Assembly Of Block Copolymers Research Articles

Controlling the Location of Nanoparticles in Colloidal Assemblies of Amphiphilic Polymers by Tuning Nanoparticle Surface Chemistry.

Here, we report a simple method to control the location of nanoparticles in colloidal block-copolymer assemblies by using nanoparticles modified with mixed surface ligands. The binary self-assembly of amphiphilic polymers of polystyrene-b-poly(acrylic acid) (PS-b-PAA) and gold nanoparticles (AuNPs) modified with a hydrophobic ligand, dodecanethiol (DT), led to polymer micelles with nanoparticles segregated in the core of polymer micelles. On the other hand, AuNPs modified with mixed ligands of mercaptoundecanol (MUL) and DT were distributed at the PS-PAA interface, reducing the interfacial energy between the two polymers. This result was in good agreement with the prediction by the surface energy calculations. We also showed that the AuNPs with mixed ligands can decorate preformed polymer assemblies by the interfacial self-assembly. Furthermore, we demonstrated the compartmentalization of two different types of nanoparticles in colloidal polymer assemblies based on the strategy.

Scale-up of a Chemo-Epitaxy Flow for Feature Multiplication Using Directed Self- Assembly of Block-Copolymers

Scale-up of a Chemo-Epitaxy Flow for Feature Multiplication Using Directed Self- Assembly of Block-Copolymers

Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance

Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (~pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9-6.2 in early endosomes and pH 5.0-5.5 in late endosomes and lysosomes) and redox and H2O2 gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of "active targeting" strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, β-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity.

Filomicelles in nanomedicine - from flexible, fragmentable, and ligand-targetable drug carrier designs to combination therapy for brain tumors.

Nanoparticles that are made by self-assembly into non-spherical shapes are promising as drug delivery vehicles. This review focuses on flexible and fragmentable filamentous micelles referred to as filomicelles made of degradable block copolymer amphiphiles. They are inspired by filoviruses and also by tubular proplatelets that break up into smaller platelets in blood flow. The synthesis and assembly of the constituent block copolymers are described together with ligand targeting and fragmentation as well as drug release in therapeutic applications to model tumors and most recently brain tumors.

Unexpected behavior of polydimethylsiloxane/poly(2-(dimethylamino)ethyl acrylate) (charged) amphiphilic block copolymers in aqueous solution

We report the synthesis and self assembly of amphiphilic block copolymers based on poly(dimethylsiloxane) and poly(2-(dimethylamino)ethyl acrylate) (PDMS-b-PDMAEA). We consider the self-catalyzed hydrolysis of PDMAEA in aqueous solution, and its effect on the self-assembly of the amphiphilic copolymer by investigating poly(dimethylsiloxane)-b-[poly(2-dimethylamino)ethyl acrylate)-co-poly(acrylic acid)] (PDMS-b-(PDMAEA-co-PAA)), obtained from hydrolysis of PDMAEA, and poly(dimethylsiloxane)-b-poly(2-(trimethylammonium iodide)ethyl acrylate) (PDMS-b-PTMAIEA), obtained from quaternization of PDMAEA. We observe that the thermal properties and self-assembly behavior in water of these amphiphilic diblock copolymers depend on the structure of the hydrophilic block, and are strongly influence by hydrolysis of the PDMAEA block. Self-assembly in aqueous solution leads to the formation of spherical micellar structures with diameters between 40 and 70 nm, which were investigated by dynamic light scattering (DLS) and transmission electron microscope (TEM). PDMS-b-(PDMAEA-co-PAA) is shown to be pH responsive, and behaves as a highly negatively charged polymer at high pH values (pH > 10) and as a highly positively charged polymer at low pH values (pH < 2). Critical micelle concentrations (cmc) of the amphiphilic block copolymers were determined by fluorescence measurement with N-phenyl-1-naphthylamine (PNA) as a fluorescence probe. Surprisingly, surface tension measurements suggest that PDMS-b-PTMAIEA is “non-surface active”, forming micelles in bulk solution instead of adsorbing at the air–water interface to form a Gibbs monolayer, even when the polymer concentration was over 100 times above its cmc value. This remarkable behavior is consistent with recent reports that suggest that “non-surface activity” can be observed for both cationic and anionic amphiphilic diblock copolymers due to the effect of image charge repulsion at the air–water interface.

