Amphiphilic Block Copolymer Micelles Research Articles

Methotrexate-Loaded Four-Arm Star Amphiphilic Block Copolymer Elicits CD8+ T Cell Response against a Highly Aggressive and Metastatic Experimental Lymphoma.

We have synthesized a well-defined four-arm star amphiphilic block copolymer [poly(DLLA)-b-poly(NVP)]4 [star-(PDLLA-b-PNVP)4] that consists of D,L-lactide (DLLA) and N-vinylpyrrolidone (NVP) via the combination of ring-opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthesis of the polymer was verified by 1H NMR spectroscopy and gel permeation chromatography (GPC). The amphiphilic four-arm star block copolymer forms spherical micelles in water as demonstrated by transmission electron microscopy (TEM) and 1H NMR spectroscopy. Pyrene acts as a probe to ascertain the critical micellar concentration (cmc) by using fluorescence spectroscopy. Methotrexate (MTX)-loaded polymeric micelles of star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer were prepared and characterized by fluorescence and TEM studies. Star-(PDLLA15-b-PNVP10)4 copolymer was found to be significantly effective with respect to inhibition of proliferation and lysis of human and murine lymphoma cells. The amphiphilic block copolymer causes cell death in parental and MTX-resistant Dalton lymphoma (DL) and Raji cells. The formulation does not cause hemolysis in red blood cells and is tolerant to lymphocytes compared to free MTX. Therapy with MTX-loaded star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer micelles prolongs the life span of animals with neoplasia by reducing the tumor load, preventing metastasis and augmenting CD8+ T cell-mediated adaptive immune responses.

New approach for producing fluorescent gold nanoparticles: Poly(ethylene oxide) homopolymers as reductants in the micelles of amphiphilic fluorosilicone-containing block copolymers

The reduction of gold salts by poly(ethylene oxide) (PEO) homopolymer is very slow and more than 2 days is needed to produce gold nanoparticles (AuNPs). In this work, however, AuNPs are rapidly produced in the micelles of novel amphiphilic poly[methyl(3,3,3-trifluoropropyl)siloxane]-b-poly(acrylic acid) (PMTFPS-b-PAA) block copolymers when using PEO as the reductant. Moreover, fluorescent AuNPs in the block copolymer micelles are presented by a direct monitoring of the micelle shape and the solution optical properties. Additional Supporting Information may be found in the online version of this article. Supplementary Information Supplementary Information Supplementary Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization.

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG750) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG750. PolyQPA-mPEG750 was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39mg/ml, 0.107mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by (1)H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG750 underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG750 polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.

Ligand-Assisted Co-Assembly Approach toward Mesoporous Hybrid Catalysts of Transition-Metal Oxides and Noble Metals: Photochemical Water Splitting

A bottom-up synthetic approach was developed for the preparation of mesoporous transition-metal-oxide/noble-metal hybrid catalysts through ligand-assisted co-assembly of amphiphilic block-copolymer micelles and polymer-tethered noble-metal nanoparticles (NPs). The synthetic approach offers a general and straightforward method to precisely tune the sizes and loadings of noble-metal NPs in metal oxides. This system thus provides a solid platform to clearly understand the role of noble-metal NPs in photochemical water splitting. The presence of trace amounts of metal NPs (≈0.1 wt %) can enhance the photocatalytic activity for water splitting up to a factor of four. The findings can conceivably be applied to other semiconductors/noble-metal catalysts, which may stand out as a new methodology to build highly efficient solar energy conversion systems.

Ligand-Assisted Co-Assembly Approach toward Mesoporous Hybrid Catalysts of Transition-Metal Oxides and Noble Metals: Photochemical Water Splitting.

A bottom-up synthetic approach was developed for the preparation of mesoporous transition-metal-oxide/noble-metal hybrid catalysts through ligand-assisted co-assembly of amphiphilic block-copolymer micelles and polymer-tethered noble-metal nanoparticles (NPs). The synthetic approach offers a general and straightforward method to precisely tune the sizes and loadings of noble-metal NPs in metal oxides. This system thus provides a solid platform to clearly understand the role of noble-metal NPs in photochemical water splitting. The presence of trace amounts of metal NPs (≈0.1 wt %) can enhance the photocatalytic activity for water splitting up to a factor of four. The findings can conceivably be applied to other semiconductors/noble-metal catalysts, which may stand out as a new methodology to build highly efficient solar energy conversion systems.

