Polymersome formation mechanism and formation rate in stirred‐tank reactors

Uniform polymersomes (polymer vesicles) made of poly(2‐methyloxazoline)₁₅‐b‐poly(dimethylsiloxane)₆₈‐b‐poly(2‐methyloxazoline)₁₅ (PMOXA15–PDMS68–PMOXA15) can be formed in miniaturized‐stirred tank reactors by the aid of a recently published process. In this study, the occurring self‐assembly mechanism was elucidated by using transmission electron microscopy. Subsequent to the initial formation of small spherical micelles and the following fusion to worm‐like micelles, two simultaneously occurring pathways, describing the transformation of further intermediate structures to the desired vesicles, were found. The resulting particle increase was followed by dynamic light scattering. Thus, the vesicle formation rate was judged by the linear increase of the particle diameter over time. While temperature showed no influence, higher initial polymer concentrations and lower final solvent concentrations accelerated the polymersome formation. Besides, the process was crucially dependent on the agitation speed. While spherical micelles did not transform into polymersomes when no stirring or too slow stirring is applied, the self‐assembly process was accelerated by increasing the agitation speed. Uniform polymeric vesicles can be formed under vigorous stirring in stirred‐tank reactors in short process times. In this study, the underlying mechanisms of vesicle formation were elucidated, showing that the polymer forms small micellar structures before undergoing two separate pathways to form the desired vesicular structures. The formation rate of the polymer vesicles was mainly dependent on the agitation speed but also on the polymer and solvent concentrations, highlighting the need for controlled formation conditions. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46077.     

Poly[N-(2-hydroxypropyl)methacrylamide-block-n-butyl acrylate] micelles in water/DMF mixed solvents

Three diblock copolymers of poly[N-(2-hydroxypropyl)methacrylamide] (poly(HPMA)) and poly(n-butyl acrylate) (poly(BA)) with varying lengths of blocks were prepared by atom transfer radical polymerization. All copolymers were found to be soluble in dimethylformamide (DMF) and poorly soluble or insoluble in water. In water and mixed DMF/H₂O solvents, the copolymers were dispersed in micellar form by controlled addition of water to DMF solutions of copolymers under continuous intensive stirring. The micellar solutions in water were prepared by dialysis of solutions in DMF/H₂O (95 vol% of H₂O) against water. Solution properties of diblock copolymers of poly(HPMA) and poly(BA) were studied using static and dynamic laser light scattering to characterize the behavior of the copolymers at the supramolecular level. The effects of preparation mode, organic solvent (DMF) and copolymer chemical composition on the formation of micelles were studied. While a slower mixing procedure was optimal for copolymers with short poly(HPMA) blocks, a faster mixing was more suitable for copolymers having longer poly(HPMA) blocks. Finally, the dimensions of micelles in water were evaluated. The most compact micelles were prepared from copolymers having short hydrophilic poly(HPMA) blocks. On the other hand, the copolymer with the longest poly(HPMA) block formed micelles with the smallest size and the lowest density.     

Does PNIPAM block really retard the micelle-to-vesicle transition of its copolymer?

The well-known coil-to-globule transition of poly(N-isopropyl acrylamide) (PNIPAM) at its LCST lasts as short as hundred of seconds with fully reversibility. However, for the PNIPAM-containing block copolymers, thermal transformation from micelles to vesicles caused by the conformation transition of PNIPAM took as long as several weeks, even at the temperatures much higher than the LCST, and without satisfactory reversibility. In the literature, this slow process has been attributed to the strong interchain hydrogen bonding in PNIPAM, which retards the transition. In this work, asymmetrically modified PNIPAM (Mw 10K), i.e. C₁₂-PNIPAM-CA with a hydrophobic hydrocarbon chain -C₁₂H₂₅ (C₁₂) at one end and a hydrophilic carboxyl group -COOH (CA) at the other, was prepared and found to form micelles with a core of the lightly associated hydrocarbon chains. When temperature is increased to the LCST of PNIPAM, the transformation from micelles to vesicles can be realized within 30 min, while the reverse process only takes a few minutes. Based on full monitoring of the transition process, it is proposed that the micelles serve as building blocks in constructing the vesicles via processes of combination, fusion, and etc., in which only local conformation adjustment of PNIPAM is involved. Therefore, reducing the restriction to the conformation change of PNIPAM chains, which is imposed by the micellar core, is one of the key factors in realizing the fast transition.     