Interplay of surface chemical composition and film thickness on graphoepitaxial assembly of asymmetric block copolymers

We study the assembly of PMMA cylinder forming poly(styrene-block-methyl methacrylate) in three different geometries: planar surface, and chemically homogeneous and heterogeneous graphoepitaxy as a function of film thickness and surface chemical composition. On planar surfaces, perpendicular orientation can be achieved by controlling the thickness of the block copolymer (BCP) on surfaces weakly preferential to either block, while on nonpreferential surfaces, perpendicular orientation is independent of thickness within 0.8d0–1.8d0 range. In chemically homogeneous trenches, lateral alignment of domains is effectively controlled by having a chemical composition that is weakly preferential to either block, rather than perfectly nonpreferential wetting condition. By defining these boundary conditions, the nucleation of the domains can be induced primarily from the side walls rather than from the trench bottom. However, in chemically heterogeneous graphoepitaxial geometry, the BCP domains are aligned along the trench walls in both perfectly nonpreferential and weakly preferential conditions. In both the homogeneous and heterogeneous approaches, the thickness is critical for perpendicular orientation on weakly preferential surfaces. These findings affirm that graphoepitaxial assembly behavior of asymmetric BCP is governed by the interplay of surface wetting characteristics and the thickness of BCP.

Supramolecular guests in solvent driven block copolymer assembly: From internally structured nanoparticles to micelles.

Supramolecular interactions between different hydrogen-bonding guests and poly(2-vinyl pyridine)-block-poly (styrene) can be exploited to prepare remarkably diverse self-assembled nanostructures in dispersion from a single block copolymer (BCP). The characteristics of the BCP can be efficiently controlled by tailoring the properties of a guest which preferentially binds to the P2VP block. For example, the incorporation of a hydrophobic guest creates a hydrophobic BCP complex that forms phase separated nanoparticles upon self-assembly. Conversely, the incorporation of a hydrophilic guest results in an amphiphilic BCP complex that forms spherical micelles in water. The ability to tune the self-assembly behavior and access dramatically different nanostructures from a single BCP substrate demonstrates the exceptional versatility of the self-assembly of BCPs driven by supramolecular interactions. This approach represents a new methodology that will enable the further design of complex, responsive self-assembled nanostructures.

Glycopolypeptide conformations in bioactive block copolymer assemblies influence their nanoscale morphology

We describe the preparation and assembly of glycosylated amphiphilic diblock copolypeptides, where the hydrophilic glycosylated segments adopt either α-helical or disordered conformations. In this study, glycosylated amphiphilic diblock copolypeptides were prepared using poly(L-leucine), poly(L), as the hydrophobic segment, and poly(α-D-galactopyranosyl-L-lysine), poly(α-gal-K), or poly(α-D-galactopyranosyl-L-cysteine sulfone), poly(α-gal-CO2), as the hydrophilic segment. The poly(α-gal-K) and poly(α-gal-CO2) segments are known to be fully α-helical (>90% at 20 °C) and fully disordered in water, respectively. We found that block copolypeptides containing galactosylated hydrophilic segments of either α-helical or disordered conformation give different assembly morphologies, where the disordered glycopolypeptide segments favor vesicle formation and also present sugar residues that can bind to biological targets.

A new approach to high resolution, high contrast electron microscopy of macromolecular block copolymer assemblies

Determining the structure of macromolecular samples is vital for understanding and adapting their function. Transmission electron microscopy (TEM) is widely used to achieve this, but, owing to the weak electron scattering cross-section of carbon, TEM images of macromolecular samples are generally low contrast and low resolution. Here we implement a fast and practically simple routine to achieve high-contrast imaging of macromolecular samples using exit wave reconstruction (EWR), revealing a new level of structural detail. This is only possible using ultra-low contrast supports such as the graphene oxide (GO) used here and as such represents a novel application of these substrates. We apply EWR on GO membranes to study self-assembled block copolymer structures, distinguishing not only the general morphology or nanostructure, but also evidence for the substructure (i.e. the polymer chains) which gives insight into their formation mechanisms and functional properties.

