Multicompartment Micelles Research Articles

Individual and simultaneous encapsulation and delivery of incompatible dyes in biocompatible multicompartment terpolymer micelles

Multicompartment micelles (MCMs) can deliver incompatible drug payloads because MCMs derive from the self-assembly of a terpolymer containing one hydrophilic block and two incompatible solvophobic blocks. In particular, MCMs resulting from the self-assembly of poly((sulfamate-carboxylate)isoprene)-block-polystyrene-block-poly(ethylene oxide) (PISC-b-PS-b-PEO) undergo irreversible transition to regular micelles at an alkaline pH. However, several aspects of these MCMs remain unexplored, such as the chemical transformation of PISC-b-PS-b-PEO into an amino-acid functional terpolymer, potential applications of these nanoparticles as dual drug delivery systems and their biocompatibility. In exploring these opportunities, we found that more than 90% of N-S bonds of sulfamate groups (of the PISC block) are cleaved upon acidic treatment of PISC-b-PS-b-PEO terpolymers, which are chemically transformed into a new polyzwitterion triblock terpolymer, that is, poly((amino-carboxylate)isoprene)-block-polystyrene-block-poly(ethylene oxide) (PACIS-b-PS-b-PEO), but retain their MCM morphology. Into these MCMs, two incompatible (Nile Red (hydrophobic) and eosin (hydrophilic)) guest molecules can be loaded separately and together in the predesigned cores without significantly disturbing the structure, as shown by cryo-TEM and light scattering. In addition to their high stability, PACIS-b-PS-b-PEO MCMs are also pH-responsive, whether loaded or unloaded, based on fluorescence spectroscopy and light scattering. In cytotoxicity tests, loaded and unloaded PACIS-b-PS-b-PEO nanoparticles proved nontoxic to various cell lines, including Balb/3T3 and MCF10A, with efficient cellular uptake, as shown by fluorescence imaging. Therefore, our findings highlight PACIS-b-PS-b-PEO as a versatile platform for preparing MCMs for multiple drug delivery.

Modular synthesis of dendritic ionic triphiles and their behavior in three-phase liquid–liquid–liquid system

Triphilic molecules possess unique features due to the presence of chemically distinct domains − oleophilic, hydrophilic, and fluorophilic. In bulk, they can form intriguing crystal structures, while in solutions, they can act as multi-purpose emulsifiers or form assemblies such as multi-compartment micelles applicable in drug delivery. However, their chemico-physical properties are still relatively unexplored. Namely, they have never been studied in a three-phase liquid–liquid–liquid system consisting of organic and fluorous solvents and water. Here we present an adaptive, modular synthesis of a novel type of dendritic ionic triphiles and a study of their solution behavior, with a focus on a three-phase toluene/water/perfluoro(methylcyclohexane) (PMC) system. The synthesis is based on the quaternization of various alkylimidazoles by a previously published type of carbosilane dendritic wedges bearing polyfluorinated chains of varied lengths at their periphery. This approach enables the facile combination of different organic and fluorous blocks and, thus, easy tailoring of final structures according to the results of this work. The distribution of triphiles in the selected three-phase system was mapped in a ternary diagram representing the mass proportions of individual domains. The distribution between toluene and PMC changes gradually depending on the sizes of the corresponding domains and significantly differs from the distribution in a biphasic system where water is absent (i.e., the fluorous partition coefficient). However, at a certain size of the fluorous domain, the molecules completely lose their affinity to the fluorous phase and gain affinity to water even though being still partially soluble in PMC. The results can help understand the structure-affinity relationship of triphilic compounds and can help find a substance with balanced affinities to all three solvents. Moreover, some of the prepared compounds manifested interesting surface activity, namely the emulsification capability on both phase interfaces or the formation of stable nanoparticles in an aqueous environment.

Seeded Raft Polymerization-Induced Self-assembly: Recent Advances and Future Opportunities.