Vesicle formation of polystyrene-block-poly (ethylene oxide) block copolymers induced by supercritical CO2 treatment

A novel route for a preparation of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) block copolymer vesicles induced by supercritical carbon dioxide (scCO₂) is demonstrated. When PS-b-PEO block copolymer solutions in tetrahydrofuran (THF) are treated with scCO₂ at 70 °C for different times, PS-b-PEO copolymers first assemble into aggregated spheres; then aggregated spheres change into large compound micelles and finally evolve into vesicles. The possible formation mechanism of the vesicles is discussed.     

Two‐component “Onionlike” micelles with a PPO core,a PDMAEMA shell and a PEO corona: formation and crosslinking

BACKGROUND: Chemical or physical crosslinking of supramolecular assemblies gives them stability in a wide range of environments. Much attention is paid to multilayer (onion‐like) polymeric micelles because their functionality is higher than classic core‐shell micelles. This work reports on the formation and crosslinking of onion‐like micelles prepared by mixing two different block copolymers containing a crosslinkable poly(dimethylaminoethyl methacrylate) (PDMAEMA) block. RESULTS: Block copolymers of a crosslinkable PDMAEMA block were synthesized by atom transfer radical polymerization of 2‐(dimethylamino)ethyl methacrylate (DMAEMA) from poly(propylene oxide) (PPO) or poly(ethylene oxide) (PEO) macroinitiators. The (PDMAEMA₁₃)‐block‐PPO₆₉‐block‐(PDMAEMA₁₃) triblock formed wormlike core‐shell micelles, which were converted into ellipsoidal onion‐like micelles on mixing with the PEO₄₅‐block‐P(DMAEMA₈‐co‐MMA₄) diblock. Onion‐like micelles were crosslinked by quaternization of DMAEMA units. CONCLUSION: Formation of onion‐like micelles by mixing two different AB (ABA) and B′C block copolymers and their subsequent crosslinking is a valuable approach towards stabilized supramolecular assemblies of a higher complexity and functionality than the individual constitutive components. Copyright © 2008 Society of Chemical Industry     

Phosphatidylcholine as substrate for human pancreatic phospholipase A2. Importance of the physical state of the substrate

The long-chain phosphatidylcholine/sodium cholate aqueous system as substrate for human pancreatic phospholipase A₂ (PLA₂) was investigated. At a constant phosphatidylcholine (PC) concentration of 8 mM, the enzyme activity increased with a decrease in cholate (C) concentration up to a PC/C ratio of approximately 0.8 and then rather abruptly decreased to lower values at a ratio above 1.5. At ratios between 0.8 and 1.5, an increasing lag phase in the PLA₂ activity was seen, indicating a progressive decrease in substrate availability to the enzyme. Reaction mixtures with a PC/C ratio of up to 0.67 were optically clear solutions composed of mixed bile salt/PC micelles of increasing mixed micellar aggregate size. Ratios between 0.67 and 1.5 were characterized by an increase in turbidity (at 330 and 450 nm) due to increasing formation of vesicles or liposomes. Above a PC/C ratio of 1.5, a sharp increase in turbidity was seen due to increasing formation of bilayer structures other than vesicles. Pure vesicles obtained by dialysis of mixed micellar solutions were not hydrolyzed by the enzyme. Addition of bile salts reversed the inhibition which was accompanied by a decrease in turbidity. Phosphatidylcholine was preferred as substrate for human PLA₂ when present in large mixed disc-like bile salt micelles. Vesicular or other types of lamellar liquid-crystalline phases of long-chain phosphatidylcholine did not serve as substrate for PLA₂.     

Effects of additives on the morphologies of thin titania films from self-assembly of a block copolymer

The effects of additives of poly(methyl methacrylate) (PMMA) and HAuCl₄ on the morphologies of hybrid titania films formed via co-assembly of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) copolymers, titania sol-gel precursor in a selective solvent were investigated. The results show that addition of PMMA or HAuCl₄ has an important influence on the morphologies of hybrid titania films. Addition of PMMA or HAuCl₄ can induce the morphology transition of the PS-b-PEO/titania sol-gel mixture from spherical micelles to vesicles. Therefore, the morphologies of the hybrid films formed on silicon substrate surfaces by spin-coating can be controlled by the addition of homopolymer (PMMA) or inorganic precursor (HAuCl₄) into the PS-b-PEO/titania sol-gel mixtures, allowing access to nanoparticles or nanoporous films. After removing the polymer matrix, nanoparticle aggregates or nanobowl-like structures are left behind on the substrate surfaces.     