Thin Film Block Copolymer Assembly in Mixtures of Highly Selective Solvents

Perpendicular orientation of block copolymer (BCP) domains in thin films is generally preferred over parallel orientation for lithographic applications. [1] Thermal annealing can be used to promote this orientation, but often requires a top coat since one block will typically wet the air interface. [2] Solvent annealing is an attractive alternative for achieving perpendicular orientation of the domains by neutralizing the surface energy of the air interface. Many examples of using solvent annealing in BCP thin films exist in the literature, involving domain non-selective [3] and selective [4] solvents. Silicon-containing polymers are desirable for lithographic applications because their high chi-parameters and high etch selectivity allow them to self-assemble into small domains and be transferred easily into an underlying substrate by oxygen etching. [5,6] This paper describes the process used to solvent anneal a new silicon-containing polymer, poly(trimethylsilyl styrene-b-lactide) (PTMSS-b-PLA) using cyclohexane vapor, a solvent that preferentially swells the PTMSS domain.

Co-assembly of Nanoparticles and Block Copolymers into Hybrid Micellar Aggregates

In this review, we outline the most recent publications and patents focusing on hybrid micellar aggregates comprising nanoparticles (NPs) and block copolymers (BCPs) in the last decade, which have attracted much interest owing to their potential applications in the fields of optics, electronics, sensors, drug delivery and release, bioimaging, targeting, and catalysis. Among them, precise location and assembly of NPs in polymers are of great importance in realizing the formation of nanocomposites with high performances. BCPs assembly offers a simple and efficient route to direct and locate NPs in polymer matrix. First, we will outline different synthetic strategies for directing inorganic NPs into the micellar aggregates based on co-assembly of NPs and BCPs. We will then discuss principles and possible mechanisms for precisely regulating NPs in polymer microdomains of BCPs based on the experimental and theoretical results. Potential applications of the hybrid micellar aggregates will finally be discussed, followed by current and future developments of this emerging area.

Kinetic quantification of protein polymer nanoparticles using non-invasive imaging

Protein polymers are repetitive amino acid sequences that can assemble monodisperse nanoparticles with potential applications as cancer nanomedicines. Of the currently available molecular imaging methods, positron emission tomography (PET) is the most sensitive and quantitative; therefore, this work explores microPET imaging to track protein polymer nanoparticles over several days. To achieve reliable imaging, the polypeptides were modified by site-specific conjugation using a heterobifunctional sarcophagine chelator, AmBaSar, which was subsequently complexed with (64)Cu. AmBaSar/(64)Cu was selected because it can label particles in vivo over periods of days, which is consistent with the timescales required to follow long-circulating nanotherapeutics. Using an orthotopic model of breast cancer, we observed four elastin-like polypeptides (ELPs)-based protein polymers of varying molecular weight, amino acid sequence, and nanostructure. To analyze this data, we developed a six-compartment image-driven pharmacokinetic model capable of describing their distribution within individual subjects. Surprisingly, the assembly of an ELP block copolymer (78 kD) into nanoparticles (R(h) = 37.5 nm) minimally influences pharmacokinetics or tumor accumulation compared to a free ELP of similar length (74 kD). Instead, ELP molecular weight is the most important factor controlling the fate of these polymers, whereby long ELPs (74 kD) have a heart activity half-life of 8.7 hours and short ELPs (37 kD) have a half-life of 2.1 hours. These results suggest that ELP-based protein polymers may be a viable platform for the development of multifunctional therapeutic nanoparticles that can be imaged using clinical PET scanners.

An Orally Administered Redox Nanoparticle That Accumulates in the Colonic Mucosa and Reduces Colitis in Mice

Drugs used to treat patients with ulcerative colitis are not always effective because of nonspecific distribution, metabolism in the gastrointestinal tract, and side effects. We designed a nitroxide radical-containing nanoparticle (RNP(O)) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals. RNP(O) was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNP(O) in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNP(O) were determined in mice with dextran sodium sulfate (DSS)-induced colitis and compared with those of low-molecular-weight drugs (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl [TEMPOL] or mesalamine). RNP(O), with a diameter of 40 nm and a shell of poly(ethylene glycol), had a significantly greater level of accumulation in the colonic mucosa than low-molecular-weight TEMPOL or polystyrene latex particles. RNP(O) was not absorbed into the bloodstream through the intestinal wall, despite its long-term retention in the colon, which prevented its distribution to other parts of the body. Mice with DSS-induced colitis had significantly lower disease activity index and less inflammation following 7 days of oral administration of RNP(O) compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine. We designed an orally administered RNP(O) that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNP(O) might be developed for treatment of patients with ulcerative colitis.

