effects of carbon numbers and concentration of alkanol cosurfactants on the CMC and thermodynamic properties of Span80 in N,N-dimethylformamide solvent were discussed.

Dipolar rearrangement during micellization explored using a potential-sensitive fluorescent probe

Dipole potential is the potential difference within the membrane bilayer, which originates due to the nonrandom arrangement of lipid dipoles and water molecules at the membrane interface. Although dipole potential is generally used in the context of bilayer membranes, the nonrandom arrangement of amphiphiles and water dipoles would also contribute to dipole potential in organized molecular assemblies such as micelles. In this work, we show that the process of micelle formation from monomers for a representative variety of detergents is associated with dipolar rearrangement. We monitor the dipolar reorganization upon micellization as a change in dipole potential, measured by the dual wavelength ratiometric approach utilizing the potential-sensitive membrane probe di-8-ANEPPS. We further utilized this phenomenon to estimate the critical micelle concentration (CMC) of a variety of detergents. CMC determined by this method are in overall agreement with the literature values of CMC for these detergents. To the best of our knowledge, these results constitute the first report showing dipolar reorientation during micellization. We conclude that dipole potential measurements could provide a novel approach to explore micellar organization.

Aggregation behavior of long-chain piperidinium ionic liquids in ethylammonium nitrate.

Micelles formed by the long-chain piperidinium ionic liquids (ILs) N-alkyl-N-methylpiperidinium bromide of general formula CnPDB (n = 12, 14, 16) in ethylammonium nitrate (EAN) were investigated through surface tension and dissipative particle dynamics (DPD) simulations. Through surface tension measurements, the critical micelle concentration (cmc), the effectiveness of surface tension reduction (Πcmc), the maximum excess surface concentration (Гmax) and the minimum area occupied per surfactant molecule (Amin) can be obtained. A series of thermodynamic parameters (, and ) of micellization can be calculated and the results showed that the micellization was entropy-driven. In addition, the DPD simulation was performed to simulate the whole aggregation process behavior to better reveal the micelle formation process.

Thermodynamics of micellization of ionic liquids C6mimBr and orientation dynamics of water for C6mimBr-water mixtures: a dielectric spectroscopy study.

The aggregation behavior of C6mimBr and its interaction with water at different concentrations and temperatures have been investigated by dielectric spectroscopy over frequency ranges from 500 MHz to 40 GHz. Dielectric determinations show that micellar aggregations form when the C6mimBr concentration is higher than 0.85 M, and the size of micellar aggregations varies inversely to temperature. The thermodynamic quantities of the micellization at different temperatures, ΔGm, ΔHm, and ΔSm were calculated, and it was found that the main driving forces of C6mimBr aggregation were controlled by different thermodynamic quantities at different temperatures: the micelle formation process is controlled by an enthalpy effect at low temperature while it is entropically driven at high temperature. Two remarkable relaxations that originate from the orientation polarization of "bulk water" and "bound water" interacting with C6mimBr were observed at about 8.2 and 15 GHz. The relaxation parameters obtained by fitting the dielectric spectra data were used to estimate the number of bound water per C6mim(+) in the micellar core. The enthalpy and entropy closely linked to the relaxation processes of bound water and bulk water were calculated using the relaxation time according to Eyring equations. The average number of hydrogen bonds of a C6mimBr-water system in different microenvironments was calculated, and the essence of cooperative orientation dynamics of water was described.

Structural analysis of bacteriorhodopsin solubilized by lipid-like phosphocholine biosurfactants with varying micelle concentrations

Surfactants that can provide a more natural substitute for lipid bilayers are important in the purification and in vitro study of membrane proteins. Here we investigate the structural response of a model membrane protein, bacteriorhodopsin (BR), to phosphocholine biosurfactants. Phosphocholine biosurfactants are a type of biomimetic amphiphile that are similar to phospholipids, in which membrane proteins are commonly embedded. Multiple spectroscopic and zeta potential measurements are employed to characterize the conformational change, secondary and tertiary structure, oligomeric status, surface charge distribution and the structural stability of BR solubilized with phosphocholine biosurfactants of varying tail length. The process of phosphocholine micelle formation is found to facilitate the solubilization of BR, and for long-chain phosphocholines, concentrations much higher than their critical micelle concentrations achieve good solubilization. Phosphocholine biosurfactants are shown to be mild compared with the ionic surfactant SDS or CTAB, and tend to preserve membrane protein structure during solubilization, especially at low micelle concentrations, by virtue of their phospholipid-like zwitterionic head groups. The increase of alkyl chain length is shown to obviously enhance the capability of phosphocholine biosurfactants to stabilize BR. The underlying mechanism for the favorable actions of phosphocholine biosurfactant is also discussed.

