Self-assembly Of Amphiphilic Block Copolymers Research Articles

Self-assembly of single-chain nanoparticles from block copolymers into inverse bicontinuous structures

Single-chain nanoparticles preferentially self-assemble into cubosomes with a broad window by intrachain cross-linking the hydrophilic chains of block copolymers, which accounts for the smaller a0 and the larger P.

Stretched or wrinkled? Looking into the polymer conformation within polymersome membranes.

Self-assembly of amphiphilic block-copolymers into polymersomes is a well-established concept. In this membrane, the hydrophilic part is considered to be loosely assembled towards the solvent, and the hydrophobic part on the inside of the membrane is considered to be more densely packed. Within the membrane, this hydrophobic part could now have a stretched conformation or be a random coil, depending on the available space and also on the chemical nature of the polymer. We now analysed the literature for works on polymersomes that determined the membrane thickness via cryo-TEM and analysed the hydrophobic part of their polymers for their conformation. Over all available block-copolymers, a variety of trends became obvious: the longer a hydrophobic block, the more coiled the conformation and the bulkier the side chains, the more stretched the polymer became. Polymers with less conformational freedom like semi-crystalline ones were present in a more stretched conformation. Both trends could be exemplified on various occasions in this cross-literature meta-study. This overview hence provides additional insight into the physical chemistry of block-copolymer membranes.

Apparent symmetry rising induced by crystallization inhibition in ternary co-crystallization-driven self-assembly

The concept of apparent symmetry rising, opposite to symmetry breaking, was proposed to illustrate the unusual phenomenon that the symmetry of the apparent morphology of the multiply twinned particle is higher than that of its crystal structure. We developed a unique strategy of co-crystallization-driven self-assembly of amphiphilic block copolymers PEO-b-PS and the inorganic cluster silicotungstic acid to achieve apparent symmetry rising of nanoparticles under mild conditions. The triangular nanoplates triply twinned by orthogonal crystals (low symmetry) have an additional triple symmetry (high symmetry). The appropriate crystallization inhibition of short solvophilic segments of the block copolymers favors the oriented attachment of homogeneous domains of hybrid nanoribbons, and consequently forms kinetic-controlled triangular nanoplates with twin grain boundaries.

In Situ Monitoring of Block Copolymer Self-Assembly via Solvent Exchange through Controlled Dialysis with Light and Neutron Scattering Detection.

Solution self-assembly of amphiphilic block copolymers (BCs) is typically performed by a solvent-to-water exchange. However, BC assemblies are often trapped in metastable states depending on the mixing conditions such as the magnitude and rate of water addition. BC self-assembly can be performed under near thermodynamic control by dialysis, which accounts for a slow and gradual water addition. In this Letter we report the use of a specifically designed dialysis cell to continuously monitor by dynamic light scattering and small-angle neutron scattering the morphological changes of PDMS-b-PEG BCs self-assemblies during THF-to-water exchange. The complete phase diagrams of near-equilibrium structures can then be established. Spherical micelles first form before evolving to rod-like micelles and vesicles, decreasing the total developed interfacial area of self-assembled structures in response to increasing interfacial energy as the water content increases. The dialysis kinetics can be tailored to the time scale of BC self-assembly by modifying the membrane pore size, which is of interest to study the interplay between thermodynamics and kinetics in self-assembly pathways.

Precision Macro (molecular) Assemblies

Structural precision in hierarchical self-assembled architectures is ubiquitous in biological systems. For instance, DNA double helix, quaternary structures of proteins, tobacco mosaic virus, microtubules, and several other elegant systems are constituted through specific molecular recognitions that are responsible for regulating numerous complex functions in nature. Inspired by such elegant examples in living systems, the self-assembly of synthetic small molecules and macromolecules has been studied with great interest, especially in the past four decades since the concept of supramolecular chemistry had been established in a formal way. In this context, solution self-assembly of amphiphilic block copolymers (ABCPs) with amorphous core- forming blocks has been studied extensively in the past three decades owing to the possibility of generating different nanostructures in water,such as micelles, vesicles, fibers, lamella, and others.Despite the fact that self-assembly of ABCPs has proven to be an effective bottom- up approach for creating multilevel structures that are gateways to highly promising soft materials for diverse applications, attempts to improve specific and nontrivial functional utilities of these systems have been hampered by a number of significant problems. Aggregation of ABCPs in block-selective solvents is commonly catalyzed by the immiscibility-driven chain collapse of the amorphous core-forming blocks. Thus, the critical packing parameter, which in turn depends on the relative volume fraction of the hydrophobic and hydrophilic block segments, is the primary factor controlling the morphology of these polymer aggregates in solutions.This limits the ability to precisely tailor the internal order orsurface functional group display in such nanostructures or control their dimensions, shapes, and dispersity, which is crucial for their elegant biological functions. Moreover, for ABCPs with amorphous core- forming blocks, non-spherical structures are rarely accessible only within a limited window of block compositions and self-assembly environments. Sometimes, those are also contaminated with other undesired morphologies. Many studies have demonstrated that non-spherical, high aspect ratio nanostructures such as one- dimensional (1D) fibers and two- dimensional (2D) plateletperform superior functions in emerging applications, compared to their spherical analogues. This has paved the way for the emergence of new macromolecular designs toward the development of internally-ordered precision anisotropic structures.

