Block Copolymer Nanoparticles Research Articles

Seeded Raft Polymerization-Induced Self-assembly: Recent Advances and Future Opportunities.

Over the past decade, polymerization-induced self-assembly (PISA) has fully proved its versatility for scale-up production of block copolymer nanoparticles with tunable sizes and morphologies; yet, there are still some limitations. Recently, seeded PISA approaches combing PISA with heterogeneous seeded polymerizations have been greatly explored and are expected to overcome the limitations of traditional PISA. In this review, recent advances in seeded PISA that have expanded new horizons for PISA are highlighted including i) general considerations for seeded PISA (e.g., kinetics, the preparation of seeds, the selection of monomers), ii) morphological evolution induced by seeded PISA (e.g., from corona-shell-core nanoparticles to vesicles, vesicles-to-toroid, disassembly of vesicles into nanospheres), and iii) various well-defined nanoparticles with hierarchical and sophisticated morphologies (e.g., multicompartment micelles, porous vesicles, framboidal vesicles, AXn -type colloidal molecules). Finally, new insights into seeded PISA and future perspectives are proposed. This article is protected by copyright. All rights reserved.

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization‐Induced Self‐Assembly in Aqueous Media

AbstractHydrolytically degradable block copolymer nanoparticles are prepared via reverse sequence polymerization‐induced self‐assembly (PISA) in aqueous media. This efficient protocol involves the reversible addition‐fragmentation chain transfer (RAFT) polymerization of N,N′‐dimethylacrylamide (DMAC) using a monofunctional or bifunctional trithiocarbonate‐capped poly(ϵ‐caprolactone) (PCL) precursor. DMAC monomer is employed as a co‐solvent to solubilize the hydrophobic PCL chains. At an intermediate DMAC conversion of 20–60 %, the reaction mixture is diluted with water to 10–25 % w/w solids. The growing amphiphilic block copolymer chains undergo nucleation to form sterically‐stabilized PCL‐core nanoparticles with PDMAC coronas. 1H NMR studies confirm more than 99 % DMAC conversion while gel permeation chromatography (GPC) studies indicate well‐controlled RAFT polymerizations (Mw/Mn≤1.30). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicate spheres of 20–120 nm diameter. As expected, hydrolytic degradation occurs within days at 37 °C in either acidic or alkaline solution. Degradation is also observed in phosphate‐buffered saline (PBS) (pH 7.4) at 37 °C. However, no degradation is detected over a three‐month period when these nanoparticles are stored at 20 °C in deionized water (pH 6.7). Finally, PDMAC30‐PCL16‐PDMAC30 nanoparticles are briefly evaluated as a dispersant for an agrochemical formulation based on a broad‐spectrum fungicide (azoxystrobin).

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Media.

Hydrolytically degradable block copolymer nanoparticles are prepared via reverse sequence polymerization-induced self-assembly (PISA) in aqueous media. This efficient protocol involves the reversible addition-fragmentation chain transfer (RAFT) polymerization of N,N'-dimethylacrylamide (DMAC) using a monofunctional or bifunctional trithiocarbonate-capped poly(ϵ-caprolactone) (PCL) precursor. DMAC monomer is employed as a co-solvent to solubilize the hydrophobic PCL chains. At an intermediate DMAC conversion of 20-60 %, the reaction mixture is diluted with water to 10-25 % w/w solids. The growing amphiphilic block copolymer chains undergo nucleation to form sterically-stabilized PCL-core nanoparticles with PDMAC coronas. 1 H NMR studies confirm more than 99 % DMAC conversion while gel permeation chromatography (GPC) studies indicate well-controlled RAFT polymerizations (Mw /Mn ≤1.30). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicate spheres of 20-120 nm diameter. As expected, hydrolytic degradation occurs within days at 37 °C in either acidic or alkaline solution. Degradation is also observed in phosphate-buffered saline (PBS) (pH 7.4) at 37 °C. However, no degradation is detected over a three-month period when these nanoparticles are stored at 20 °C in deionized water (pH 6.7). Finally, PDMAC30 -PCL16 -PDMAC30 nanoparticles are briefly evaluated as a dispersant for an agrochemical formulation based on a broad-spectrum fungicide (azoxystrobin).

Group‐Transfer Polymerization‐Induced Self‐Assembly (GTPISA) in Non‐polar Media: An Organocatalyzed Route to Block Copolymer Nanoparticles at Room Temperature

AbstractPolymerization‐induced self‐assembly (PISA) enables the synthesis at large scale of a wide variety of functional nanoparticles. However, a large number of works are related to controlled radical polymerization (CRP) methods and are generally undertaken at elevated temperatures (>50 °C). Here is the first report on methacrylate‐based nanoparticles fabricated by group transfer polymerization‐induced self‐assembly (GTPISA) in non‐polar media (n‐heptane). This GTPISA process is achieved at room temperature (RT) using 1‐methoxy‐1‐(trimethylsiloxy)‐2‐methylprop‐1‐ene (MTS) and tetrabutylammonium bis‐benzoate (TBABB) as initiator and organic catalyst, respectively. Under these conditions, well‐defined metal‐free and colorless diblock copolymers are produced with efficient crossover from the non‐polar stabilizing poly(lauryl methacrylate) (PLMA) block to the non‐soluble poly(benzyl methacrylate) (PBzMA) segment. The resulting PLMA‐b‐PBzMA block copolymers simultaneously self‐assemble into nanostructures of various sizes and morphologies. GTPISA in non‐polar solvent proceeds rapidly at RT and avoids the use of sulfur or halogenated compounds or metallic catalysts associated with the implementation of CRP methods, thus expanding the potential of PISA formulations for applications in non‐polar environments.

