Multicompartment Micelles Research Articles

Triphilic block copolymers with perfluorocarbon moieties in aqueous systems and their biochemical perspectives

Synthetic polymers incorporating fluorine segments or blocks are highly interesting for biomedical and pharmaceutical research due to the singular biological activity imparted by the fluorinated moieties. However, rather demanding traditional living polymerization techniques required to obtain well-defined block copolymers had typically been a major hurdle for a faster development of the field. Recently, block copolymers and telechelic polymers comprising segments with different chemical affinities, therefore termed as “polyphilic”, have become easily accessible, thanks to alternative controlled radical polymerization techniques. They can be applied alone or in conjunction with novel quantitative post-polymerization reactions which allow to “click” additional segments via functional groups. Triphilic polymers exhibit a rich variety of morphologies in solvents selective for one of the blocks including multicompartment micelles, which forecasts innovative pharmaceutical applications as for example vehicles of nanometre size for the simultaneous delivery of incompatible drug components to cells. In this highlight we focus on our recent contributions, current trends and perspectives regarding triphilic block copolymers and telechelic polymers formed exclusively from hydrophilic, lipophilic and fluorophilic building blocks.

Tuning of multicompartment micelles from cross-linkable ABC triblock copolymer with the addition of core-forming homopolymer

AbstractMulticompartment disks with bumpy edges could be synthesized controllably by dissolving a linear ABC amphiphilic triblock copolymer of polystyrene-b-polybutadiene-b-poly (2-vinylpridine) (PS440-b-PBd1020-b-P2VP114) in selective solvent mixtures of toluene and methanol. The disk size was controllable by the initial copolymer concentration. Diameter of the disks increased with the increase of the copolymer concentration. Interestingly, through adding a homo-PS to the system morphological transition took place from multicompartment disk with bumpy edges to sphere, and to hollow sphere with bumpy surfaces. Furthermore, the diameters of the hollow spheres increased with the increase of the homo-PS content, whereas the diameters of the hollows remained unchanged. Moreover, the PB block could be cross-linked by UV irradiation, stabilizing the preformed structure.

Mixed, Multicompartment, or Janus Micelles? A Systematic Study of Thermoresponsive Bis-Hydrophilic Block Terpolymers

We present a systematic investigation of the extent of compartmentalization in micelles formed by a series of bis-hydrophilic block terpolymers with two outer water-soluble segments. The corona blocks are constructed from poly(ethylene oxide) (PEO) and the thermoresponsive poly(N-isopropyl-acrylamide) (PNiPAAm). The fraction of PNiPAAm is varied to establish its influence on the supramicellar aggregation and corona phase behavior. We demonstrate that--when the collapse of PNiPAAm is triggered--a clustering of micelles into superstructures only occurs when the contour length of the thermoresponsive block is longer than that of the PEO chains. The volume fractions play a minor role. The extent of superstructure formation increases with the amount of heating cycles, pointing to a rearrangement of micelles with a mixed corona into a phase-segregated corona. The collapse of PNiPAAm is exploited to artificially raise the incompatibility and drive phase segregation. A uniform population of biphasic Janus micelles cannot be obtained. After repeated heating cycles, the mixture consists of a range of multicompartment architectures, whose patch distribution can be derived from aggregate structures found in cryo-TEM obtained at high temperature. In the last section, we relate our results to previously studied systems and attempt to derive some generalities. First, we try to answer the question of how likely it is in terms of thermodynamics to obtain truly self-assembled Janus micelles. Furthermore, our results can provide an estimation for the volume ratio or/and block lengths required in micelles composed out of two corona blocks to induce supramicellar aggregation when a hydrophilic-to-hydrophobic phase transition is triggered in one of the blocks.

