Block Copolymer Micelles Research Articles

Polynorbornene-derived block copolymer micelles via ring‐opening metathesis polymerization with capacity of hydrogen sulfide generation

Hydrogen sulfide (H2S), a gasotransmitter, has recently attracted significant attention for its therapeutic properties. In order to achieve controlled H2S release, polymer-based H2S donors are essential. In this report, we constructed amphiphilic block copolymer (PNEG-b-PNSATO) consisting of norbornene-mPEG (Nor-mPEG) as a hydrophilic part and norbornene-conjugated SATO moiety (Nor-SATO) as a hydrophobic part via ring-opening metathesis polymerization (ROMP). Different SATO donor contents were tested with different hydrophilic/hydrophobic polymer ratios in order to find the ideal block copolymer to release H2S, for example, PNEG8k-b-PNSATO4k, PNEG8k-b-PNSATO8k, PNEG8k-b-PNSATO12k. The block copolymers could form micelles with a range of sizes from 41 to 57 nm. The PNEG-b-PNSATO polymeric micelles release H2S at a prolonged release rate (peak time of 60–70 min). PNEG-b-PNSATO polymeric micelles were assessed by MTT assay against L929 cells, showing excellent biocompatibility. Fluorescent imaging was used to gauge H2S release. Additionally, the PNEG-b-PNSATO polymeric micelles were demonstrated to protect against oxidative damage induced by a lethal dose of H2O2, demonstrating the possibility of using this system to achieve H2S therapeutic effects.

Tetrahedral Liquid‐Crystalline Networks: An A15‐Like Frank–Kasper Phase Based on Rod‐Packing

AbstractThe Pm n cubic and other low‐symmetry Frank–Kasper phases are known to be formed by soft spheres, ranging from metals to block copolymer micelles and colloidal nanoparticles. Here, we report a series of X‐shaped polyphiles composed of sticky rods and two non‐symmetric branched side‐chains, which self‐assemble into the first example of a cubic liquid‐crystalline phase representing a tetrahedral network of rods with a Pm n lattice. It is the topological dual to the Weaire–Phelan foam, being the Voronoi tessellation of the A15 sphere packing, from which this network is obtained by Delaunay triangulation.

Tetrahedral Liquid-Crystalline Networks: An A15-Like Frank-Kasper Phase Based on Rod-Packing.

The Pm 3‾ n cubic and other low‐symmetry Frank–Kasper phases are known to be formed by soft spheres, ranging from metals to block copolymer micelles and colloidal nanoparticles. Here, we report a series of X‐shaped polyphiles composed of sticky rods and two non‐symmetric branched side‐chains, which self‐assemble into the first example of a cubic liquid‐crystalline phase representing a tetrahedral network of rods with a Pm 3‾ n lattice. It is the topological dual to the Weaire–Phelan foam, being the Voronoi tessellation of the A15 sphere packing, from which this network is obtained by Delaunay triangulation.

Dendritic-Linear Copolymer and Dendron Lipid Nanoparticles for Drug and Gene Delivery.

Polymers constitute a diverse class of macromolecules that have demonstrated their unique advantages to be utilized for drug or gene delivery applications. In particular, polymers with a highly ordered, hyperbranched structure─"dendrons"─offer significant benefits to the design of such nanomedicines. The incorporation of dendrons into block copolymer micelles can endow various unique properties that are not typically observed from linear polymer counterparts. Specifically, the dendritic structure induces the conical shape of unimers that form micelles, thereby improving the thermodynamic stability and achieving a low critical micelle concentration (CMC). Furthermore, through a high density of highly ordered functional groups, dendrons can enhance gene complexation, drug loading, and stimuli-responsive behavior. In addition, outward-branching dendrons can support a high density of nonfouling polymers, such as poly(ethylene glycol), for serum stability and variable densities of multifunctional groups for multivalent cellular targeting and interactions. In this paper, we review the design considerations for dendron-lipid nanoparticles and dendron micelles formed from amphiphilic block copolymers intended for gene transfection and cancer drug delivery applications. These technologies are early in preclinical development and, as with other nanomedicines, face many obstacles on the way to clinical adoption. Nevertheless, the utility of dendron micelles for drug delivery remains relatively underexplored, and we believe there are significant and dramatic advancements to be made in tumor targeting with these platforms.

