Block Copolymer Micelles Research Articles

Chemically Fueled Block Copolymer Self‐Assembly into Transient Nanoreactors**

AbstractIn chemically fueled supramolecular materials, molecular self‐assembly is coupled to a fuel‐driven chemical reaction cycle. The fuel‐dependence makes the material dynamic and endows it with exciting properties like adaptivity and autonomy. In contrast to the large work on the self‐assembly of small molecules, we herein designed a diblock copolymer, which self‐assembles into transient micelles when coupled to a fuel‐driven chemical reaction cycle. Moreover, we used these transient block copolymer micelles to locally increase the concentration of hydrophobic reagents and thereby function as a transient nanoreactor.

Synthesis, self-assembly and thermoresponsive behavior of Poly(lactide-co-glycolide)-b-Poly(ethylene glycol)-b-Poly(lactide-co-glycolide) copolymer in aqueous solution

Thermoresponsive block copolymer (BCP) micelles have attracted increasing attentions due to their potential in biological applications. Many studies have investigated facile strategies to tune the cloud point (Tcp) of thermoresponsive polymer, such as changing hydrophobic/hydrophilic block ratio, micelle concentration and addition of salt. Considering the dependence of properties and functions of BCPs on thermal-induced structural transition, it is necessary to understand the universal mechanism of structural changes during temperature-induced phase transition; whereas it is challenging to achieve precise structure and properties of BCP micelles with Tcp changes. Herein, we choose thermoresponsive poly (L-lactide-co-glycolide)-poly (ethylene glycol)-poly (L-lactide-co-glycolide) (PLGA-PEG-PLGA) block copolymer as a model system and utilize synchrotron-radiation small-angle X-ray scattering (SAXS) technique to systematically investigate the assembled structure of PLGA-PEG-PLGA and the mechanism for thermally induced structural transition of BCP micelle. With the increase of PLGA hydrophobic block, the Tcp significantly decreases, ascribed to the enhancement of the core size, aggregation number, as well as the packing density of PLGA in micelle core. Moreover, the increase of micelle concentration and the addition of salt also decreases the Tcp. Furthermore, temperature-induced drug release is also investigated, the release rate is much faster at above Tcp.

General synthesis of hollow mesoporous conducting polymers by dual-colloid interface co-assembly for high-energy-density micro-supercapacitors

Rational design and precise regulation over the morphology, structure, and pore size of functional conducting mesoporous polymers with enriched active sites and shorten electron–ion transport pathway are extremely important for developing high-performance micro-supercapacitors (MSCs), but still remain a great challenge. Herein, a general dual-colloid interface co-assembly strategy is proposed to fabricate hollow mesoporous polypyrrole nano-bowls (mPPy-nbs) for high-energy-density solid-state planar MSCs. By simply adjusting the size of block copolymer micelles, the diameter of polystyrene nanospheres and the amount of pyrrole monomer, mesopore size of the shell, void and shell thickness of mPPy-nbs can be simultaneously controlled. Importantly, this strategy can be further utilized to synthesize other hollow mesoporous polymers, including poly(tris(4-aminophenyl)amine), poly(1,3,5-triaminobenzene) and their copolymers, demonstrative of excellent universality. The structurally optimized mPPy-nb exhibits high specific surface area of 122 m2 g−1and large capacitance of 225 F g−1 at 1 mV s−1. Furthermore, the MSCs assembled by mPPy-nbs deliver impressive volumetric capacitance of 90 F cm−3 and energy density of 2.0 mWh cm−3, superior to the most reported polymers-based MSCs. Also, the fabricated MSCs present excellent flexibility with almost no capacitance decay under varying bending states, and robust serial/parallel self-integration for boosting voltage and capacitance output. Therefore, this work will inspire the new design of mesoporous conducting polymer materials toward high-performance microscale supercapacitive devices.

Improved gene delivery to K-562 leukemia cells by lipoic acid modified block copolymer micelles

Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]101-b-[n-(butyl methacrylate)124-co-(lipoic acid methacrylate)22]} (P(DMAEMA101-b-[nBMA124-co-LAMA22])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.

High Aspect Ratio Polymeric Nanoneedle Arrays

AbstractHigh aspect ratio (HAR) nanoneedle arrays can be used to tune the intrinsic properties of substrates such as their wettability and reflectivity. Here, a simple and scalable fabrication method for producing dense arrays of freestanding polyethylene glycol (PEG) nanoneedles with sub 50 nm tips and surface coverage up to 83 needles per µm2 is presented. Two distinct sets of silicon nanoneedle master arrays with base diameters between 15 and 265 nm and heights between 146 and 613 nm are fabricated using block copolymer micelle lithography. Replication of selected silicon masters using photocurable polymers produces HAR PEG nanoneedle arrays with feature base diameters ranging between 15 and 292 nm and heights between 133 and 656 nm. At their maximum, the aspect ratio of the pillars is 4.6. PEG nanoneedle arrays are produced using polymers with two different molecular weights as well as two different photoinitiators, showing the versatility of the process.