Multicompartment Micelle Morphology Evolution in Degradable Miktoarm Star Terpolymers

Multicompartment micelles with segmented wormlike structures consisting of alternating poly(ethylethylene) (PEE) and poly(gamma-methyl-epsilon-caprolactone) (PMCL) layers were formed upon dispersing samples of micro-[PEE][poly(ethylene oxide)][PMCL] (micro-EOC) miktoarm star block terpolymers in neutral water. Subjecting these dispersions to a pH 12 aqueous buffer at 50 degrees C led to the hydrolytic degradation of the PMCL chains. After 4 weeks, the majority of the micro-EOC molecules were degraded into PEE-b-poly(ethylene oxide) (EO) diblocks and PMCL homopolymers. Although the resulting EO diblocks were expected to assemble into simple cylindrical micelles, the actual "daughter micelle" morphologies were much richer. The initial segmented wormlike micelles evolved into raspberry-like vesicle structures composed of spherical PMCL subdomains embedded in a PEE matrix. This dramatic change in the morphology of the multicompartment micelles is due to rearrangement of micro-EOC/EO/PMCL composite micelles to a structure that minimizes unfavorable interfacial interactions between the three mutually immiscible polymers. This type of micelle-to-micelle morphological evolution induced by block degradation in a miktoarm star terpolymer system holds promise for the development of "smart" delivery capabilities.

Reversible peptide particle formation using a mini amino acid sequence

Interest in nanostructures, artificial compartments and smart materials is steadily increasing as a result of beneficial applications in sensors, tissue engineering, nanoreactors and drug delivery systems. Block copolymers, peptide-based hybrid materials, expressed protein-like copolymers, and peptides that self-assemble in aqueous solution fulfill the demands of such applications while providing maximum biocompatibility. Herein, we focus on the formation of self-assembled particles using an amphiphilic amino acid (AA) sequence derived by solid-phase peptide synthesis (SPPS) and describe its purification and characterisation. The prepared undecamer features a repetitive L-tryptophan and D-leucine [LW-DL] motif representing the hydrophobic block, and an N-terminally attached hydrophilic (lysine or acetylated lysine) section. For peptides containing charged lysine, aggregation into micelles and a minor fraction of peptide particles was observed. Charge shielding with anionic counter ions shifted the equilibrium towards the larger peptide aggregates, with their size depending on the counter ion's position in the Hofmeister series. Similarly, the corresponding uncharged (acetylated) peptide was also demonstrated to assemble into micelles and subsequently into peptide particles, termed ‘peptide beads’, which we hypothesise to be multicompartment micelles. The formation of the peptide beads was studied as a function of temperature and solvent composition by means of electron paramagnetic resonance (EPR), dynamic and static light scattering, fluorimetry and electron microscopy. The results suggest an equilibrium between single peptide molecules, micelles, and peptide beads. Interestingly once formed the peptide beads show high mechanical stability and preserve their shape and dimensions even after isolation from solution.

Patchy multi-compartment micelles are formed by direct dissolution of an ABC triblock copolymer in water

Patchy multi-compartment micelles are formed on direct dissolution of a primary amine-based triblock copolymer, poly(ethylene oxide)-b-poly(e-caprolactone)-b-poly(2-aminoethyl methacrylate), PEO-b-PCL-b-PAMA, in water, with PCL chains forming the micelle cores and the PEO and PAMA chains forming phase-segregated patchy or hemispherical coronas. By selectively silicifying the PCL cores with tetramethyl orthosilicate (TMOS), the phase-separated character of these micelles is revealed by transmission electron microscopy.

Synthesis of Ternary, Hydrophilic−Lipophilic−Fluorophilic Block Copolymers by Consecutive RAFT Polymerizations and Their Self-Assembly into Multicompartment Micelles

Linear amphiphilic diblock and ternary triblock copolymers were synthesized by the RAFT method in three successive steps, using oligo(ethylene oxide) monomethyl ether acrylate, butyl or 2-ethylhexyl acrylate, and 1H,1H,2H,2H-perfluorodecyl acrylate. The diblock and the triblock copolymers, which consist of a hydrophilic, a lipophilic, and a fluorophilic block, self-assemble in water into spherical micellar aggregates. Imaging by cryogenic transmission electron microscopy (cryo-TEM) revealed that the cores of the micellar aggregates made from these “triphilic” copolymers undergo local phase separation to form various ultrastructures, which depend sensitively on the given block sequence. While the sequence hydrophilic−lipophilic−fluorophilic resulted in multicompartment cores with core−shell−corona morphology, the sequence lipophilic−hydrophilic−fluorophilic provided new “patched double micelle” and larger “soccer ball” structures.