Natural and Synthetic Micelles for the Delivery of Small Molecule Drugs, Imaging Agents and Nucleic Acids.

The poor solubility, lack of targetability, quick renal clearance, and degradability of many therapeutic and imaging agents strongly limit their applications inside the human body. Amphiphilic copolymers having self-assembling properties can form core-shell structures called micelles, a promising nanocarrier for hydrophobic drugs, plasmid DNA, oligonucleotides, small interfering RNAs (siRNAs), and imaging agents. Fabrication of micelles loaded with different pharmaceutical agents provides numerous advantages, including therapeutic efficacy, diagnostic sensitivity, and controlled release to the desired tissues. Moreover, their smaller particle size (10-100 nm) and modified surfaces with different functional groups (such as ligands) help them to accumulate easily in the target location, enhancing cellular uptake and reducing unwanted side effects. Furthermore, the release of the encapsulated agents may also be triggered from stimuli-sensitive micelles under different physiological conditions or by an external stimulus. In this review article, we discuss the recent advancements in formulating and targeting of different natural and synthetic micelles, including block copolymer micelles, cationic micelles, and dendrimers-, polysaccharide- and protein-based micelles for the delivery of different therapeutic and diagnostic agents. Finally, their applications, outcomes, and future perspectives have been summarized.

PLA-PEG Diblock Copolymer Micelle as Nanocarrier for Anti-Obesity Drug Delivery System

Obesity is a metabolic condition that accounts for life-threatening disorders like cancer, cardiovascular diseases, and type 2 diabetes. There are several anti-obesity drugs currently available on the market, but many of them show poor bioavailability due to low water solubility. Several attempts have been made by researchers to improve the solubility of orally administered drugs, but many of them did not work properly. Herein, we introduced a block copolymer micelle consisting of poly (lactic acid)-co-poly (ethylene glycol) to improve the solubility of the anti-obesity drug "Fenofibrate.” The block copolymer was synthesized using the polycondensation method, while the micelle was formed when water was added dropwise to the copolymer. Finally, laser light scattering and DLS analysis were used to confirm the micelle formation. The size of the micelle increased from 158 nm to 249 nm after the fenofibrate drug loading inside the hydrophobic core. The polymer PLA-co-PEG can be used as a carrier for orally administered fenofibrate drugs in the future for better water solubility and efficiency.

Assembly of Semiconductor Nanorods into Circular Arrangements Mediated by Block Copolymer Micelles.

The collective properties of ordered ensembles of anisotropically shaped nanoparticles depend on the morphology of organization. Here, we describe the utilization of block copolymer micelles to bias the natural packing tendency of semiconductor nanorods and organize them into circularly arranged superstructures. These structures are formed as a result of competition between the segregation tendency of the nanorods in solution and in the polymer melt; when the nanorods are highly compatible with the solvent but prefer to segregate in the melt to the core-forming block, they migrate during annealing toward the core–corona interface, and their superstructure is, thus, templated by the shape of the micelle. The nanorods, in turn, exhibit surfactant-like behavior and protect the micelles from coalescence during annealing. Lastly, the influence of the attributes of the micelles on nanorod organization is also studied. The circular nanorod arrangements and the insights gained in this study add to a growing list of possibilities for organizing metal and semiconductor nanorods that can be achieved using rational design.