Filtration-based synthesis of micelle-derived composite membranes for high-flux ultrafiltration.

Ideal membrane configurations for efficient separation at high flux rates consist of thin size-selective layers connected to macroporous supports for mechanical stabilization. We show that micelle-derived (MD) composite membranes combine efficient separation of similarly sized proteins and water flux 5-10 times higher than that of commercial membranes with similar retentions. MD composite membranes were obtained by filtration of solutions of amphiphilic block copolymer (BCP) micelles through commercially available macroporous supports covered by sacrificial nanostrand fabrics followed by annealing and removal of the nanostrand fabrics. Swelling-induced pore generation in the BCP films thus covering the macroporous supports yielded ∼210 nm thin nanoporous size-selective BCP layers with porosities in the 40% range tightly connected to the macroporous supports. Permselectivity and flux rates of the size-selective BCP layers were adjusted by the BCP mass deposited per membrane area and by proper selection of swelling times. The preparation methodology described here may pave the way for a modular assembly system allowing the design of tailored separation membranes.

Unimolecular micelles of amphiphilic cyclodextrin-core star-like block copolymers for anticancer drug delivery.

Well-defined star-like amphiphilic polymers composed of a β-cyclodextrin core, from which 21 hydrophobic poly(lactic acid) arms and hydrophilic poly(ethylene glycol) arms are grafted sequentially, form robust and uniform unimolecular micelles that are biocompatible and efficient in the delivery of anticancer drugs.

Antireflective coatings with adjustable refractive index and porosity synthesized by micelle-templated deposition of MgF2 sol particles.

Minimizing efficiency losses caused by unwanted light reflection at the interface between lenses, optical instruments and solar cells with the surrounding medium requires antireflective coatings with adequate refractive index and coating thickness. We describe a new type of antireflective coating material with easily and independently tailorable refractive index and coating thickness based on the deposition of colloidal MgF2 nanoparticles. The material synthesis employs micelles of amphiphilic block copolymers as structure directing agent to introduce controlled mesoporosity into MgF2 film. The coatings thickness can be easily adjusted by the applied coating conditions. The coatings refractive index is determined by the materials porosity, which is controlled by the amount of employed pore template. The refractive index can be precisely tuned between 1.23 and 1.11, i.e., in a range that is not accessible to nonporous inorganic materials. Hence, zero reflectance conditions can be established for a wide range of substrate materials.

Core-shell nanoreactors for efficient aqueous biphasic catalysis.

Water-borne phosphine-functionalized core-cross-linked micelles (CCM) consisting of a hydrophobic core and a hydrophilic shell were obtained as stable latexes by reversible addition-fragmentation chain transfer (RAFT) in water in a one-pot, three-step process. Initial homogeneous aqueous-phase copolymerization of methacrylic acid (MAA) and poly(ethylene oxide) methyl ether methacrylate (PEOMA) is followed by copolymerization of styrene (S) and 4-diphenylphosphinostyrene (DPPS), yielding P(MAA-co-PEOMA)-b-P(S-co-DPPS) amphiphilic block copolymer micelles (M) by polymerization-induced self-assembly (PISA), and final micellar cross-linking with a mixture of S and diethylene glycol dimethacrylate. The CCM were characterized by dynamic light scattering and NMR spectroscopy to evaluate size, dispersity, stability, and the swelling ability of various organic substrates. Coordination of [Rh(acac)(CO)2 ] (acac=acetylacetonate) to the core-confined phosphine groups was rapid and quantitative. The CCM and M latexes were then used, in combination with [Rh(acac)(CO)2 ], to catalyze the aqueous biphasic hydroformylation of 1-octene, in which they showed high activity, recyclability, protection of the activated Rh center by the polymer scaffold, and low Rh leaching. The CCM latex gave slightly lower catalytic activity but significantly less Rh leaching than the M latex. A control experiment conducted in the presence of the sulfoxantphos ligand pointed to the action of the CCM as catalytic nanoreactors with substrate and product transport into and out of the polymer core, rather than as a surfactant in interfacial catalysis.