Dissipative particle dynamics study on the multicompartment micelles self-assembled from the mixture of diblock copolymer poly(ethyl ethylene)-block-poly(ethylene oxide) and homopolymer poly(propylene oxide) in aqueous solution

Dissipative particle dynamics (DPD) method is applied to model the self-assembly of diblock copolymer poly(ethyl ethylene)-block-poly(ethylene oxide) (PEE-b-PEO) and homopolymer poly(propylene oxide) (PPO) in aqueous solution. In this study, several segments are coarse-grained into a single simulation bead based on the experimental density. For the self-assembly of pure diblock copolymer PEE-b-PEO in dilute solution, the DPD simulation results are in good agreement with experimental data of micelle morphologies and sizes. The chain lengths of the block copolymers and the volume ratios between PPO and PEE-b-PEO are varied to find the conditions of forming multicompartment micelles. The micelles with core–shell–corona structure and the micelles with two compartments are both formed from the mixture of PEE-b-PEO and PPO in aqueous solution.

Multicompartment Nanoparticles Formed by a Heparin-Mimicking Block Terpolymer in Aqueous Solutions

A new amphiphilic block terpolymer poly((sulfamate-carboxylate)isoprene)-block-polystyrene-block-poly(ethylene oxide), PISC230-PS52-PEO151, with a narrow molecular weight distribution (PDI = 1.05), was synthesized via the post polymerization reaction of the anionically prepared precursor block terpolymer polyisoprene-block-polystyrene-block-poly(ethylene oxide) with chlorosulfonyl isocyanate. The formation and structure of self-assemblies of the polyelectrolyte block terpolymer in dilute aqueous solutions were studied by static and dynamic light scattering, atomic force and cryogenic transmission electron microscopy, fluorometry, and 1H NMR spectroscopy. In acidic solutions, the terpolymers self-assemble into kinetically trapped multicompartment micelles, with the core consisting of discrete PS and PISC domains and PEO in the shell. If the solution pH is adjusted to the alkaline region, the multicompartment micelles undergo an irreversible transition to regular micelles, with a PS core and a mixed shell f...

Interpolyelectrolyte Complexes of Dynamic Multicompartment Micelles

Dynamic core-shell-shell-corona micelles are formed between two oppositely charged block copolymer systems. Preformed polybutadiene-block-poly(N-methyl-2-vinylpyridinium)-block-poly(methacrylic acid) (PB-P2VPq-PMAA) block terpolymer micelles with a soft polybutadiene core, an interpolyelectrolyte complex (IPEC) shell made out of poly(N-methyl-2-vinylpyridinium) and poly(methacrylic acid), and a negatively charged PMAA corona were mixed in different ratios at high pH with positively charged poly(N-methyl-2-vinylpyridinium)-block-poly(ethylene oxide) (P2VPq-PEO) diblock copolymers. Under these conditions, mixing results in the formation of a second IPEC shell onto the PB-P2VPq-PMAA precursor micelles, surrounded by a PEO corona. The resulting multicompartmented IPECs exhibit dynamic behavior, highlighted by a structural relaxation within a period of 10 days, investigated by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and scanning force microscopy (SFM). After a short mixing time of 1 h, the IPECs exhibit a star-shaped structure, whereas after 10 days, spherical core-shell-shell-corona objects could be observed. To further increase complexity and versatility of the presented systems, the in situ formation of gold nanoparticles (Au NPs) in both the precursor micelles and the equilibrated IPEC was tested. For the PB-P2VPq-PMAA micelles, NP formation resulted in narrowly distributed Au NPs located within the PMAA shell, whereas for the core-shell-shell-corona IPEC, the Au NPs were confined within the IPEC shell and shielded from the outside through the PEO corona.