双亲性聚合物胶束研究进展

两亲性嵌段聚合物在选择性溶剂中可以自组装成为一系列的形态结构,如球状胶束、柱状胶束、层状胶束、囊泡和微管结构,尤其自组装形成胶束,这一结构可做为药物输送材料已成为高分子科学和生物医学研究领域的热点之一。文章对上述领域进行综述,结合作者研究的课题,分成三大类进行阐述：胶束的制备方法;影响胶束的因素;胶束的表征方法。     

Micellization of linear A-b-(B-alt-C)n multiblock terpolymers in A-selective solvents

We used three-dimensional self-consistent field theory to investigate the micellization behavior of A-b-(B-alt-C)_n multiblock terpolymers in the presence of a solvent that is selective to the terminal A-block. In particular, we focused on the effects of the incompatibility parameter between B and C, χ_BC, and the composition of the solvophilic A-block, f_A, on the formation of micelles from ABC triblock and A(BC)₃ multiblock terpolymers, respectively. We observed a general trend that a segmented packing of B- and C-layers along the axial direction of the micelles is favored than the coaxial packing with the increasing of χ_BC or decreasing of f_A. The separation of B and C blocks within a micelle leads to the formation of a variety of multicompartment micelle morphologies, such as core–shell–corona spherical micelles, hamburgers, and bump-surface micelles, in the ABC triblock copolymers. In the A(BC)₃ multiblock terpolymers, we discovered more fascinating micelles by implementing the SCFT simulation than by the DPD simulation. Besides the BC-segmented worm-like micelles, which have been found in the DPD simulation work, concentric multilayer spheres and vesicles can be formed by the solvent-induced effect when the solvophilic A-block is a majority component. The SCFT method provides an efficient way to screen promising molecular architectures for the ability to self-assemble into technologically promising hierarchical structures.     

Self-assembly of micelles into designed networks

The EO₂₀PO₇₀EO₂₀ (molecular weight 5800) amphiphile as a template is to form dispersed micelle structures. Silver nanoparticles, as inorganic precursors synthesized by a laser ablation method in pure water, are able to produce the highly ordered vesicles detected by TEM micrography. The thickness of the outer layer of a micelle, formed by the silver nanoparticles interacting preferentially with the more hydrophilic EO₂₀ block, was around 3.5 nm. The vesicular structure ensembled from micelles is due to proceeding to the mixture of cubic and hexagonal phases.     

Self-assembly of polystyrene-b-poly(4-vinylpyridine) in deoxycholic acid melt

It is well known that amphiphilic block copolymers in selective solvents self-assemble into micellar structures, where solvophilic blocks tend to contact with solvents while solvophobic blocks are shielded from the solvents. Different from the conventional micellization in liquid systems, we report that the block copolymer, polystyrene-b-(4-vinylpyridine) (PS-b-P4VP), can self-assemble in melted deoxycholic acid (DCA) at high temperatures and the structures are retained in “solid state” after being cooled down to room temperature. Probing by transmission electron microscopy (TEM), we found that a series of self-assembled structures, including spherical micelles, wormlike micelles and vesicles can be obtained by varying the length of the block copolymers and the morphologies are dependent on the annealing temperature and time. We also demonstrate how to extract the structures that are trapped in solid state by removing DCA using appropriate solvents. The extracted vesicles, which are loaded with solid molecules, are potential for applications in nanocapsules and controlled release.     

Solution self‐assembly of tailor‐made macromolecular building blocks prepared by controlled radical polymerization techniques

This review describes the preparation of colloidal aggregates (spherical micelles, cylindrical micelles, polymer vesicles, multicompartment micelles, polyion complexes, schizophrenic micelles) using bottom‐up self‐assembly approaches. In particular, it focuses primarily on the self‐organization of well‐defined macromolecular building blocks (macrosurfactants, polysoaps, polyelectrolytes) synthesized by controlled radical polymerization techniques such as atom transfer radical polymerization, reversible addition fragmentation transfer polymerization and nitroxide‐mediated polymerization. The goal of this review is to highlight that these versatile techniques of polymer synthesis allow the preparation of unprecedented nanostructures in dilute solutions. Copyright © 2006 Society of Chemical Industry     

In vitro behavior of marine lipid-based liposomes. Influence of pH, temperature, bile salts, and phospholipase A2