Vitamin A - modified Betulin polymer micelles with hepatic targeting capability for hepatic fibrosis protection

Targeting hepatic stellate cells (HSCs) can improve the therapeutic efficacy of medicines used to treat hepatic fibrosis. The present work aimed to study the feasibility of homing devices with vitamin A(VA) chemically attached for delivering betulin(Bt)specifically to HSCs. The manufacture and characterisation of VA modified poly (ethylene glycol) -poly (lactide-co-glycolide) block copolymer micelles loaded with Bt (Bt/ VAPPMs) and their potential therapeutic benefits in vitro and in vivo are described in this paper. Bt/VAPPMs were made in a nearly spherical core-shell configuration with diameters under 200nm.In vitro release study showed that Bt/VAPPMs exhibited steady and continuous release for over 168 hours. Bt/VAPPMs had good biocompatibility at the cellular level, according to the safety evaluation, and elicited no inflammatory response in mice. More importantly, as uptake behavior studied in cells and bioimaging experiments in vivo, Bt/VAPPMs exhibited an instinctive liver- targeting capability to focus on activated HSCs. Efficacy tests revealed that administering Bt/VAPPMs effectively inhibits collagen I expression in LX-2 cells in vitro, and this effect was also seen in a mouse model of liver fibrosis. Overall, results demonstrated that Bt/VAPPMs is a promising drug delivery system that possesses specific HSCs targeting ability for treating hepatic fibrosis.

Interfacial Rearrangements of Block Copolymer Micelles Toward Gelled Liquid-Liquid Interfaces with Adjustable Viscoelasticity.

Though amphiphiles are ubiquitously used for altering interfaces, interfacial reorganization processes are in many cases obscure. For example, adsorption of micelles to liquid-liquid interfaces is often accompanied by rapid reorganizations toward monolayers. Then, the involved time scales are too short to be followed accurately. A block copolymer system, which comprises poly(ethylene oxide)110 -b-poly{[2-(methacryloyloxy)ethyl]diisopropylmethylammonium chloride}170 (i.e., PEO110 -b-qPDPAEMA170 with quaternized poly(diisopropylaminoethyl methacrylate)) is presented. Its reorganization kinetics at the water/n-decane interface is slowed down by electrostatic interactions with ferricyanide ([Fe(CN)6 ]3- ). This deceleration allows an observation of the restructuring of the adsorbed micelles not only by tracing the interfacial pressure, but also by analyzing the interfacial rheology and structure with help of atomic force microscopy. The observed micellar flattening and subsequent merging toward a physically interconnected monolayer lead to a viscoelastic interface well detectable by interfacial shear rheology (ISR). Furthermore, the "gelled" interface is redox-active, enabling a return to purely viscous interfaces and hence a manipulation of the rheological properties by redox reactions. Additionally, interfacial Prussian blue formation stiffens the interface. Such manipulation and in-depth knowledge of the rheology of complex interfaces can be beneficial for the development of emulsion formulations in industry or medicine, where colloidal stability or adapted permeability is crucial.

A Radiolabeling Method for Precise Quantification of Polymers

Radiolabeling a protein, molecule, or polymer can provide accurate and precise quantification in biochemistry, biomaterials, pharmacology, and drug delivery research. Herein, we describe a method to 125I label two different polymers for precise quantification in different applications. The surfaces of model contact lenses were modified with phenylboronic acid to bind and release the natural polymer, hyaluronic acid (HA); HA uptake and release were quantified by radiolabeling. In the second example, the in vivo distribution of a mucoadhesive micelle composed of the block copolymer of poly(lactide)-b-poly(methacrylic acid-co-acrylamidophenylboronic acid) was investigated. The presence of phenyl boronic acid groups (PBA), which bind to mucosal surfaces, was proposed to improve the retention of the micelle. 125I labeling of polymers was examined for quantification of microgram amounts of HA present on a contact lens or to evaluate the enhanced retention of PBA micelles on mucosal surfaces in vivo. The introduction of phenol groups onto the polymers allowed for the labeling. HA was modified with phenol groups through a coupling reaction of its carboxylic acid with hydroxybenzylamine. Phenol functional block copolymer micelles with and without PBA were synthesized by including N-(4-hydroxyphenethyl)acrylamide during polymerization. The phenol groups of HA and the block copolymers were labeled with 125I using a modified ICl labeling method. 125I labeling enabled quantification of HA loading and release including the effect of varying amounts of PBA on the contact lens surfaces. Micelles made from 125I-labeled block copolymers with and without PBA were administered intranasally to Brown Norway rats. The animals were sacrificed either immediately after or 4 h after their last nasal instillation, and the nasopharyngeal tissues were removed and quantified. Radioactivity measurements demonstrated that the presence of the PBA mucosal binding groups led to approximately four times higher retention. The HA and block copolymer 125I labeling presented in this article demonstrates the utility of the method for quantification and tracking of microgram quantities of polymers in diverse applications.