Morphology and Structure Control of Multicompartment Micelles from Triblock Copolymer Blends

Control of the overall morphology and inner structure of multicompartment micelles from binary blends of triblock copolymers in solution was studied by dissipative dynamics simulations. The effects of the block sequence, block ratio, block length, and chain architecture on the morphology and structure of mixed multicompartment micelles were investigated systematically. This work shows that by changing the block composition or chain architecture of one copolymer in the binary blends, the mixed degree, relative distance, and degree of participation of core-forming blocks from two triblock copolymers can be tuned, and diverse morphologies of mixed micelles with alterable domain arrangements and overall size can be obtained. This work shows that blending of copolymers is an effective way to control the morphology and inner structure of multicompartment micelles, providing useful information on the preparation of mixed micelles with unique properties for practical applications.

A New Strategy To Form Multicompartment Micelles: Fluorocarbon−Hydrocarbon Ion-Pair Surfactant

The hydrophobic core of the multicompartment micelles consists of incompatible and clearly separated distinct subdomains which make them different from the classical micelles. Owing to these properties multicompartment micelles have a great potential to be used as solubilization agents and carriers for a wide variety of applications where it is important to prevent the uncontrolled interaction of the solubilizates before reaching the target and to convey them to the specified point simultaneously. Here we show that effective compartmentalization inside the micelle and high solubilization capacity for the two immiscible water-insoluble materials in cases of both simultaneous and separate solubilization can be achieved by newly designed ion-pair hybrid surfactant CH(3)(CH(2))(11)(OCH(2)CH(2))(23)N(+)(C(2)H(5))(3)SO(3)(-)(CF(2))(7)CF(3) (C(12)E(23)N(+)SO(3)(-)F(8)) through the agency of favorable molecular design. Molecular structure is tailored by the approach of using a balance of forces to obtain compartmentalization, which is without precedent. This new molecule also has the properties of quite low critical micelle concentration and an extensive surfactant concentration range for solubilization which are additional important advantageous features.

Helical Vesicles, Segmented Semivesicles, and Noncircular Bilayer Sheets from Solution-State Self-Assembly of ABC Miktoarm Star Terpolymers

Multicompartment micelles, especially nanostructured vesicles, offer tremendous potential as delivery vehicles of therapeutic agents and nanoreactors. Solution-state self-assembly of miktoarm star terpolymers provides a versatile and powerful route to obtain multicompartment micelles. Here we report simulations of solution-state self-assembly of ABC star terpolymers composed of a solvophilic A arm and two solvophobic B and C arms. A variety of multicompartment micelles are predicted from the simulations. Phase diagrams for typical star terpolymers are constructed. It is discovered that the overall micelle morphology is largely controlled by the volume fraction of the solvophilic A arms, whereas the internal compartmented and/or segregated structures depend on the ratio between the volume fractions of the two solvophobic arms. The polymer-solvent and polymer-polymer interactions can be used to tune the effective volume fraction of the A-arm and, thereby, induce morphological transitions. For terpolymers with equal or nearly equal length of B and C arms, several previously unknown structures, including vesicles with novel lateral structures (helices or stacked donuts), segmented semivesicles, and elliptic or triangular bilayer sheets, are discovered. When the lengths of B and C arms are not equal, novel micelles such as multicompartment disks and onions are observed.

Multicompartment Micelles from pH-Responsive Miktoarm Star Block Terpolymers

We describe the synthesis of pH-responsive miktoarm star block terpolymers mu-[polystyrene][poly(ethylene oxide)][poly(2-(dimethylamino)ethyl acrylate)] (mu-SODA) using a combination of two successive living anionic polymerizations and one reversible addition-fragmentation chain-transfer polymerization. Poly[2-(dimethylamino)ethyl acrylate] (PDMAEA) is a weak polybase that is hydrophilic at low pH and hydrophobic at high pH because of the protonation of the dimethylamino functional group with decreasing pH. In addition, our results suggest that PDMAEA is immiscible with polystyrene (PS), a feature that is desirable for the formation of multicompartment micelles. Using a combination of dynamic light scattering and cryogenic transmission electron microscopy, we demonstrate that mu-SODA micelles formed in water evolve from mixed corona (PEO + PDMAEA corona; PS core) and predominantly spherical micelles to multicompartment (PEO corona; PS + PDMAEA core) micelles with increasing pH.