Topology-controlled self-assembly of amphiphilic block copolymers.

Contemporary synthetic chemistry approaches can be used to yield a range of distinct polymer topologies with precise control. The topology of a polymer strongly influences its self-assembly into complex nanostructures however a clear mechanistic understanding of the relationship between polymer topology and self-assembly has not yet been developed. In this work, we use atomistic molecular dynamics simulations to provide a nanoscale picture of the self-assembly of three poly(ethylene oxide)-poly(methyl acrylate) block copolymers with different topologies into micelles. We find that the topology affects the ability of the micelle to form a compact hydrophobic core, which directly affects its stability. Also, we apply unsupervised machine learning techniques to show that the topology of a polymer affects its ability to take a conformation in response to the local environment within the micelles. This work provides foundations for the rational design of polymer nanostructures based on their underlying topology.

Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles.

Self-assembly of amphiphilic block copolymers display a multiplicity of nanoscale periodic patterns proposed as a dominant tool for the 'bottom-up' fabrication of nanomaterials with different levels of ordering. The present review article focuses on the recent updates to the self-association of amphiphilic block copolymers in aqueous media into varied core-shell morphologies. We briefly describe the block copolymers, their types, microdomain formation in bulk and micellization in selective solvents. We also discuss the characteristic features of block copolymers nanoaggregates viz., polymer micelles (PMs) and polymersomes. Amphiphilic block copolymers (with a variety of hydrophobic blocks and hydrophilic blocks; often polyethylene oxide) self-assemble in water to micelles/niosomes similar to conventional nonionic surfactants with high drug loading capacity. Double hydrophilic block copolymers (DHBCs) made of neutral block-neutral block or neutral block-charged block can transform one block to become hydrophobic under the influence of a stimulus (physical/chemical/biological), and thus induced amphiphilicity and display self-assembly are discussed. Different kinds of polymer micelles (viz. shell and core-cross-linked, core-shell-corona, schizophrenic, crew cut, Janus) are presented in detail. Updates on polymerization-induced self-assembly (PISA) and crystallization-driven self-assembly (CDSA) are also provided. Polyion complexes (PICs) and polyion complex micelles (PICMs) are discussed. Applications of these block copolymeric micelles and polymersomes as nanocarriers in drug delivery systems are described.

From Lipids to Micelles- A Tentative Analysis of Drug Delivery

Polymer micelles (PM) are core-shell nanostructures formed by the self-assembly of amphiphilic block copolymers. Due to its hollow form and biocompatibility, it is an excellent drug carrier and has a wide range of uses in the pharmaceutical field. This review summarizes the latest developments in PM development and its applications. First, I explained the basic structure and several types of micelles. This process introduces experiments and parameters to control the shape of the vesicles used for drug delivery. Next, we talked about various common synthetic methods such as the solvent conversion method and the solvent-free method. In addition, we introduce polymer micelles into conventional pharmacies and the difficulties of modern medicine. Finally, it summarizes the morphology, synthesis method and application of PM in the medical field, and provides insights into the future development of vesicle degradation and the biocompatibility of PM preparation and the resulting morphology. In addition to the above, this article also introduces different methods of PM targeting, imaging, and triggered release in pharmaceutical applications.

Sorafenib-loaded silica-containing redox nanoparticles for oral anti-liver fibrosis therapy.