Length of the Core Forming Block Effect on Fusion and Fission Dynamics at Equilibrium in PEO–PPO–PEO Triblock Copolymer Micelles in the Spherical Regime

The slow kinetics of block copolymer micelles make their dynamical pathways as important as the copolymer architecture in the self-assembly of nanostructures. Two types of dynamical pathways could ...

Core-Cross-linked Fluorescent Worm-Like Micelles for Glucose-Mediated Drug Delivery.

We herein report the fabrication of core-crosslinked, fluorescent, and surface-functionalized worm-like block copolymer micelles as drug delivery vehicles. The polyether-based diblock terpolymer [allyl-poly(ethylene oxide)-block-poly(2-ethylhexyl glycidyl ether-co-furfuryl glycidyl ether)] was synthesized via anionic ring opening polymerization, and self-assembly in water as a selective solvent led to the formation of long filomicelles. Subsequent cross-linking was realized using hydrophobic bismaleimides as well as a designed fluorescent cross-linker for thermally induced Diels-Alder reactions with the furfuryl units incorporated in the hydrophobic block of the diblock terpolymer. As a fluorescent cross-linker, we synthesized and incorporated a cyanine 5-based bismaleimide in the cross-linking process, which can be used for fluorescence tracking of the particles. Furthermore, we covalently attached glucose to the allyl end groups present on the surface of the micelles to investigate active glucose-mediated transport into suitable cell lines. First studies in 2D as well as 3D cell culture models suggest a glucose-dependent uptake of the particles into cells despite their unusually large size compared to other nanoparticle systems used in drug delivery.

Effect of Core-Crosslinking on Protein Corona Formation on Polymeric Micelles.

Most nanomaterials acquire a protein corona upon contact with biological fluids. The magnitude of this effect is strongly dependent both on surface and structure of the nanoparticle. To define the contribution of the internal nanoparticle structure, protein corona formation of block copolymer micelles with poly(N-2-hydroxypropylmethacrylamide) (pHPMA) as hydrophilic shell, which are crosslinked-or not-in the hydrophobic core is comparatively analyzed. Both types of micelles are incubated with human blood plasma and separated by asymmetrical flow field-flow fractionation (AF4). Their size is determined by dynamic light scattering and proteins within the micellar fraction are characterized by gel electrophoresis and quantified by liquid chromatography-high-resolution mass spectrometry-based label-free quantitative proteomics. The analyses reveal only very low amounts of plasma proteins associated with the micelles. Notably, no significant enrichment of plasma proteins is detectable for core-crosslinked micelles, while noncrosslinked micelles show a significant enrichment of plasma proteins, indicative of protein corona formation. The results indicate that preventing the reorganization of micelles (equilibrium with unimers) by core-crosslinking is crucial to reduce the interaction with plasma proteins.

A New Synthetic Strategy for Polymeric Bromine Precursors: One‐Step Change from Bromine‐Containing Polymers to Functional Polymers

AbstractPostmodification methods are effective tools in preparing functional polymers, and novel end‐group reactions have attracted much attention from researchers for postmodification applications. Here, a new high‐efficiency postmodification method is proposed, which can change bromine‐containing polymers to functional polymers in one step. Phenol, 1‐hydroxynaphthalene, and 4‐(2‐phenyldiazenyl)‐phenol (AzoOH) are successfully grafted onto the polymeric branch chain of bromine‐containing polymers, i.e., homopolymer, bromoethyl methyl acrylate, (pBMEA) and amphiphilic block copolymer p(BMEA)‐b‐p(mPEG), with a high grafting rate that is near 100%. Also, the micelles of the postmodified amphiphilic block copolymer p(BMEA‐Azo)‐b‐p(mPEG) are broken up under ultraviolet irradiation. The proposed method can be used as a platform to prepare a variety of stimuli‐responsive polymeric nanoparticles.

PH-Dependent Structure of Block Copolymer Micelles Featuring a Polyampholyte Corona: A Combined Experimental and Theoretical Approach

Herein, we describe the preparation as well as experimental and theoretical investigations of block copolymer micelles based on amphiphilic, pH-responsive block copolymers featuring bipyridine liga...