Multicompartment Core Micelles of Triblock Terpolymers in Organic Media

The formation of multicompartment micelles featuring a “spheres on sphere” core morphology in acetone as a selective solvent is presented. The polymers investigated are ABC triblock terpolymers, polybutadiene-b-poly(2-vinyl pyridine)-b-poly(tert-butyl methacrylate) (BVT), which were synthesized via living sequential anionic polymerization in THF. Two polymers with different block lengths of the methacrylate moiety were studied with respect to the formation of multicompartmental aggregates. The micelles were analyzed by static and dynamic light scattering as well as by transmission electron microscopy. Cross-linking of the polybutadiene compartment could be accomplished via two different methods, “cold vulcanization” and with photopolymerization after the addition of a multifunctional acrylate. In both cases, the multicompartmental character of the micellar core is fully preserved, and the micelles could be transformed into core-stabilized nanoparticles. The successful cross-linking of the polybutadiene core is indicated by 1H NMR and by the transfer of the aggregates into nonselective solvents such as THF or dioxane.

Synthesis and Micellar Self-Assembly of Ternary Hydrophilic−Lipophilic−Fluorophilic Block Copolymers with a Linear PEO Chain

Linear amphiphilic diblock and ternary triblock copolymers were synthesized by the RAFT method in two successive steps using a poly(ethylene oxide) (PEO) macrochain transfer agent, butyl or 2-ethylhexyl acrylate, and 1H,1H,2H,2H-perfluorodecyl acrylate. The diblock and the triblock copolymers, which consist of a hydrophilic, a lipophilic, and a short fluorophilic block, self-assemble in water into spherical micellar aggregates. Imaging by cryogenic transmission electron microscopy (cryo-TEM) revealed that the micellar cores of the aggregates made from these "triphilic" copolymers can undergo local phase separation to form a unique ultrastructure. In these multicompartment micelles, it appears that extended nonspherical domains, presumably made of nanocrystallites of the fluorocarbon block, are embedded in the hydrocarbon matrix forming the spherical micellar core. This novel internal structure of a micellar core is attributed to the mutual incompatibility of the fluorocarbon and hydrocarbon side chains in combination with the tendency of the used fluorocarbon acrylate monomer to undergo side-chain crystallization.

Bump-Surface Multicompartment Micelles from a Linear ABC Triblock Copolymer: A Combination Study by Experiment and Computer Simulation

Novel bump-surface multicompartment micelles formed by a linear amphiphilic ABC triblock copolymer via self-assembly in selective solvent were successfully observed both in simulation and experiment. The results revealed that the block A forms the most inner core, and the blocks B and C form the inner and outer layers, respectively, and the bumps were formed by block A and more likely to be born on curving surfaces. Moreover, the micelle shape could be controlled by changing the solvent selectivity of the blocks A and B. Spherical, cylindrical, and discoidal micelles with bumpy surfaces were obtained both in experiment and simulation.

Complex domain architecture of multicompartment micelles from a linear ABC triblock copolymer revealed by cryogenic electron tomography

Cryo-electron tomography of raspberry-like multicompartment micelles formed by a linear ABC triblock copolymer in water revealed that the fluorocarbon domains may be dispersed all over the hydrocarbon core.

Formation of hydrophobic bridges between multicompartment micelles of miktoarm star terpolymers in water

We report on the unexpected finding of the formation of hydrophobic bridges between polybutadiene patches of multicompartment micelles based on amphiphilic miktoarm star terpolymers in water.

Multicompartment micelles from a metallo-supramolecular tetrablock quatercopolymer

Multicompartment micelles with tunable compartment solubility have been prepared in alcohols from a metallo-supramolecular poly(p-tetrafluoromethylstyrene)-block-poly(tert-butylacrylate)-block-poly(styrene)-[Ru]-poly(ethylene glycol) tetrablock quaterpolymer.