Liver fibrosis is a chronic disease resulting from repetitive or prolonged liver injury with limited treatment options. Sorafenib has been reported to be a potential antifibrotic agent; however, its therapeutic effect is restricted because of its low bioavailability and severe adverse effects in the gastrointestinal (GI) tract. In this study, we developed sorafenib-loaded silica-containing redox nanoparticles (sora@siRNP) as an oral nanomedicine to treat liver fibrosis. The designed siRNP were prepared by self-assembly of amphiphilic block copolymers, which possess antioxidant nitroxide radicals as a side chain of the hydrophobic segment and porous silica particles in the nanoparticle core. The silica moieties in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption, which could be useful in harsh GI conditions after oral drug administration. Based on in vitro evaluation, sora@siRNP exerted antiproliferative and antifibrotic effects against hepatic stellate cells (HSCs) and low toxicity against normal endothelial cells. A pharmacokinetic study showed that siRNP significantly improved the bioavailability and distribution of sorafenib in the liver. In an in vivo study using a mouse model of CCl4-induced liver fibrosis, oral administration of sora@siRNP significantly suppressed the fibrotic area in comparison to free sorafenib administration. In mice with CCl4-induced fibrosis, free sorafenib administration did not suppress the expression of α-smooth muscle actin; however, mice treated with sora@siRNP showed significantly suppressed expression of α-smooth muscle actin, indicating the inhibition of HSC activation, which was confirmed by in vitro experiments. Moreover, oral administration of free sorafenib induced severe intestinal damage and increased leakage into the gut, which can be attributed to the generation of reactive oxygen species (ROS). Our antioxidant nanocarriers, siRNP, reduced the adverse effects of local ROS scavenging in the GI tract. Our results suggest that sora@siRNP could serve as a promising oral nanomedicine for liver fibrosis.

A block copolymer templated approach for the preparation of nanoporous polymer structures and cellulose fiber hybrids by ozone treatment

Porous nanostructures were derived after self-assembly of amphiphilic block copolymers and subsequent ozone-mediated block segment degradation. Highly ordered pores were obtained for BCP films and for coatings at cellulose fibers’ surfaces.

Self-Assembled Nanoparticles Based on Block-Copolymers of Poly(2-Deoxy-2-methacrylamido-d-glucose)/Poly(N-Vinyl Succinamic Acid) with Poly(O-Cholesteryl Methacrylate) for Delivery of Hydrophobic Drugs.

The self-assembly of amphiphilic block-copolymers is a convenient way to obtain soft nanomaterials of different morphology and scale. In turn, the use of a biomimetic approach makes it possible to synthesize polymers with fragments similar to natural macromolecules but more resistant to biodegradation. In this study, we synthesized the novel bio-inspired amphiphilic block-copolymers consisting of poly(N-methacrylamido-d-glucose) or poly(N-vinyl succinamic acid) as a hydrophilic fragment and poly(O-cholesteryl methacrylate) as a hydrophobic fragment. Block-copolymers were synthesized by radical addition–fragmentation chain-transfer (RAFT) polymerization using dithiobenzoate or trithiocarbonate chain-transfer agent depending on the first monomer, further forming the hydrophilic block. Both homopolymers and copolymers were characterized by 1H NMR and Fourier transform infrared spectroscopy, as well as thermogravimetric analysis. The obtained copolymers had low dispersity (1.05–1.37) and molecular weights in the range of ~13,000–32,000. The amphiphilic copolymers demonstrated enhanced thermal stability in comparison with hydrophilic precursors. According to dynamic light scattering and nanoparticle tracking analysis, the obtained amphiphilic copolymers were able to self-assemble in aqueous media into nanoparticles with a hydrodynamic diameter of approximately 200 nm. An investigation of nanoparticles by transmission electron microscopy revealed their spherical shape. The obtained nanoparticles did not demonstrate cytotoxicity against human embryonic kidney (HEK293) and bronchial epithelial (BEAS-2B) cells, and they were characterized by a low uptake by macrophages in vitro. Paclitaxel loaded into the developed polymer nanoparticles retained biological activity against lung adenocarcinoma epithelial cells (A549).

Access to different transient assemblies through kinetic control over the self-assembly of amphiphilic block copolymers using a versatile micromixer

Kinetic control over self-assembly may lead to various out-of-equilibrium supramolecular objects with distinctly different functions based on identical building blocks, but the engineering approach towards such goal is still lacking, limiting the practical applications. Here we show how a variety of transient assemblies bearing different architectures can be prepared from the same amphiphilic block copolymer (BCP) using a high-efficiency micromixer. Upon simply tuning the mixing parameters, the self-assembly kinetics of the BCP were effectively interfered, giving rise to a series of kinetically favored assemblies under continuous production. Interestingly, all these different assemblies were capable of converting into thermodynamically more stable state over time, showing typical out-of-equilibrium feature. Importantly, the kinetically favored assemblies loading with gold nanoparticles showed very different catalytic activities from the thermodynamic one, demonstrating their different functionalities. Such engineering approach towards out-of-equilibrium supramolecular assemblies may promote the implementation of flow chemistry technique in supramolecular chemistry for engineering applications.