Frontispiece: Self‐Assembled Fluorescent Block Copolymer Micelles with Responsive Emission

Polymer Micelles Self-assembled fluorescent block copolymer micelles with responsive emission are reported by Birgit Weber et al. in their Research Article (e202117570).

"Self-Adaptive" Coassembly of Colloidal "Saturn-like" Host-Guest Complexes Enabled by Toroidal Micellar Rubber Bands.

The creation of inclusion complexes with "Saturn-like" geometries has attracted increasing attention for supramolecular systems, but expansion of the concept to nanoscale colloidal systems remains a challenge. Here, we report a strategy to assemble toroidal polyisoprene-b-poly(2-vinylpyridine) (PI-b-P2VP) block copolymer micelles with a PI core and a P2VP corona and inorganic (e.g., silica) nanoparticles of variable shape and dimensions into "Saturn-like" constructs with high fidelity and yield. The precise nesting of the nanoparticles between the toroidal building units is realized by virtue of hydrogen bonding and self-adaptive expansion of the flexible toroidal units enabled by a flexible, low Tg PI core. Once the toroidal units are cross-linked, the self-adaptive feature is lost and coassembly yields instead out-of-cavity bound nanoparticles. "Saturn-like" assemblies can also be formed along silica nanosphere-decorated cylindrical micelles or, alternatively, at the hydroxyl-functionalized termini of cylindrical micelles to yield colloidal [3]rotaxanes.

Microfluidic Synthesis of Block Copolymer Micelles: Application as Drug Nanocarriers and as Photothermal Transductors When Loading Pd Nanosheets.

The synthesis of polymeric nanoparticles from a block copolymer based on poly(ethylene glycol) and a polymethacrylate containing the nucleobase analog 2,6-diacylaminopyridine is optimized by microfluidics to obtain homogeneous spherical micelles. Loading and delivery properties are studied using naproxen as a model. The incorporation of a Pd precursor in the polymer organic solution fed into the micromixer allows the preparation of Pd(II) precursor-polymer hybrid systems and the subsequent reduction with CO leads to the in situ synthesis of Pd nanosheets inside of the hydrophobic core of the polymeric micelles. This methodology is highly efficient to yield all polymeric nanoparticles loaded with Pd nanosheets as detected by electron microscopy and energy-dispersive X-ray spectroscopy. The cell viability of these Pd nanosheets-containing polymeric nanoparticles is evaluated using five cell lines, showing a high cytocompatibility at the tested concentrations without detrimental effects in cell membrane and nuclei. Furthermore, the use of these hybrid polymeric nanoparticles as photothermal transductors is evaluated using near infrared as irradiation source as well as its application in photothermal therapy using different cell lines demonstrating a high efficiency in all cell cultures.

Tunable Adhesion and Interfacial Structure of Layer‐by‐Layer Assembled Block co‐polymer Micelle and Polyelectrolyte Coatings