Aggregation Behavior of Trisiloxane-Tailed Surface Active Ionic Liquids in Aqueous Solution: Coarse-Grained Molecular Dynamics Study

The aggregation behaviors of two trisiloxane-tailed surface active ionic liquids in water have been investigated by coarse-grained (CG) molecular dynamics simulation on the basis of MARTINI force field. The new CG model is developed from the optimized molecule computed by using density functional theory. Direct comparison of angles and bonds obtained from all-atom (AA) simulations with those calculated from the CG model has been conducted to validate the latter model. Excellent agreement between AA and CG demonstrates that the potential of the new CG model can represent the complex system well. The long time CG simulation has been performed to understand the formation process of micelles when dissolving ionic liquids in water. Vesicles were observed at the final stage of the simulation and their partially truncated views and density profiles were obtained to describe the structure in detail.

Detecting the micellization of anionic surfactants by a colorimetric and fluorescent probe based on electrostatic attraction

A novel fluorescent probe labeled with cation, N-n-alkyl-4-(1-methylpiperazine)-1,8-naphthalimide iodide ([C8ndi]I), has been applied as a colorimetric and fluorometric probe for detecting the micellization of anionic surfactants. The critical micellization concentration (cmc) of anionic surfactants can be conveniently determined by the change on absorption and fluorescence spectra of [C8ndi]I. The probe displays highly sensitive and selective spectroscopic responses accompanied with distinctive color change (from colorless to light green). These methods are proved to be reliable as the results are in accordance with those of the standard methods. Besides the advantage of visual detection, the multiple spectroscopic methods (absorption and fluorescence) by using [C8ndi]I as probe are also simple and convenient. One can choose any spectroscopic parameter, such as position or intensity of the absorption and emission peaks, to monitor the micelle formation process of anionic surfactants.

Atomic Model and Micelle Dynamics of QS-21 Saponin

QS-21 is a saponin extracted from Quillaja saponaria, widely investigated as a vaccine immunoadjuvant. However, QS-21 use is mainly limited by its chemical instability, significant variety in molecular composition and low tolerance dose in mammals. Also, this compound tends to form micelles in a concentration-dependent manner. Here, we aimed to characterize its conformation and the process of micelle formation, both experimentally and computationally. Therefore, molecular dynamics (MD) simulations were performed in systems containing different numbers of QS-21 molecules in aqueous solution, in order to evaluate the spontaneous micelle formation. The applied methodology allowed the generation of micelles whose sizes were shown to be in high agreement with small-angle X-ray scattering (SAXS). Furthermore, the ester linkage between fucose and acyl chain was less solvated in the micellar form, suggesting a reduction in hydrolysis. This is the first atomistic interpretation of previous experimental data, the first micellar characterization of saponin micelles by SAXS and first tridimensional model of a micelle constituted of saponins, contributing to the understanding of the molecular basis of these compounds.

Mixed system of ionic liquid and non-ionic surfactants in aqueous media: Surface and thermodynamic properties

The mixed system of ionic liquid (IL) tetraethyl ammonium tetrafluoroborate [TEA(BF4)] and numerous ethylene oxide based non-ionic surfactants in aqueous media were studied using surface tension, viscosity and dynamic light scattering (DLS) measurements. Various surface properties like critical micelle concentration (cmc), maximum surface excess concentration (Γmax), minimum surface area per surfactant molecule (Amin), surface tension at the cmc (γcmc), adsorption efficiency (pC20), and effectiveness of surface tension reduction (πcmc) as well as thermodynamic parameters of micellization have been determined. DLS and viscosity measurements revealed that the micellar growth was attributed to the bridged solvophilicity of the POE chain in surfactants at elevated temperatures. In most of the cases, the progression ensues from exothermic to endothermic with increase in temperature of the mixed system. Thermodynamic parameter indicates that the micelle formation process is enthalpy driven at low temperature and entropy driven at higher temperature.