To deliver polyunsaturated fatty acids (PUFA) by the oral route, liposomes based on a natural mixture of marine lipids were prepared by filtration and characterized in media that mimic gastrointestinal fluids. First the influence of large pH variations from 1.5–2.5 (stomach) to 7.4 (intestine) at the physiological temperature (37°C) was investigated. Acidification of liposome suspensions induced instantaneous vesicle aggregation, which was partially reversible when the external medium was further neutralized. Simultaneously, complex morphological bilayer rearrangements occurred, leading to the formation of small aggregates. These pH- and temperature-dependent structural changes were interpreted in terms of osmotic shock and lipid chemical alterations, i.e., oxidation and hydrolysis, especially in the first hours of storage. Besides, oxidative stability was closely related to the state of liposome aggregation and the supramolecular organization (vesicles or mixed micelles). The effects of bile salts and phospholipase A₂ (PLA₂) on the liposome structures were also studied. Membrane solubilization by bile salts was favored by preliminary liposome incubation in acid conditions. PLA₂ showed a better activity on liposome structures than on the corresponding mixed lipid-bile salt micelles. As a whole, in spite of slight morphological modifications, vesicle structures were preserved after an acid stress and no lipid oxidation products were detected during the first 5 h of incubation. Thus, marine lipids constituted an attractive material for the development of liposomes as potential oral PUFA supplements.     

Synthesis and micelle behavior of (PNIPAm-PtBA-PNIPAm)m amphiphilic multiblock copolymer

A linear amphiphilic multiblock copolymer (PNIPAm-PtBA-PNIPAm)_m was successfully synthesized by a two-step reversible addition-fragmentation transfer (RAFT) polymerization in the presence of a cyclic trithiocarbonate as RAFT agent. The micelle behavior of (PNIPAm-PtBA-PNIPAm)_m multiblock copolymer in aqueous solution was then investigated by means of normal TEM, cryo-TEM, static and dynamic light scattering. The morphology, size, and size distribution of (PNIPAm-PtBA-PNIPAm)_m micelles were found to be dependent on the initial concentration of multiblock copolymer in THF. Spherical micelles, associated aggregates of spherical micelles, cage-like micelles, layered structures, and vesicular micelles were experimentally observed, which were in good agreement with the prediction of theory and simulations on linear amphiphilic multiblock copolymer in selective solvent. The (PNIPAm-PtBA-PNIPAm)_m micelles also exhibit thermo-sensitive behavior in aqueous solution because of the PNIPAm blocks.     

Aggregated assemblies of hexadecyltrimethylammonium bromide and phospholipids at the interface and in the bulk solution

Interactions between hexadecyltrimethylammonium bromide (HTAB) and l-α-phosphatidylcholine (PC), 1,2-didecanoyl-sn-glycero-3-phosphocholine (DPC), and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (PPC) at the air/water interface and in the bulk solution were evaluated using interfacial tension, fluorescence, and conductivity measurements to study the aggregation processes of HTAB in fixed concentrations of aqueous lipid solutions containing 7–36 μM of each lipid. The interfacial and fluorescence measurements showed the occurrence of two kinds of aggregation processes in HTAB-PC and HTAB-DPC systems, which were identified by the three breaks at low lipid concentrations, i.e., 7–14μM. The first aggregation process, C ₁, involved the incorporation of HTAB monomers into the lipid vesicles and the subsequent disruption of the vesicular structure leading to the formation of mixed micelles. The second aggregation process, C ₂, which started at the second break, indicated the completion of the mixed micelles and the initiation of independent micelle formation process which was completed at the third break. At higher PC or DPC concentration, i.e., 14–22 μM, the first break, which indicated the initiation of the first aggregation process, was not observed; only the second and third breaks were visible. This is ascribed to the presence of comparatively large vesicles, which were able to accommodate HTAB monomers initially without any drastic change in their architecture. In the presence of PPC, the aggregation process of HTAB was similar to that in pure water as studied from the interfacial tension measurements, whereas the bulk behavior indicated the presence of strong structure transitions upon incorporation of HTAB monomers in the PPC vesicles. A difference between the aggregation behaviors of HTAB with PPC was explained on the basis of the stronger hydrophobicity of PPC over PC and DPC.     

Effect of Silica Nanoparticles on Wormlike Micelles with Different Entanglement Degrees

Enhancing the viscoelastic properties of wormlike micelles by adding nanoparticles has been widely reported. Various mechanisms have been proposed to explain how nanoparticles strengthen the network formed by wormlike micelles. It remains unclear whether nanoparticles produce the same effect on systems with different entanglement degrees. To clarify this issue, the concentration of potassium chloride was used to control the entanglement degree of wormlike micelles. The rheological behavior of different nanoparticle-enhanced wormlike micellar systems (NEWMS) was investigated using rheology. Three critical parameters including zero-shear viscosity (η₀), relaxation time (τ_R), and contour length (L) were calculated to analyze the effect of nanoparticles on the different wormlike micellar systems. An appropriate mechanism describing the interaction between nanoparticles and wormlike micelles with different structures was proposed.     