AbstractUnderstanding and tuning nanoscale structure is critical in developing new coatings and adhesives. In this work layer‐by‐layer assembly of block co‐polymer (BCP) micelles and oppositely charged polyelectrolytes produces structurally unique coatings with wet adhesion comparable to that of mussel adhesive proteins. Cationic (CAT) and anionic (ANI) BCPs, synthesized by atom transfer radical polymerization (ATRP), are used to create colloidally stable, self‐assembled, spherical BCP micelles. The assembly of BCP micelle and polyelectrolyte multilayers is monitored in situ where CAT‐ and ANI‐BCP micelles exhibit linear and super‐linear growth, respectively. Imaging of the surfaces reveals that CAT‐BCP micelles yield flat, uniform layers whereas ANI‐BCP micelle assemblies form islands that increase in surface area with each additional layer. The adhesion of these layers, measured by colloidal probe atomic force microscopy (CP‐AFM), shows that the distinct layers of CAT‐BCP micelle assemblies produce alternating high and low adhesion surfaces whereas ANI‐BCP micelle assemblies continually increase in adhesion with each additional bilayer. The unique behavior of each assembly demonstrates that both composition and structure play important roles in wet adhesion of submicron layers and that each can be tuned to target performance for different applications.

Self-Assembled Fluorescent Block Copolymer Micelles with Responsive Emission.

Responsive fluorescent materials offer a high potential for sensing and (bio‐)imaging applications. To investigate new concepts for such materials and to broaden their applicability, the previously reported non‐fluorescent zinc(II) complex [Zn(L)] that shows coordination‐induced turn‐on emission was encapsulated into a family of non‐fluorescent polystyrene‐block‐poly(4‐vinylpyridine) (PS‐b‐P4VP) diblock copolymer micelles leading to brightly emissive materials. Coordination‐induced turn‐on emission upon incorporation and ligation of the [Zn(L)] in the P4VP core outperform parent [Zn(L)] in pyridine solution with respect to lifetimes, quantum yields, and temperature resistance. The quantum yield can be easily tuned by tailoring the selectivity of the employed solvent or solvent mixture and, thus, the tendency of the PS‐b‐P4VP diblock copolymers to self‐assemble into micelles. A medium‐dependent off–on sensor upon micelle formation could be established by suppression of non‐micelle‐borne emission background pertinent to chloroform through controlled acidification indicating an additional pH‐dependent process.

Selbstassemblierte fluoreszierende Blockcopolymer‐Mizellen mit responsiver Emission

Responsive, fluoreszierende Materialien versprechen neue Anwendungen in der Sensorik und der (biologischen) Bildgebung. In dieser Studie stellen wir einen konzeptionell neuartigen Zugang zu solchen Materialien auf Basis der Selbstassemblierung von nicht-fluoreszierenden Bausteinen zu fluoreszierenden Materialien vor. Stark emittierende Kompositmaterialien werden nach Verkapselung des nicht-fluoreszierenden Zink(II)-Komplexes [Zn(L)] in eine Reihe von nicht-fluoreszierenden Polystyrol-block-Poly(4-vinylpyridin) (PS-b-P4VP) Diblockcopolymer-Mizellen erhalten. Die koordinationsinduzierte Turn-On Emission von [Zn(L)] im P4VP-Kern übertrifft die von gelösten [Zn(L)] in Pyridin hinsichtlich wichtiger Gütefaktoren, wie Lebensdauer, Quantenausbeute und Temperaturbeständigkeit. Die Quantenausbeute kann leicht über das Medium eingestellt werden, indem die Tendenz der PS-b-P4VP Diblockcopolymere zur Selbstassemblierung zu Mizellen über die Selektivität des verwendeten Lösungsmittels oder Lösungsmittelgemisches angepasst wird. Ein medienabhängiger Off-On Sensor, der mit der Mizellbildung gekoppelt ist, konnte durch Unterdrückung des nicht mizellenbasierten Emissionshintergrunds in Chloroform durch kontrolliertes Ansäuern realisiert werden, was auf einen zusätzlichen pH-abhängigen Prozess hinweist.