Aggregation behavior of naphthalimide fluorescent surfactants in aqueous solution

A group of novel fluorescent surfactants, N-n-alkyl-4-(1-methylpiperazine)-1,8-naphthalimide iodine [Cnndi]I (n = 8, 10, and 12), have been synthesized and their aggregation behavior in aqueous solution have been explored by surface tension, electric conductivity, hydrogen-1 NMR spectra, absorption, and fluorescence spectra. Compared with traditional cationic surfactants, the [Cnndi]I have a rather lower critical micelle concentration and higher surface activity. Absorption and fluorescence spectra were proved to be facile method to monitor directly the aggregation states of fluorescent surfactant molecules in solution and revealed clearly the formation of face-to-face stacked structure of the [Cnndi]I molecules driven by the π–π interactions. The micelle formation process for [Cnndi]I was demonstrated to be enthalpy-driven in the temperature range investigated. Possible aggregation process was given based on the experimental results. The combination of dye and surfactant provides a way for monitoring the formation process of micelle directly by fluorescence spectra.

Electrical impedance spectroscopy for determining critical micelle concentration of ionic emulsifiers

Electrical impedance spectroscopy (EIS) was conducted to investigate the micelle formation process for ionic emulsifiers, sodium dodecyl sulfate (SDS) and Aerosol MA80. Electrical impedance values were measured with variable emulsifier concentrations at frequencies ranging from 1Hz to 100kHz. The data were analyzed with the help of equivalent circuits to resolve the conductance, capacitance and phase angle parameters as a function of frequency and sample concentration. The EIS parameters were found to exhibit sharp changes due to structured transformations in emulsion and established that critical micelle concentration (CMC) could be determined accurately at specific frequency ranges. We compared the capability and accuracy of measuring the CMC using the EIS impedimetry approach with that of DC conductivity measured using a conductometer for the ionic emulsifiers. We found that conductometry is not able to identify the CMC of Aerosol MA80, while the EIS is able to determine the CMC accurately for both types of emulsifiers.

Study of Micelle Formation by Fluorocarbon Surfactant N-(2-hydroxypropyl)perfluorooctane Amide in Aqueous Solution

Micelles formed by fluorocarbon surfactant N-(2-hydroxypropyl)perfluorooctane amide in aqueous solution were studied through surface tension, dynamic light scatting (DLS), isothermal titration calorimetry (ITC), and dissipative particle dynamic (DPD) simulations. Through surface tension measurements, the effectiveness of surface tension reduction, the maximum surface excess concentration, and the minimum area occupied per surfactant molecule at the air/water interface were investigated. The critical micelle concentration (cmc) at different temperatures and a series of thermodynamic parameters (ΔG(m)0, ΔH(m)0, ΔS(m)0, ΔG(ads)0, ΔH(m)(A) and ΔC(p(m))0) of micellization were evaluated. The thermodynamic parameters showed that the micelle formation was entropy-driven. The micelle formation was also confirmed by ITC and DLS. In addition, the DPD simulations were conducted to simulate the whole process of micelle formation to make micelle formation better understood.

Molecular dynamics study of the structure and mechanism of formation of molecular associates in aqueous solutions of surfactants

The process of micelle formation in an aqueous solution of the surfactant was simulated by the computer experiment. It was established by the molecular dynamics method that micelles are formed through the formation of premicellar associates of the surfactant. The practical absence of an attraction between single molecules of sodium pentadecyl sulfonate (SPDS) and premicellar associates dissolved in water was shown for a SPDS—water system. The function of the radial distribution of Na+ counterions towards polar groups of SPDS molecules in water and on the surfaces of micelles and premicellar associates was studied by the molecular dynamics method. The presence of dissociated and non-dissociated polar groups of the SPDS molecular on the micelle surface was found. The data obtained are consistent with the existence concepts on micelle formation processes.

Study of mixed micellar aqueous solutions of sodium dodecyl sulfate and amino acids

Thermodynamic properties of sodium dodecyl sulfate (SDS) in micellar aqueous solutions of L-serine and L-threonine were determined by fluorescence spectroscopy and dynamic light scattering techniques. The values of Gibbs free energy, enthalpy and entropy of the process of micelle formation were calculated using the critical micelle concentration and degree of dissociation. Changes in critical micelle concentration of SDS with the addition of amino acids were examined by both conductivity and pyrene I 1/I 3 ratio methods at different temperatures. The pyrene fluorescence spectra were used to study the change of micropolarity produced by the interaction of SDS with amino acids. The aggregation behavior of SDS was explained in terms of structural changes in mixed solutions. The data on dynamic light scattering suggest that size of SDS micelles was influenced by the presence of amino acids.