Amphiphilic block copolymer micelles with fluorescence as nano-carriers for doxorubicin delivery

Well-defined and nontoxic core–shell polymeric micelles, containing fluorescence units, were employed for efficient drug delivery of doxorubicin (DOX). The self-assembled structures were generated from triblock copolymers of poly(e-caprolactone)-block-poly(glycidyl methacrylate)-block-poly(poly(ethylene glycol)methyl ether methacrylate) (PCL-b-PGMA-b-P(PEGMA)) with fluorescence units. Various experiments like structural characterization, fluorescence properties, cell viability studies, encapsulation studies, measuring cytotoxicity against fibroblasts and bladder cancer cells are performed on these polymeric micelles. All of these results demonstrate that these self-assembled micelles may be promising carriers for intravesical delivery of DOX for bladder cancer therapy.

Modulation of Interparticle Interactions and Specific Absorption Rate in Magnetomicelles through Changes in the Molecular Weight of the Hydrophobic Polymer Block

Magnetomicelles are amphiphilic block copolymer micelles, which contain magnetic nanoparticles in the core. Magnetomicelles have been proposed as magnetic fluid hyperthermia agents for cancer treatment. Magnetic interactions between nanoparticles within a micelle affect the amount of heat that they dissipate. Here, magnetomicelles are prepared varying the molecular weight of the core‐forming polymer block. The magnetomicelles are magnetically characterized in liquid suspensions and embedded in a polymer matrix. The results show that as the molecular weight of the core‐forming polymer block increases, both the interparticle magnetic interactions and specific absorption rate decrease. This is probably due to mixing between the polymer and the magnetic nanoparticles, which increases the interparticle distance.

PH-Regulated Controlled Swelling and Sustained Release from the Core Functionalized Amphiphilic Block Copolymer Micelle.

pH-responsive amphiphilic block copolymers based on poly(ethylene glycol)monomethyl ether-b-poly(methyl methacrylate-co-methacrylamidepropanoic acid) (PEO-b-PMMA-co-PMAPA) with different MMA/MAPA ratios were synthesized from respective amine-reactive prepolymers based on poly(ethylene glycol)monomethyl ether-b-poly(methyl methacrylate-co-methacryloxysuccinimide) (PEO-b-PMMA-co-PMASI) in such a way that the pH-responsive carboxylic acid groups were randomly distributed in the hydrophobic (PMMA) block. In aqueous medium, they formed micellar aggregates. Control experiments showed stability and critical aggregation concentration and dye encapsulation properties were better for carboxylic acid functionalized micelles at acidic pH compared to a structurally similar block copolymer micelle that lacked any carboxylic acid group. This was attributed to H-bonding among the carboxylic acid groups. In basic pH upon deprotonation, controlled swelling of the aggregates was observed due to repulsion among the negatively charged carboxylate groups. The extent of swelling/deswelling was well controlled by simply changing the percentage of the pH-responsive units in the hydrophobic block and could be probed quantitatively by pH-dependent dynamic light scattering (DLS) and fluorescence resonance energy transfer (FRET) studies. The aggregates were able to encapsulate a hydrophobic guest such as pyrene at the interior of the micelle, and sustained release of this hydrophobic probe was achieved selectively at basic pH due to swelling of the micelles instead of complete disassembly that generally leads to burst release.