Over the past decade, polymerization-induced self-assembly (PISA) has fully proved its versatility for scale-up production of block copolymer nanoparticles with tunable sizes and morphologies; yet, there are still some limitations. Recently, seeded PISA approaches combing PISA with heterogeneous seeded polymerizations have been greatly explored and are expected to overcome the limitations of traditional PISA. In this review, recent advances in seeded PISA that have expanded new horizons for PISA are highlighted including i) general considerations for seeded PISA (e.g., kinetics, the preparation of seeds, the selection of monomers), ii) morphological evolution induced by seeded PISA (e.g., from corona-shell-core nanoparticles to vesicles, vesicles-to-toroid, disassembly of vesicles into nanospheres), and iii) various well-defined nanoparticles with hierarchical and sophisticated morphologies (e.g., multicompartment micelles, porous vesicles, framboidal vesicles, AXn -type colloidal molecules). Finally, new insights into seeded PISA and future perspectives are proposed. This article is protected by copyright. All rights reserved.

Nonorthogonal Cascade Catalysis in Multicompartment Micelles.

Multicompartment micelles (MCMs) containing acid and base sites in discrete domains are prepared from poly(norbornene)-based amphiphilic bottlebrush copolymers in aqueous media. The acid and base sites are localized in different compartments of the micelle, enabling the nonorthogonal reaction sequence: deacetalization - Knoevenagel condensation - Michael addition of acetals to 2-amino chromene derivatives. Computational simulations using dissipative particle dynamics (DPD) elucidated the bottlebrush composition required to effectively site-isolate the nonorthogonal catalysts. This contribution presents MCMs as a new class of nanostructures for one-pot multistep nonorthogonal cascade catalysis, laying the groundwork for the isolation of three or more incompatible catalysts to synthesize value-added compounds in a single reaction vessel, in water.

Catalytically Active Multicompartment Micelles.

This article presents the self-assembly behavior of multicompartment micelles (MCMs) in water into morphologies with multiple segregated domains and their use as supports for aqueous catalysis. A library of poly(norbornene)-based amphiphilic bottlebrush copolymers containing covalently attached l-proline in the hydrophobic, styrene, and pentafluorostyrene domains and a poly(ethylene glycol)-containing repeat unit as the hydrophilic block have been synthesized using ring-opening metathesis polymerization. Interaction parameter (χ) values between amphiphilic blocks were determined using a Flory–Huggins-based computational model. The morphologies of the MCMs are observed via cryogenic transmission electron microscopy and modeled using dissipative particle dynamic simulations. The catalytic activities of these MCM nanoreactors were systematically investigated using the aldol addition between 4-nitrobenzaldehyde and cyclohexanone in water as a model reaction. MCMs present an ideal environment for catalysis by providing control over water content and enhancing interactions between the catalytic sites and the aldehyde substrate, thereby forming the aldol product in high yields and selectivities that is otherwise not possible under aqueous conditions. Catalyst location, block ratio, and functionality have substantial influences on micelle morphology and, ultimately, catalytic efficiency. “Clover-like” and “core–shell” micelle morphologies displayed the best catalytic activity. Our MCM-based catalytic system expands the application of these nanostructures beyond selective storage of guest molecules and demonstrates the importance of micelle morphology on catalytic activity.

Structural Transformation of a Multicompartment Micelle Induced by Photo-Switchable Spiropyran–Merocyanine Transition: Dissipative Particle Dynamics Simulation Approach

Structural Transformation of a Multicompartment Micelle Induced by Photo-Switchable Spiropyran–Merocyanine Transition: Dissipative Particle Dynamics Simulation Approach

Morphology Control of Multicompartment Micelles in Water through Hierarchical Self-Assembly of Amphiphilic Terpolymers