Naked micelles: well-defined polymer nanoparticles from photo-cleavable block copolymer micelles

We report that photo-cleaving the corona of block copolymer micelles provides well-defined nanoparticles with surface charges accessible for electrostatic modification.

Block copolymer micelles enable facile synthesis of organic-inorganic perovskite nanostructures with tailored architecture.

We report a distinct method for the production of organic-inorganic hybrid perovskite (OIHP) nanostructures using block copolymer micelles as scaffolds. We reveal that various nanostructures can be obtained by controlling the parameters related to micelle disassembly. The strategy reported herein can be generalized for the fabrication of diverse nanostructures toward target-oriented potential applications.

Creation of polymeric nanostructures by living coordination block copolymerization of allene derivatives with fluoroalkyl substituents under polymerization-induced self-assembly conditions and their application to superhydrophobic surfaces

Block copolymer micelles with a fluorous corona were synthesized via living allene polymerization in fluorous media and a polymerization-induced self-assembly (PISA) process, resulting in excellent superhydrophobic optically transparent coatings.

Hydrogen sulfide-activatable prodrug-backboned block copolymer micelles for delivery of chemotherapeutics

A novel hydrogen sulfide-activatable block copolymer prodrug with high tumor specificity was developed for cancer chemotherapy.

Core-crosslinked, temperature- and pH-responsive micelles: design, physicochemical characterization, and gene delivery application.

Stimuli-responsive block copolymer micelles can provide tailored properties for the efficient delivery of genetic material. In particular, temperature- and pH-responsive materials are of interest, since their physicochemical properties can be easily tailored to meet the requirements for successful gene delivery. Within this study, a stimuli-responsive micelle system for gene delivery was designed based on a diblock copolymer consisting of poly(N,N-diethylacrylamide) (PDEAm) as a temperature-responsive segment combined with poly(aminoethyl acrylamide) (PAEAm) as a pH-responsive, cationic segment. Upon temperature increase, the PDEAm block becomes hydrophobic due to its lower critical solution temperature (LCST), leading to micelle formation. Furthermore, the monomer 2-(pyridin-2-yldisulfanyl)ethyl acrylate (PDSAc) was incorporated into the temperature-responsive PDEAm building block enabling disulfide crosslinking of the formed micelle core to stabilize its structure regardless of temperature and dilution. The cloud points of the PDEAm block and the diblock copolymer were investigated by turbidimetry and fluorescence spectroscopy. The temperature-dependent formation of micelles was analyzed by dynamic light scattering (DLS) and elucidated in detail by an analytical ultracentrifuge (AUC), which provided detailed insights into the solution dynamics between polymers and assembled micelles as a function of temperature. Finally, the micelles were investigated for their applicability as gene delivery vectors by evaluation of cytotoxicity, pDNA binding, and transfection efficiency using HEK293T cells. The investigations showed that core-crosslinking resulted in a 13-fold increase in observed transfection efficiency. Our study presents a comprehensive investigation from polymer synthesis to an in-depth physicochemical characterization and biological application of a crosslinked micelle system including stimuli-responsive behavior.

Investigating the influence of block copolymer micelle length on cellular uptake and penetration in a multicellular tumor spheroid model.

The efficient penetration of drug nanocarriers into tumors is an important prerequisite for therapeutic and diagnostic success. The physicochemical properties of nanocarriers, including size, shape and surface chemistry have been shown to influence their transport in biological systems. Recent studies have shown that elongated nanoparticles (NPs) can exhibit advantageous properties in comparison to spherical NPs, but these experiments have involved a variety of different materials, many of which are characterized by a broad size distribution. Here we describe a series of rigid rod-like micelles of uniform width, with narrow length distributions, and common surface chemistry, and examine their cell uptake and penetration into multicellular tumor spheroids (MCTSs) formed from two human breast cancer cell lines (MDA-MB-436 and MDB-MB-231). These micelles were prepared from a polyferrocenylsilane (PFS) diblock copolymer (BCP) with a corona block consisting of a statistical polymer of aminopropyl methacrylamide and oligo(ethyleneglycol methacrylate) (PFS27-b-PAPMA3-stat-POEGMA48). The rigid rod micelles, with a common width (12 nm) and lengths ranging from 80 to 2000 nm, were prepared by seeded growth crystallization-driven self-assembly in ethanol and then transferred to water. To consider whether changing the shape of these micelles affects its uptake and penetration behavior, analogous spherical micelles were prepared by direct nanoprecipitation into water. Both micelle shape and length were found to influence cellular uptake and penetration into 500 μm MCTSs. Laser confocal fluorescence microscopy was used to examine penetration of these micelles into three-dimensional MCTS up to 90 μm depth. Micelles with an elongated shape and short length (80 nm) demonstrated the deepest penetration into the MCTSs formed by MDA-MB-436 cells. Micelles with lengths of 200 nm also showed substantial penetration into these MCTS, but the extent and depth of tumor penetration of the rod-like micelles decreased with increasing aspect ratio. MCTS of MDA-MB-231 cells had a less dense, more open structure than those formed by MDA-MB-436 cells. Here more extensive penetration was observed, particularly for the longer micelle samples.