Structural Engineering in the Self-Assembly of Amphiphilic Block Copolymers with Reactive Additives: Micelles, Vesicles, and Beyond.

Control of polymer assemblies in solution is of great importance to determine the properties and applications of these polymer nanostructures. We report a novel co-self-assembly strategy to control the self-assembly outcomes of a micelle-forming amphiphilic block copolymer (BCP) of poly(ethylene oxide) (PEO) and poly[3-(trimethoxysilyl)propyl methacrylate] (PTMSPMA), PEO114-b-PTMSPMA228. With a reactive and hydrophobic additive tetraethyl orthosilicate (TEOS), the assembly nanostructures of PEO114-b-PTMSPMA228 are tunable. The swelling of the PTMSPMA block by hydrophobic TEOS increases the hydrophobic-to-hydrophilic ratio that enables a continuous morphological evolution from spherical micelles to vesicles and eventually to large compound vesicles. TEOS that co-hydrolyzes with the PTMSPMA block can further stabilize and fix these hybrid nanostructures. With high TEOS concentrations, these polymer assemblies can be further converted through thermal annealing into unique silica nanomaterials, including nanospheres, hollow nanoparticles with dual shells, and mesoporous silica frameworks that cannot be synthesized through conventional syntheses otherwise.

Recyclable DMAP-Functionalized polymeric nanoreactors for highly efficient acylation of alcohols in aqueous systems

Fabrication of highly efficient and recyclable nanoreactors via macromolecular self-assembly represents a promising strategy for green organic transformation. In this study, small-molecule catalysts 4-(N,N-dimethylamino)pyridine (DMAP) functionalized nanoreactors were constructed by self-assembly of amphiphilic block copolymers with DMAP moieties in the hydrophobic block, leading to heterogeneous catalysts with excellent dispersity in water. The key preparation route included reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(N-methyl-N-(4-pyridyl)amino)ethyl methacrylate (MAPMA) and methyl methacrylate (MMA) using poly (oligomeric (ethylene glycol) methyl ether methacrylate) (POEGMA) as a hydrophilic macromoleculer RAFT reagent. The characterization by dynamic light scattering (DLS) and transmission electron microscopy (TEM) shows that the nanoreactors possess a core-shell nanostructure with the diameter of around 110 nm. The resulting polymeric nanoreactors showed excellent catalytic activity for acylation of alcohols in water. High conversion of a variety of alcohol (>99%) and excellent product selectivity were achieved. The high catalytic efficiency of the nanoreactors may be attributed to the enhancement of the interaction between the reactant and the catalyst in the confined hydrophobic space, which simulates how enzymes usually work. Moreover, the catalyst could be easily recovered by thermos-responsive separation and reused with high activity for more than 5 cycles. This study presents an efficient approach to achieve green catalytic reactions which are normally incompatible to aqueous conditions, potentially applicable to other catalytic systems such as metal-mediated organic transformations.

Polymeric Micelles: Morphology, Synthesis, and Pharmaceutical Application

Polymeric micelles (PMs) are nanosized core-shell molecules formed by the self-assembly of amphiphilic block copolymers. Their unique morphologies, biocompatibility have allowed them to serve as drug carriers and have found wide applications in the pharmaceutical industry. This review summarizes the recent progress of PM development and its applications in the pharmaceutical field. Firstly, we discussed the fundamentals of polymeric micelles, the formation mechanism, and their relative morphologies. Then we listed various common synthetic methods, including the solvent-free method, solvent-switch method, microfluid method, etc. Secondly, we illustrated the application of polymeric micelles in pharmaceutical applications on targeting, imaging, and stimuli-responsive drug release. In the end, we summarize the fundamental aspect of how to prepare polymeric micelles, their resulting morphology, and their applications in the medical field. Finally, we provide insights into polymeric micelles’ future developments on their longer shelf life and better environmental adaptability.

Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy

Summary We directly initiate and visualize the formation of polymeric nanomaterials via variable-temperature liquid-cell transmission electron microscopy (VT-LCTEM). With temperature control in the liquid cell, reversible addition-fragmentation chain transfer polymerization was thermally initiated, leading to the formation of amphiphilic block copolymers that assemble upon dispersion polymerization-induced self-assembly (PISA). In combination with traditional ex situ analyses, VT-LCTEM enabled not only the characterization of the nanoparticles in situ but also the observation of a thermal phase transition. Critically, because these assemblies form from thermoresponsive components, any temperature changes during sample preparation and analysis can alter morphologies, necessitating direct in situ characterization of reaction progression. We believe that the findings and the technique described herein will lead to unprecedented possibilities for the development and characterization of self-organizing soft matter.