Directed Assembly of Non-equilibrium ABA Triblock Copolymer Morphologies on Nanopatterned Substrates

The majority of past work on directed assembly of block copolymers on chemically nanopatterned surfaces (or chemical patterns) has focused on AB diblock copolymers, and the resulting morphologies have generally corresponded to equilibrium states. Here we report a study on directed assembly of ABA triblock copolymers. Directed assembly of thin films of symmetric poly(methyl methacrylate-b-styrene-b-methyl methacrylate) (PMMA-b-PS-b-PMMA) triblock copolymers is shown to be capable of achieving a high degree of perfection, registration, and accuracy on striped patterns having periods, L(s), commensurate with the bulk period of the copolymer, L(o). When L(s) is incommensurate with L(o), the triblock copolymer domains can reach dimensions up to 55% larger or 13% smaller than L(o). The range over which triblock copolymers tolerate departures from a commensurate L(s) is significantly larger than that accessible with the corresponding diblock copolymer material on analogous directed assembly systems. The assembly kinetics of the triblock copolymer is approximately 3 orders of magnitude slower than observed in the diblock system. Theoretically informed simulations are used to interpret our experimental observations; a thermodynamic analysis reveals that triblocks can form highly ordered, non-equilibrium metastable structures that do not arise in the diblock.

Core–Shell Reversion of Gold Hybrid Polymeric Micelles Fabricated by Tunable Assembly of Block Copolymer

Core–Shell Reversion of Gold Hybrid Polymeric Micelles Fabricated by Tunable Assembly of Block Copolymer

Graphoepitaxy of Block‐Copolymer Self‐Assembly Integrated with Single‐Step ZnO Nanoimprinting

A highly efficient, ultralarge-area nanolithography that integrates block-copolymer lithography with single-step ZnO nanoimprinting is introduced. The UV-assisted imprinting of a photosensitive sol-gel precursor creates large-area ZnO topographic patterns with various pattern shapes in a single-step process. This straightforward approach provides a smooth line edge and high thermal stability of the imprinted ZnO pattern; these properties are greatly advantageous for further graphoepitaxial block-copolymer assembly. According to the ZnO pattern shape and depth, the orientation and lateral ordering of self-assembled cylindrical nanodomains in block-copolymer thin films could be directed in a variety of ways. Significantly, the subtle tunability of ZnO trench depth enabled by nanoimprinting, generated complex hierarchical nanopatterns, where surface-parallel and surface-perpendicular nanocylinder arrays are alternately arranged. The stability of this complex morphology is confirmed by self-consistent field theory (SCFT) calculations. The highly ordered graphoepitaxial nanoscale assembly achieved on transparent semiconducting ZnO substrates offers enormous potential for photonics and optoelectronics.

Chemical Patterns from Surface Grafted Resists for Directed Assembly of Block Copolymers

We demonstrate a direct e-beam patternable one-component block copolymer (BCP) resist to fabricate a chemical pattern for the directed assembly of a symmetric block copolymer. The resist consists of a low molecular weight poly(styrene-block-methyl methacrylate) with a hydroxyl group at the PMMA chain end (PS-b-PMMA-OH), which anchors the chains to the surface. This short-tethered PMMA block provided sufficient sensitivity to allow scission by e-beam. The length of the untethered PS block was fine-tuned to impart the required contrast between the patterned and the unpatterned region for 1:1 assembly of an overlying BCP blend. Two BCP resists with a PS fraction of 0.25 (16SM) and 0.34 (18SM), with a total molecular weight less than 20K, were synthesized, and the assembly of a ternary BCP blend was studied. 16SM- and 18SM-anchored substrates showed nonpreferential and PS preferential surfaces, respectively. Both 18SM and 16SM could be patterned by e-beam to fabricate a 1:1 chemical pattern with a line pitch of 70 nm for the assembly of a BCP ternary blend. 18SM gave fewer defects than 16SM due to an increased contrast in interfacial energies between adjacent stripes in the chemical surface pattern. Two additional PS-b-PMMA-OH polymers with a molecular weight of 39K (F(PS) = 0.76) and 69K (F(PS) = 0.83) were synthesized to study the effect of PS cross-linking upon exposure to e-beam. As the PS fraction increases, the line pattern becomes blurred and ultimately ineffective in guiding the BCP assembly. The blurring is attributed to cross-linking of adjacent PS chains.