Multicompartment micelles (MCMs) allow the simultaneous storage of multiple cargoes such as dyes, catalysts, or drugs, and have therefore gained attention in catalysis, nanotechnology, and nanomedicine. In the present work, we describe design rules to control the morphology of MCMs in water including spheres, cylinders, sheets, and vesicles. For that, we synthesized a series of poly(ethylene oxide) (PEO)-b-polystyrene (PS)-b-poly(methyl acrylate) (PMA) triblock terpolymers and systematically varied the length of the PS and PMA block. Using a stepwise hierarchical assembly process, we first form patchy precursor micelles in organic solvent with PS core and mixed PEO/PMA corona. In the second step, these micelles act as subunits, which assemble (or cluster) in water into MCMs, where PEO forms the stabilizing corona, PS the compartment, and PMA the inner core. We find that the shape of the final MCM can be predicted by ascribing a Janus balance to precursor micelles as the molar ratio of PEO to PMA, which provides a synthetic handle to target specific MCM morphologies.

Metal-free synthesis and self-assembly of poly(ethylene glycol) methyl ether-block-poly(ε-decalactone)-block-poly(methyl methacrylate) triblock terpolymers

Derived from sustainable sources, ε-decalactone (ε-DL) emerges as a renewable alternative to synthetic cyclic esters. However, its copolymerization with different monomers often requires using metal complexes potentially toxic to humans and the environment. Here, we report the synthesis and self-assembly of poly(ethylene glycol) methyl ether-block-poly(ε-decalactone)-block-poly(methyl methacrylate) (mPEG-block-PDL-block-PMMA) triblock terpolymers via two synthetic pathways using a simple phosphazene- or phosphate-based metal-free catalytic system. Our size exclusion chromatography (SEC) results showed that the two-step synthetic mechanism combining bis(4-nitrophenyl) phosphate (BNPP) and 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylidenamino]-2λ5,4λ5-catenadi(phosphazene) (t-BuP4) provided a better polymerization control than sequential copolymerization. In addition, our SAXS and AFM analysis also demonstrated that the blocks are incompatible in the terpolymers, further promoting their self-assembly into multicompartment micelles in water, as confirmed by cryo-TEM. Therefore, mPEG-block-PDL-block-PMMA triblock terpolymers may be used as both environmentally friendly alternatives to metal-catalyzed polymers and drug delivery systems.

Fabrication of diverse multicompartment micelles by redispersion of triblock terpolymer bulk morphologies.

Redispersing block copolymer (BCP) bulk films in selective solvents is a simple and efficient method to prepare BCP micelles and polymersomes. While ABC triblock terpolymers are known to form multicompartment micelles (MCMs) with intricate nanoarchitecture, this is typically done by solvent exchange instead of redispersion of bulk films despite obvious advantages of greatly reduced solvent usage. Here, we provide guidelines on how to form MCMs with defined shapes and inner structure through direct redispersion of terpolymer bulk morphologies in selective plasticizing solvents. For this purpose, we redisperse a series of polystyrene-b-polybutadiene-b-poly(tert-butyl methacrylate) (PS-b-PB-b-PT) triblock terpolymers in acetone/isopropanol mixtures, where PT is always soluble, PB always insoluble, and PS will range from soft (high acetone content) to kinetically frozen (high isopropanol content). We investigate the effect of solvent mixtures, block composition, and thermal annealing on MCM shape and core morphology. Additionally, we performed terpolymer blend experiments to open up a simple route to further diversify the range of accessible MCM morphologies.

Light-induced reversible self-assembly of multi-compartment patchy micelles

The diblock copolymer P4VP-b-PAzoMA self-assembles into a hierarchical structure through a two-step process. Intriguingly, hierarchical structure could reversibly self-assemble under UV and visible light due to the existence of azobenzene moieties.