A general and robust strategy for the synthesis of nearly monodisperse colloidal nanocrystals

Colloidal nanocrystals exhibit a wide range of size- and shape-dependent properties and have found application in myriad fields, incuding optics, electronics, mechanics, drug delivery and catalysis, to name but a few. Synthetic protocols that enable the simple and convenient production of colloidal nanocrystals with controlled size, shape and composition are therefore of key general importance. Current strategies include organic solution-phase synthesis, thermolysis of organometallic precursors, sol-gel processes, hydrothermal reactions and biomimetic and dendrimer templating. Often, however, these procedures require stringent experimental conditions, are difficult to generalize, or necessitate tedious multistep reactions and purification. Recently, linear amphiphilic block co-polymer micelles have been used as templates to synthesize functional nanocrystals, but the thermodynamic instability of these micelles limits the scope of this approach. Here, we report a general strategy for crafting a large variety of functional nanocrystals with precisely controlled dimensions, compositions and architectures by using star-like block co-polymers as nanoreactors. This new class of co-polymers forms unimolecular micelles that are structurally stable, therefore overcoming the intrinsic instability of linear block co-polymer micelles. Our approach enables the facile synthesis of organic solvent- and water-soluble nearly monodisperse nanocrystals with desired composition and architecture, including core-shell and hollow nanostructures. We demonstrate the generality of our approach by describing, as examples, the synthesis of various sizes and architectures of metallic, ferroelectric, magnetic, semiconductor and luminescent colloidal nanocrystals.

Heteroepitaxial Formation of Aligned Mesostructured Silica Films with Large Structural Periodicities from Mixed Surfactant Systems

Liquid-crystal phases consisting of cylindrical micelles of amphiphilic block copolymers and silica precursors are epitaxially built up on aligned surface micelles formed by an alkyl-PEO surfactant, Brij56, irrespective of the large difference in the intrinsic structural periodicities resulting in the formation of fully aligned mesostructured silica films with large lattice constants. Brij56 works as an alignment controlling agent on rubbing-treated polyimide through selective adsorption from a precursor solution containing the two surfactants, a block copolymer and Brij56, through strong hydrophobic interactions to form an anisotropic surface micelle structure. Aligned mesostructured silica layers with larger periodicities, which dominantly consist of block copolymers, form on these aligned surface micelles by gradually changing the vertical periodicity keeping the lateral intermicelle distance constant. This can be regarded as a kind of heteroepitaxy because the lattice constant at the surface is different from that of the bulk of the film. On the basis of this new concept, highly aligned mesostructured silica films with structural periodicities as large as 10 nm are successfully formed, which has never been achieved when the block copolymers are used alone as the structure-directing agent. The periodicity of the aligned films can precisely be controlled by an appropriate choice of block copolymers and the mixing ratio of the two surfactants, which increases the opportunity for applications of these films with highly anisotropic mesoscale structure.

Intracellular Drug Delivery Nanocarriers of Glutathione-Responsive Degradable Block Copolymers Having Pendant Disulfide Linkages

Self-assembled micelles of amphiphilic block copolymers (ABPs) with stimuli-responsive degradation (SRD) properties have a great promise as nanotherapeutics exhibiting enhanced release of encapsulated therapeutics into targeted cells. Here, thiol-responsive degradable micelles based on a new ABP consisting of a pendant disulfide-labeled methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene oxide) (PEO) block were investigated as effective intracellular nanocarriers of anticancer drugs. In response to glutathione (GSH) as a cellular trigger, the cleavage of pendant disulfide linkages in hydrophobic PHMssEt blocks of micellar cores caused the destabilization of self-assembled micelles due to change in hydrophobic/hydrophilic balance. Such GSH-triggered micellar destabilization changed their size distribution with an appearance of large aggregates and led to enhanced release of encapsulated anticancer drugs. Cell culture results from flow cytometry and confocal laser scanning microscopy for cellular uptake as well as cell viability measurements for high anticancer efficacy suggest that new GSH-responsive degradable PEO-b-PHMssEt micelles offer versatility in multifunctional drug delivery applications.

Dimensionally Stable Ru/Ir/TiO2-Anodes with Tailored Mesoporosity for Efficient Electrochemical Chlorine Evolution

Chlorine evolution is one of the most important electrochemical reactions applied in industry. We present a method for the synthesis of chlorine evolution catalysts with improved performance. The performance increase results from the introduction of controlled mesoporosity into the pore system of Ru- and Ir-containing TiO2 catalysts by pore templating with micelles of amphiphilic block-copolymers. Micelle-templated TiO2-based catalysts were synthesized with loadings up to 15 wt % of either Ru, Ir, or a combination of both active metals. The catalysts’ walls are composed of nanocrystalline mixed oxides with rutile structure. The templated mesopores are about 10 nm in size and form an ordered cubic pore system with good pore connectivity. All studied catalysts are active in chlorine evolution. Adding templated mesoporosity doubles the catalyst performance at identical catalyst composition. The influences of film thickness, composition, and porosity of the developed catalytic coatings on the catalytic perfor...