Spraying of Ultrathin Isoporous Block Copolymer Membranes-A Story about Challenges and Limitations.

Isoporous membranes can be prepared by a combination of self-assembly of amphiphilic block copolymers and the non-solvent induced phase separation process. As the general doctor-blade technique suffers from high consumption of expensive block copolymer, other methods to reduce its concentration in the casting solution are sought after. Decreasing the block copolymer concentration during membrane casting and applying the block copolymer solution on a support membrane to obtain ultrathin isoporous membrane layers with e.g., spraying techniques, can be an answer. In this work we focused on the question if upscaling of thin block copolymer membranes produced by spraying techniques is feasible. To upscale the spray coating process, three different approaches were pursued, namely air-brush, 1-fluid nozzles and 2-fluid nozzles as generally used in the coating industry. The different spraying systems were implemented successfully in a membrane casting machine. Thinking about future development of isoporous block copolymer membranes in application it was significant that a continuous preparation process can be realised combining spraying of thin layers and immersion of the thin block copolymer layers in water to ensure phase-separation. The system was tested using a solution of polystyrene-block-poly(4-vinylpyridine) diblock copolymer. A detailed examination of the spray pattern and its homogeneity was carried out. The limitations of this method are discussed.

Where are those lipid nano rings?

Highly curved toroidal micelles with diameters as small as 100 nm have been successfully constructed by self-assembly of amphiphilic block copolymers. These structures may have potential applications in gene or drug delivery. Experimental observations suggest that toroidal micelles likely originate from spherical or disc-like micelles which are tricked into forming toroidal micelles upon external stimuli (‘smart’ materials). Since self-assembly of polymeric and lipid surfactants is guided by the same physical principles, we hypothesize that ‘smart’ lipid surfactants can be equivalently tricked into forming highly curved toroidal micelles that are tenfold smaller (≃10 nm diameter). Paradoxically, these ‘nano rings’ have never been observed. Using coarse-grained molecular dynamics (MD) simulations in conjunction with a state-of-the-art free energy calculation method (a string method), we illustrate how a thermo-responsive lipid surfactant is able to form toroidal micelles. These micelles originate from disc-like micelles that are spontaneously perforated upon heat shocking, thereby supporting a longstanding hypothesis on the possible origin of polymeric toroidal micelle phases observed in experiments. We illustrate that kinetically stable ‘nano rings’ are substantially shorter lived than their tenfold larger polymeric analogs. The estimated life-time (milliseconds) is in fact similar to the characteristic breaking time of the corresponding worm-like micelle. Finally, we resolve the characteristic finger print which ‘nano rings’ leave in time-resolved X-ray spectra and illustrate how the uptake of small DNA fragments may enhance their stability. Despite a shared kinetics of self-assembly, length scale dependent differences in the life-time of surfactant phases can occur when phases are kinetically rather than thermodynamically stable. This results in the apparent absence or presence of toroidal micelle phases on different length scales. Our theoretical work precisely illustrates that the universality of surfactants nevertheless remains conserved even at different length scales.

Complementary Nucleobase Interactions Drive the Hierarchical Self-Assembly of Core–Shell Bottlebrush Block Copolymers toward Cylindrical Supramolecules

The self-assembly of amphiphilic block copolymers has facilitated the preparation of a wide variety of nano-objects of diverse morphology. Ready access to these nanostructures has opened up new pos...

The chemistry of cross-linked polymeric vesicles and their functionalization towards biocatalytic nanoreactors

Self-assembly of amphiphilic block copolymers into polymersomes continues to be a hot topic in modern research on biomimetics. Their well-known and valued mechanical strength can be increased even further if they are cross-linked. These additional bonds prevent a collapse or disassembly of the polymersomes and open the way towards smart nanoreactors. A variety of chemistries have been applied to obtain the desired cross-linked polymersomes, and therefore, the chemical approaches performed over time will be highlighted in this mini-review. Due to the large number of studies, a selected set of photo-cross-linked and pH-sensitive polymersomes will be specifically highlighted. This system has proven to be a very potent candidate for the formation of nanoreactors and drug delivery systems, and even for the formation of functional multicompartment cell mimics.Graphical abstract