Patch formation on diblock copolymer micelles confined in templates for inducing patch orientation and cyclic colloidal molecules

HypothesisChemically or physically distinct patches can be induced on the micelles of amphiphilic block copolymers, which facilitate directional binding for the creation of hierarchical structures. Hence, control over the direction of patches on the micelles is a crucial factor to attain the directionality on the interactions between the micelles, particularly for generating colloidal molecules mimicking the symmetry of molecular structures. We hypothesized that direction and combination of the patches could be controlled by physical confinement of the micelles. ExperimentsWe first confined spherical micelles of diblock copolymers in topographic templates fabricated from nanopatterns of block copolymers by adjusting the coating conditions. Then, patch formation was conducted on the confined micelles by exposing them with a core-favorable solvent. Microscopic techniques of SEM, TEM, and AFM were employed to investigate directions of patches and structures of combined micelles in the template. FindingsThe orientation of the patches on the micelles was guided by the physical confinement of the micelles in linear trenches. In addition, by confining the micelles in a circular hole, we obtained a specific polygon arrangement of the micelles depending on the number of micelles in the hole, which enabled the formation of cyclic colloidal molecules consisting of micelles.

Modulating Boronic Ester Stability in Block Copolymer Micelles via the Neighbor Effect of Copolymerized Tertiary Amines for Controlled Release of Polyphenolic Drugs.

The traceless and pH-sensitive properties of boronic esters are attractive for the synthesis of polymer-drug conjugates, but current platforms suffer from both low stability under physiologically relevant conditions and synthetically demanding optimization to tune drug release profiles. We hypothesized that the high catechol affinity and stability of Wulff-type boronic acids could be mimicked by copolymerization of phenyl boronic acid with a tertiary amine and subsequent micellization. This strategy yielded a versatile platform for the preparation of reversible polymer-drug conjugates, which more than doubled the oxidative stability of encapsulated polyphenolic drug cargo at physiologically relevant pH and enabled simple and incremental tuning of drug release kinetics. Moreover, we validated, with 19F NMR, that these copolymers exhibit uniquely high catechol affinity that could not be replicated by combinations of similarly functionalized small molecules. Overall, this report demonstrates that copolymerization of boronic acid and tertiary amine monomers is a powerful and modular approach to improving boronic ester chemistry for drug delivery applications.

Separated Micelles Formation of pH-Responsive Random and Block Copolymers Containing Phosphorylcholine Groups.

The self-assembly of pH-responsive random and block copolymers composed of 2-(N,N-diisopropylamino)ethyl methacrylate and 2-methacryloyloxyethyl phosphorylcholine was investigated in aqueous media. Their pH-responsive behaviors were investigated in aqueous media by dynamic light scattering (DLS) and fluorescence measurements using a pyrene hydrophobic fluorescence probe. In an acidic environment, these copolymers existed as single polymer chains that did not interact with each other. In contrast, upon increasing the pH of the solution above the critical value of ~8, separated micelles were formed in the mixture, which was indicated by bimodal distribution in DLS results with radius of 4.5 and 10.4 nm, corresponding to the random and block copolymer micelles, respectively. Fluorescence resonance energy transfer efficiencies were near to zero in the mixture of the donor labeled block and acceptor labeled random copolymers under both acidic and basic pH. These results demonstrated the coexistence of two distinct micelles.

Triblock Copolymer Micelles with Tunable Surface Charge as Drug Nanocarriers: Synthesis and Physico-Chemical Characterization.

Polymeric micelles have gained increasing interest as efficient drug delivery systems for cancer treatment and diagnosis. The aim of the present study was to construct and to evaluate novel polymeric nanosized drug carriers with tunable surface charges. Initially, amphiphilic triblock copolymers with predetermined molar mass characteristics were synthesized by applying controlled polymerization techniques. The copolymers self-assembled in aqueous media into core–shell spherical micelles, comprising a biodegradable hydrophobic poly(D,L-lactide) core, positively charged middle layer of poly((2-dimethylamino)ethyl methacrylate), and an outer shell of neutral hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate), with various densities of the short polyether side chains. The block copolymer micelles with average diameters of about 70 nm and surface charges varying from strongly positive to neutral were characterized and loaded with the model, natural, hydrophobic drug curcumin. Characteristics such as drug loading efficiency, in-vitro drug release profiles, and stability under physiological conditions were evaluated and discussed in terms of nanocarriers’ composition. As a result, the most promising candidates for potential application in nanomedicine were identified.