Reversibly Crosslinked Polymeric Micelles Formed by Autonomously Exchangeable Dynamic Covalent Bonds

Abstract We report the preparation of amphiphilic block copolymer micelles with dynamic covalent bonds as autonomously exchangeable crosslinkers with high tolerance against oxygen. Diarylbibenzofuranone (DABBF) was employed as a crosslinker owing to its durability to oxygen and autonomous exchangeability at ambient temperature. It was confirmed that the amphiphilic block copolymer containing the DABBF unit has the capability to form micelles and can form a crosslinking with an exchangeable structure in the presence of oxygen.

Ketal containing amphiphilic block copolymer micelles as pH-sensitive drug carriers

pH-Responsive linkages have been widely exploited in the development of polymeric drug delivery systems, which trigger drug release selectively at tumor tissues or endosomes and lysosomes of cells. Herein we report new pH-sensitive amphiphilic poly(ketal adipate)-co-poly(ethylene glycol) block copolymers (PKA-PEG), which have acid-cleavable ketal linkages in their hydrophobic backbone. PKA-PEG copolymers self-assemble to form stable micelles with a mean diameter of ~175 nm, which can encapsulate a payload of anticancer drugs and rapidly dissociate to release drug payload at the acid environment. The micelles are biocompatible and exhibit abilities to disrupt endosomes to enhance the cytosol drug delivery. Taken together, we anticipate that the pH-sensitive PKA-PEG micelles have great potential as anticancer drug carriers.

Fusion of poly(vinyl acetate-b-vinyl alcohol) spherical micelles in water induced by poly(ethylene oxide)

Rapid and reversible morphology changes in aqueous dispersions of amphiphilic block copolymers are important for the development of complex fluids with switchable bulk properties. In this communication, we report the unusual ability of poly(ethylene oxide) to induce the fusion of spherical poly(vinyl acetate-b-vinyl alcohol) (PVAc-b-PVA) amphiphilic block copolymer micelles in water. While PVAc-b-PVA block copolymer micelles (diameters ∼22–25 nm) undergo depletion–flocculation upon addition of large amounts of 11 kg mol−1 PEO homopolymer (30.7 wt% in H2O), addition of relatively small amounts of PEO (3.1 wt% in the final dispersion) triggers their fusion into worm-like micelles. Diluting the worm-like micelle dispersions with pure water induces their reversion to spherical micelles. We suggest two tentative mechanisms for this morphology change induced by PEO homopolymer addition.

Ultrasound-Responsive Block Copolymer Micelles Based on a New Amplification Mechanism

A new approach for amplifying the effect of high-intensity focused ultrasound (HIFU) in disassembling amphiphilic block copolymer (BCP) micelles in aqueous solution was investigated. The diblock copolymer is comprised of a water-soluble poly(ethylene oxide) (PEO) block and a block of poly(2-(2-methoxyethoxy)ethyl methacrylate) (PMEO(2)MA) that is hydrophobic at temperatures above its lower critical solution temperature (LCST). We show that by introducing a small amount of HIFU-labile 2-tetrahydropyranyl methacrylate (THPMA) comonomer units into the PMEO(2)MA that forms the micelle core at T > LCST, an ultrasound irradiation of a micellar solution could induce the hydrolysis of THPMA groups. As a result, the LCST of the thermosensitive polymer increases due to the conversion of hydrophobic THPMA comonomer units onto hydrophilic methacrylic acid. Consequently, the BCP micelles disassemble without actually changing the solution temperature. In addition to the characterization results of transmittance measurements, variable-temperature (1)H NMR, SEM, and DLS, a (13)C NMR spectral analysis provided critical evidence for the hydrolysis reaction of THPMA groups under HIFU irradiation.