Synthesis of Biologically Decomposable Terpolymer Nanocapsules and Higher‐Order Nanoassemblies Using RCMP‐PISA

AbstractTerpolymers are used to generate bio‐decomposable self‐assemblies. PEG‐PVL‐PGMA terpolymers are synthesized via a combination of organocatalyzed living radical polymerization (RCMP) with polymerization‐induced self‐assembly (PISA), generating vesicle, multicompartment micelle (MCM), and core‐compartmentalized worm (CCW), where PEG, PVL, and PGMA are poly(ethylene glycol) monomethyl ether, poly(δ‐valerolactone), and poly(glycidyl methacrylate) and PGMA is grown during the PISA. MCM and CCW are uniquely obtainable using terpolymers. The PVL segment is biodegradable, and the obtained assemblies are bio‐decomposable. Heavy metal‐free and sulfur‐free synthesis and bio‐decomposability of the assemblies are attractive features.

Structure-Controlled Preparation of Multicompartment Micelles with Tunable Emission through Hydrodynamics-Dependent Self-Assembly in Microfluidic Chips

Multicompartment micelles (MCMs) attracted much attention since they have subdivided domains that could be employed to encapsulate and transport diverse compounds simultaneously. Usually, preparation of MCMs relied on precise synthesis of block copolymers (BCPs) and elegant control of assembly kinetics, making it difficult to successively produce MCMs. Herein, we report a facile yet effective method for preparing MCMs by adjusting the hydrodynamics in microfluidic channels. It was found that well-defined MCMs were formed through hydrodynamics-dependent secondary assembly in microfluidic chips. By adjusting the flow diffusion process by varying the flow rate ratio and total flow rate, both the internal structure and size of MCMs could be effectively changed. A product diagram of micellar morphologies associated to the initial polymer concentration and flow rate ratio of water/BCPs solution was constructed. More interestingly, quantum dots (QDs) could be selectively loaded into different domains of the MCMs. Consequently, the Förster resonance energy transfer among QDs could be effectively suppressed. Thus, the emission spectrum of MCMs/QDs hybrid particles could be easily tuned by changing the ratio of QDs, showing great potential application in photonics and sensors.

Discovery of unusual morphological evolution of A-graft-(B-block-C) graft terpolymers by tuning the length of B component

The self-assembly behaviors and morphological evolutions of the A-g-BC graft terpolymers in A-backbone-attractive solvents were examined by using the real-space implemented self-consistent field theory. The concentric structure-in-structure (B-enwrap-C) and surface-patched structure-on-structure (B-patch-C) multicompartment micelles were observed by tailoring the B block lengths. At longer length of B blocks, the A-g-BC graft terpolymers prefer to form the common concentric B-enwrap-C multicompartment micelles, while the B-patch-C multicompartment micelles with B patches on C surface favor the shorter length of B blocks. It was found that the formation of B-patch-C is driven by the conformational entropy of the B blocks. In addition, when the length of B block decreases into a much lower value, an unusual morphological evolution from raspberry-like to concentric multicompartment micelles was discovered, which was revealed to be driven by the conformational entropy of the inner blocks of A backbone between two adjacent graft points. The gained results could provide a deep insight into the mechanism behind the morphological evolution between concentric structure-in-structure (B-enwrap-C) and surface-patched structure-on-structure (B-patch-C) multicompartment micelles.

Reversible multilayered vesicle-like structures with fluid hydrophobic and interpolyelectrolyte layers

Hydrophobic blocks of amphiphilic block copolymers often form glassy micellar cores at room temperature with a rigid structure that limits their applications as nanocapsules for targeted delivery. Nevertheless, we prepared and analyzed core/shell micelles with a soft core, formed by a self-assembled block copolymer consisting of a hydrophobic block and a polycation block, poly(lauryl acrylate)-block-poly(trimethyl-aminoethyl acrylate) (PLA-QPDMAEA), in aqueous solution. By light and small-angle neutron scattering, by transmission electron microscopy and by fluorescence spectroscopy, we showed that these core/shell micelles are spherical and cylindrical with a fluid-like PLA core and a positively charged outer shell and that they can encapsulate and release hydrophobic solutes. Moreover, after mixing these PLA-QPDMAEA core/shell micelles with another diblock copolymer, consisting of a hydrophilic block and a polyanion block, namely poly(ethylene oxide)-block-poly(methacrylic acid) (PEO-PMAA), we observed the formation of novel vesicle-like multicompartment structures containing both soft hydrophobic and interpolyelectrolyte (IPEC) layers. By combining small-angle neutron scattering with self-consistent field modeling, we confirmed the formation of these complex vesicle-like structures with a swollen PEO core, an IPEC inner layer, a PLA soft layer, an IPEC outer layer and a loose PEO corona. Thus, these multicompartment micelles with fluid and IPEC layers and a hydrophilic corona may be used as nanocapsules with several tunable properties, including the ability to control the thickness of each layer, the charge of the IPEC layers and the stability of the micelles, to deliver both hydrophobic and multivalent solutes.