Preparation of magnetic iron-oxide nanoparticles by successive reduction-oxidation in reverse micelles: Effects of reducing agent and atmosphere

The chemical reduction of ferrous or ferric ions to metallic iron by a reducing agent such as sodium borohydride (NaBH₄), hydrazine (N₂H₄), or sodium phosphonate (NaH₂PO₂) and its subsequent oxidation were investigated for the preparation of iron-oxide nanoparticles in reverse micelles. The crystal structure and crystallinity of the oxide nanoparticles were found to depend on the oxidation potential of the reducing agent and the catalytic activity of the surface of deposited iron. In addition, it was demonstrated that the process used for oxidizing the metallic iron was critical for the formation of oxide nanoparticles, and that the enhancement of magnetic properties was achieved by providing a flow of oxygen during the oxidation process.     

Amino‐terminated polylactide micelles with an external poly(ethylene oxide) corona as carriers of drug‐loaded anionic liposomes

Micelles were prepared from a mixture of NH₂‐terminated poly(l ‐lactide) and poly(d ,l ‐lactide)‐block‐poly(ethylene oxide) (molar ratio of 3:7). The micelles were complexed with bilayer lipid vesicles (liposomes) composed of anionic palmitoyloleoylphosphatidylserine and zwitterionic dioleoylphosphatidylcholine in a molar ratio of 3:7. The micelles and micelle–liposome complexes were characterized using dynamic light scattering, laser electrophoresis, fluorimetry, transmission electron microscopy, enzymatic hydrolysis and cell viability with the following main findings. (i) Average diameter of micelle cores was found to be 70 ± 10 nm. (ii) Each micelle carried ca 20 000 amino groups. (iii) In a pH 7 solution the impact of the protonated NH₂ groups in the total surface of micelles was negligible owing to their screening by bulky poly(ethylene oxide) blocks. (iv) The micelles were stable in slightly acidic and neutral aqueous solutions, but aggregated in slightly alkaline solutions. (v) The micelles showed no cytotoxicity up to 0.04 mg mL^?1 concentration (the maximum concentration in the experiment). (vi) Each micelle adsorbed ca 30 anionic liposomes loaded with the antitumor antibiotic doxorubicin; the liposomes retained their integrity upon binding with micelles. (vii) The initial micelles and the micelle–liposome complexes showed two‐week stability to enzymatic hydrolysis. © 2018 Society of Chemical Industry     

Synthesis and Properties of Quaternary Ammonium Gemini Surfactants with Hydroxyethyl at Head Groups

A series of cationic gemini surfactants C_mH_{2m + 1}N⁺(CH₂CH₂OH)₂ (CH₂)_s N⁺(CH₂CH₂OH)₂C_mH_{2m + 1} 2Br⁻, referred to as m-s-m (OH) (m = 8,10,12, s = 3,4), were prepared by quaternization of dihydroxyethyl tertiary amines with dibromoalkane. The dihydroxyethyl tertiary amines were synthesized by nucleophilic substitution of diethanolamine with bromoalkane. The characterization of the m-s-m (OH) surfactants was performed using ¹H NMR and MS. The surface activities and aggregation behavior in aqueous solution of the m-s-m (OH) surfactants were studied using surface tension measurements, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The surface tension and critical micellar concentration of these surfactants in aqueous solution decreased dramatically due to the introduction of hydroxyethyl at the head group. The micelles and/or vesicles formed in the aqueous solution of m-s-m (OH) surfactants were strongly dependent upon the lengths of spacer chains and carbon chains. The number of vesicles increases and that of micelles decreases when the lengths of spacer chains and carbon chains increase.     

Self-supporting pH- and temperature-responsive ethyl cellulose-g-PDMAEMA microporous membranes through non–solvent-induced phase separation process

First, ethyl cellulose-g-poly(2-(dimethylamino) ethyl methacrylate) (EC-g-PDMAEMA) was synthesized through atom transfer radical polymerization. Second, the polymer was used to prepare self-supporting microporous membranes through nonsolvent-induced phase separation process. The chemical structures of EC_0.2-g-PDMAEMA₁₅ was confirmed by ¹H NMR and FTIR. And the copolymer micelles were characterized by UV, laser particle-size analysis, and TEM. The results indicated that the copolymer had pH- and temperature-responsive behaviors. Furthermore, the morphology study of microporous membranes indicated that the pores became smaller and more uniform with the increase of tetrahydrofuran (THF) content and “open time”, and the most optimal preparation conditions were using 75% THF/25% DMF (v/v) as solvents with the “open time” 30?s. What’s more, the membranes were responsive to pH and temperature stimulus in terms of water flux.