The core composition of DNA block copolymer micelles dictates DNA hybridization properties, nuclease stabilities, and cellular uptake efficiencies.

Here, we report how the nature of the hydrophobic core affects the molecular interactions of DNA block copolymer assemblies. Three different amphiphilic DNA block copolymers, DNA-b-polystyrene (DNA-b-PS), DNA-b-poly(2-vinylpyridine) (DNA-b-P2VP), and DNA-b-poly(methyl acrylate) (DNA-b-PMA) were synthesized and assembled into spherical micelles composed of a hydrophobic polymer core and DNA corona. Interestingly, DNA block copolymer micelles having different hydrophobic cores exhibited markedly different molecular and biological interactions. DNA-b-PS exhibited higher melting temperature, sharper melting transition, higher stability to nuclease-catalyzed DNA degradation, and higher cellular uptake efficiency compared to DNA-b-P2VP and DNA-b-PMA. The investigation of the self-assembly behavior revealed a much higher aggregation number and DNA density for DNA-b-PS micelles, which explains the superior properties of DNA-b-PS. These results demonstrate that the type of the hydrophobic core polymer, which has been largely overlooked, has a profound impact on the molecular and biological interactions of the DNA shell.

Free-standing membranes from the chemical exfoliation of mesoporous amorphous titania thin film.

Thin films are typically bound to their substrate, limiting their integration on rough, porous, curved or chemically/thermally sensitive surfaces. Instead of employing tedious and expensive back-etching processes, specific chemical routes can enable the exfoliation of such thin structures. Herein, we demonstrate that an alkaline treatment can exfoliate a hybrid thin film comprising amorphous titania embedded in well-ordered block-copolymer micelles, which can be redeposited elsewhere. We provide sufficient evidence of the preservation of pore ordering and the importance of neutralizing the solution to spare the system from the redissolution of the titania species.

Static and dynamic properties of block copolymer based grafted nanoparticles across the non-ergodicity transition

We present a systematic investigation of static and dynamic properties of block copolymer micelles with cross-linked cores, representing model polymer-grafted nanoparticles, over a wide concentration range from a dilute regime to an arrested (crystalline) state, by means of light and neutron scattering, complemented by linear viscoelasticity. We have followed the evolution of their scattering intensity and diffusion dynamics throughout the non-ergodicity transition, and the observed results have been contrasted against those of appropriately coarse-grained Langevin dynamics simulations. These stable model soft particles of the core–shell type are situated between ultrasoft stars and hard spheres, and the well-known star pair interaction potential is not appropriate to describe them. Instead, we have found that an effective brush interaction potential provides very satisfactory agreement between experiments and simulations, offering insights into the interplay of softness and dynamics in spherical colloidal suspensions.

Ultrasensitive antibody-aptamer plasmonic biosensor for malaria biomarker detection in whole blood

Development of plasmonic biosensors combining reliability and ease of use is still a challenge. Gold nanoparticle arrays made by block copolymer micelle nanolithography (BCMN) stand out for their scalability, cost-effectiveness and tunable plasmonic properties, making them ideal substrates for fluorescence enhancement. Here, we describe a plasmon-enhanced fluorescence immunosensor for the specific and ultrasensitive detection of Plasmodium falciparum lactate dehydrogenase (PfLDH)—a malaria marker—in whole blood. Analyte recognition is realized by oriented antibodies immobilized in a close-packed configuration via the photochemical immobilization technique (PIT), with a top bioreceptor of nucleic acid aptamers recognizing a different surface of PfLDH in a sandwich conformation. The combination of BCMN and PIT enabled maximum control over the nanoparticle size and lattice constant as well as the distance of the fluorophore from the sensing surface. The device achieved a limit of detection smaller than 1 pg/mL (<30 fM) with very high specificity without any sample pretreatment. This limit of detection is several orders of magnitude lower than that found in malaria rapid diagnostic tests or even commercial ELISA kits. Thanks to its overall dimensions, ease of use and high-throughput analysis, the device can be used as a substrate in automated multi-well plate readers and improve the efficiency of conventional fluorescence immunoassays.