Multicompartment Self-assemblies of Triblock Copolymer for Drug Delivery

Novel multicompartment self-assemblies of triblock copolymer polystyrene–polyisoprene–poly(2-vinylpyridine) (PS-PI-P2VP) for drug delivery are demonstrated. The triblock copolymer assemblies in dilute solutions in a common solvent (tetrahydrofuran) undergo transformations from core-shell-corona micelles to multicompartment micelles by adding P2VP-selective solvent (water). The effects of water content and pH on the assembled structures were systematically investigated. Multicompartment micelles are also obtained by adding a surfactant, 4-biphenylcarboxylic acid, into the solution. Such multicompartment self-assemblies are used as carriers for encapsulation and release of an anticancer drug doxorubicin hydrochloride (DOX). The drug loading content and drug loading efficiency of DOX were evaluated. The DOX release experiments were performed at 37°C under pH 5.5 and pH 7.4. The DOX release rate was improved as pH decreased from pH 7.4 to 5.0, with 45.6% release of DOX in 32 h.

Silk Sericin-Polylactide Protein-Polymer Conjugates as Biodegradable Amphiphilic Materials and Their Application in Drug Release Systems.

Silk sericin (SS) is a byproduct of silk production. In order to transform it into value-added products, sericin can be used as a biodegradable and pH-responsive building block in drug delivery materials. To this end, amphiphilic substances were synthesized via the conjugation of hydrophobic polylactide (PLA) to the hydrophilic sericin using a bis-aryl hydrazone linker. PLA was esterified with a terephthalaldehydic acid to obtain aromatic aldehyde terminated PLA (PLA-CHO). In addition, lysine groups of SS were modified with the linker succinimidyl-6-hydrazino-nicotinamide (S-HyNic). Then, both macromolecules were mixed to form the amphipilic protein-polymer conjugate in buffer-DMF solution. The formation of bis-aryl hydrazone linkages was confirmed and quantified by UV-vis spectroscopy. SS-PLA conjugates self-assembled in water into spherical multicompartment micelles with a diameter of around 100 nm. Doxorubicin (DOX) was selected as a model drug for studying the pH-dependent drug release from SS-PLA nanoparticles. The release rate of the encapsulated drug was slower than that of the free drug and dependent on pH, faster at pH 5.0, and it resulted in a larger cumulative amount of drug released than at physiological pH of 7.4. The SS-PLA conjugate of high PLA branches showed smaller particle size and lower loading capacity than the one with low PLA branches. Both SS-PLA conjugates had negligible cytotoxicity, whereas after loading with DOX, the SS-PLA micelles were highly toxic for the human liver carcinoma immortalized cell line HepG2. Therefore, the SS-based biodegradable amphiphilic material showed great potential as a drug carrier for cancer therapy.

Multicompartment Polymeric Nanocarriers for Biomedical Applications.

Multicompartment polymeric nanocarriers which mimic the compartmentalized architecture of living cells have received considerable research attention in the biomedical field. The advancement of synthetic polymeric chemistry has allowed multicompartment polymeric nanocarriers to be tailored for biomedical applications such as drug delivery, encapsulated catalysis, and artificial cellular mimics. In this review, polymer-based multicompartment nanocarriers (multicompartment micelles, multicompartment polymersomes, and capsosomes) have been discussed. This review focuses on multicompartment systems applied to biomedical applications over the last ten years. The synthetic procedures and structural properties that impact the specific application are also highlighted.