Effects of Solvent Composition on the Assembly and Relaxation of Triblock Copolymer-Based Polyelectrolyte Gels

The role of solvent selectivity has been explored extensively with regard to its role in the phase behavior of block copolymer assemblies. Traditionally, thermally induced phase separation is employed for generating micelles upon cooling a block copolymer dissolved in a selective solvent. However few amphiphilic, polyelectrolyte-containing block copolymers demonstrate a thermally accessible route of micellization, and solvent exchange routes are frequently employed instead. Here, we describe the use of mixed solvents for obtaining thermoreversible gelation behavior of poly(methyl methacrylate)-poly(methacrylic acid)-poly(methyl methacrylate) (PMMA–PMAA–PMMA) triblock copolymers. One solvent component (dimethyl sulfoxide) is a good solvent for both blocks, and the second solvent component (water) is a selective solvent for the polymer midblock. Rheological frequency sweeps at variable solvent compositions and temperatures demonstrate an adherence to time–temperature–composition superposition, so that chang...

Stimuli-responsive organization of block copolymers on DNA nanotubes

DNA nanotubes are an attractive class of materials that can be assembled with precise control over their size, shape, length and porosity, and can encapsulate and release materials in response to specific added molecules. In parallel, block copolymer assemblies can provide biocompatibility, stability, nuclease resistance, the ability to encapsulate small molecules, long-range assembly and numerous additional functionalities that can be tuned with subtle chemical modifications. Herein, we describe a new class of hybrid materials in which block copolymer assemblies are sequence-specifically and longitudinally positioned on robust DNA nanotubes constructed using rolling circle amplification. These materials are dynamic, allowing the polymer structures to be cleanly removed from the DNA nanotubes only when a specific DNA sequence is added, and creating a single-stranded form of these nanotubes. Specifically, we first describe the use of rolling circle amplification to create a long DNA strand containing a repeat sequence. This is used as a guide strand in a new method to construct robust nanotubes with a non-nicked backbone. We then synthesize polymer–DNA conjugates through on-column functionalization of a DNA strand with a polymer. These conjugates self-assemble into spherical aggregates, which then position themselves onto the DNA nanotubes using sequence-specific hybridization, creating a ‘striped' structure. The polymer aggregates can be cleanly lifted off the nanotubes using a strand displacement strategy, thus uncapping these DNA nanotubes. We also show that this longitudinal alignment of polymer aggregates on DNA nanotubes is general for a variety of DNA–block copolymers.

A simple approach to characterizing block copolymer assemblies: graphene oxide supports for high contrast multi-technique imaging.

Block copolymers are well-known to self-assemble into a range of 3-dimensional morphologies. However, due to their nanoscale dimensions, resolving their exact structure can be a challenge. Transmission electron microscopy (TEM) is a powerful technique for achieving this, but for polymeric assemblies chemical fixing/staining techniques are usually required to increase image contrast and protect specimens from electron beam damage. Graphene oxide (GO) is a robust, water-dispersable, and nearly electron transparent membrane: an ideal support for TEM. We show that when using GO supports no stains are required to acquire high contrast TEM images and that the specimens remain stable under the electron beam for long periods, allowing sample analysis by a range of electron microscopy techniques. GO supports are also used for further characterization of assemblies by atomic force microscopy. The simplicity of sample preparation and analysis, as well as the potential for significantly increased contrast background, make GO supports an attractive alternative for the analysis of block copolymer assemblies.