PH-Controlled Hierarchical Assembly/Disassembly of Multicompartment Micelles in Water.

Multicompartment micelles (MCMs) have become attractive drug delivery systems as they allow the separate storage of two or more incompatible cargos in their core compartments (e.g., drugs and dyes for imaging). A recent hierarchical self-assembly process for hydrophobic terpolymers in organic solvents showed the ability to form very homogeneous MCM populations, yet the transfer of this process into water requires a better understanding of the formation mechanism and influence of chain mobility during assembly. Here, the synthesis of a linear poly(oligo(ethylene glycol) methacrylate)-block-poly(benzyl acrylate)-block-poly(4-vinylpyridine) (POEGMA-b-PBzA-b-P4VP) triblock terpolymer by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported as well as its step-wise assembly into MCMs in water with POEGMA corona, PBzA patches, and P4VP core. Reversible assembly/disassembly of the MCMs is investigated through protonation/deprotonation of the P4VP core. Interestingly, the low glass transition temperature (Tg ) of the hydrophobic PBzA middle block causes MCMs to directly disassemble into molecularly dissolved chains instead of patchy micelles due to mechanical stress from electrosteric repulsion of the protonated P4VP corona chains. In addition, pH resistant MCMs are created by core-crosslinking and fluorescent properties are added by covalent anchoring of fluorescent dyes via straightforward click chemistry.

Synthesis and complex self-assembly of amphiphilic block copolymers with a branched hydrophobic poly(2-oxazoline) into multicompartment micelles, pseudo-vesicles and yolk/shell nanoparticles

A new PEO-b-PEHOx amphiphilic diblock copolymer was achieved which unlocked new complex self-assembled structures. Thanks to its hydrophobic oxazoline block with a long branched side chain, EHOx, various potent structures were obtained.

Hierarchical self-assembly of a PS-b-P4VP/PS-b-PNIPAM mixture into multicompartment micelles and their response to two-dimensional confinement.

Hierarchical self-assembly offers an elegant and energy-efficient bottom-up strategy for the fabrication of complex materials with precisely controllable morphologies and internal structures. Herein, pupa-like multicompartment micelles (MCMs) were readily fabricated via the hierarchical self-assembly of a polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) and polystyrene-block-poly(N-isopropylacrylamide) (PS-b-PNIPAM) block copolymer mixture in a THF/water mixture solvent, which were unable to be obtained by any of the individual block copolymers (BCPs). This means that the hierarchical self-assembly is a result of the synergistic cooperation between the two BCPs. Moreover, a kinetic study revealed that the MCMs were formed by hierarchical self-assembly of small spherical micelles (SSMs), which were co-assembled from the PS-b-P4VP/PS-b-PNIPAM mixture. Subsequently, we investigated the self-assembly of a PS-b-P4VP/PS-b-PNIPAM mixed solution confined in the nanopores of an anodic aluminum oxide (AAO) template. In such two-dimensional confinement, long multicompartment micelles (LMCMs) with a period multilayer structure were obtained. Notably, the confinement effect of nanopores on the hierarchical self-assembly could be distinguished into two different situations according to the activity of secondary assembly of the preformed SSMs from different BCP compositions, i.e., dynamic and static confinement. The dynamic confinement can affect the Brownian movement of SSMs and thus promotes their fusion to form spherical micelles with larger size compared with the SSMs formed under an unconfined condition. For the situation where AAO nanopores were partially filled with the preformed SSMs, the static confinement could decrease the stretching of BCP chains along the short axis of LMCMs and thus induce the formation of long range ordered multilayer nanostructures. These results illustrated that the synergistic effect played an important role in the hierarchical assembly of BCPs; meanwhile, such hierarchical self-assembly could be further manipulated by cylindrical confinement to rationally tune the nanostructures and dimensions of the BCP assemblies.