Group-Transfer Polymerization-Induced Self-Assembly (GTPISA) in Non-polar Media: An Organocatalyzed Route to Block Copolymer Nanoparticles at Room Temperature.

Polymerization-induced self-assembly (PISA) enables the synthesis at large scale of a wide variety of functional nanoparticles. However, a large number of works are related to controlled radical polymerization (CRP) methods and are generally undertaken at elevated temperatures (>50 °C). Here is the first report on methacrylate-based nanoparticles fabricated by group transfer polymerization-induced self-assembly (GTPISA) in non-polar media (n-heptane). This GTPISA process is achieved at room temperature (RT) using 1-methoxy-1-(trimethylsiloxy)-2-methylprop-1-ene (MTS) and tetrabutylammonium bis-benzoate (TBABB) as initiator and organic catalyst, respectively. Under these conditions, well-defined metal-free and colorless diblock copolymers are produced with efficient crossover from the non-polar stabilizing poly(lauryl methacrylate) (PLMA) block to the non-soluble poly(benzyl methacrylate) (PBzMA) segment. The resulting PLMA-b-PBzMA block copolymers simultaneously self-assemble into nanostructures of various sizes and morphologies. GTPISA in non-polar solvent proceeds rapidly at RT and avoids the use of sulfur or halogenated compounds or metallic catalysts associated with the implementation of CRP methods, thus expanding the potential of PISA formulations for applications in non-polar environments.

Synthesis of Hydrophobic Block Copolymer Nanoparticles in Alcohol/Water Stabilized by Poly(methyl methacrylate) via RAFT Dispersion Polymerization-Induced Self-Assembly

Poly(methyl methacrylate) (PMMA) is an important common polymer widely used in industry. While PMMA has been used as a core-forming block for polymerization-induced self-assembly (PISA), a powerful approach for the synthesis of block copolymer nanoparticles, it has not been utilized as a corona block due to PMMA being insoluble in common solvents for PISA formulations (e.g., water and alcohols). Exploiting the solubility of PMMA-dithiobenzoate (DTB) in ethanol/water mixtures, such macroRAFT agents have in the present work been successfully employed for reversible addition–fragmentation chain transfer (RAFT) PISA in ethanol/water (80/20 by volume). RAFT dispersion polymerization of benzyl methacrylate mediated by PMMA-DTB macroRAFT agents with various degrees of polymerization has been investigated. Transmission electron microscopy analyses revealed well-defined block copolymer nano-objects, including spheres, worms, as well as vesicles. Nanoparticles comprising a PMMA outer layer would have superior compatibility with various hydrophobic polymer matrices, thereby enabling various new applications such as, e.g., use as nanofillers.

Controlling the Self‐Assembly of Hierarchical PS‐b‐P4VP Structures Prepared by Dip‐Coating and Emulsion Breath Figure Techniques

AbstractThe breath figure (BF) method is a common laboratory‐scale pathway for fabricating porous structures. The emulsion BF approach, one of the BF variations, has attracted increasing attention since it bypasses the high humidity requirement, which is characteristic for the conventional BF method. In this paper, we used the emulsion BF technique with PS‐b‐P4VP block copolymer (BCP) and SiO2 nanoparticles (NPs) as the stabilizers for water droplets. We combined this with the dip‐coating technique to obtain a hierarchical structure consisting of BF pores and BCP nanodomains. By altering the dip‐coating speeds and the NPs’ surface wetting properties and size, the average diameters of BF pores could be controlled. Notably, we were able to achieve both nano and microscale BF pores in the network. The effect of NPs for stabilization and dip‐coating parameters on BF pores and BCP nanodomains formation was established, extending the comprehension of this underdeveloped subject.

Nanocarrier of Pin1 inhibitor based on supercritical fluid technology inhibits cancer metastasis by blocking multiple signaling pathways.

Cancer metastasis is the primary cause of all cancer-related deaths due to the lack of effective targeted drugs that simultaneously block multiple signaling pathways that drive the dissemination and growth of cancer cells. The unique proline isomerase Pin1 activates numerous cancer pathways, but its role in cancer metastasis and the inhibitory efficacy of Pin1 inhibitors on cancer metastasis are unknown. Moreover, the applicability of Pin1 inhibitor-all-trans retinoic acid (ATRA) is limited due to its several drawbacks. Herein, uniform ATRA-loaded polylactic acid-polyethylene glycol block copolymer nanoparticles (ATRA-NPs) with high encapsulation efficiency, good cellular uptake, excellent controlled release performance and pharmacokinetics are developed using supercritical carbon dioxide processing combined with an optimized design. ATRA-NPs exhibited excellent biosafety and significant inhibition on the growth and metastasis of hepatocellular carcinoma. Pin1 played a key role in cancer metastasis and was the main target of ATRA-NPs. ATRA-NPs exerted their potent anti-metastatic effect by inhibiting Pin1 and then simultaneously blocking multiple signaling pathways and cancer epithelial-mesenchymal progression. Since ATRA-NPs could effectively couple the inhibition of cancer cell dissemination with cancer growth, it provided a novel therapeutic strategy for efficiently inhibiting cancer metastasis.

Encapsulation of phenylacetic acid in block copolymer nanoparticles during polymerization induced self‐assembly

AbstractPolymerization induced self‐assembly (PISA) is an in situ method for producing block copolymer nanoparticles. Performing PISA in the presence of a pharmaceutical drug causes the nanoparticles to encapsulate the drug. While this approach is straightforward, the effects of drug loading and block copolymer composition remain unclear. Here, we investigate encapsulation of the drug phenylacetic acid (PA) in poly(glycerol monomethacrylate)‐block‐poly(2‐hydroxypropyl methacrylate) (PGMA‐PHPMA) nanoparticles during PISA. Nanoparticle morphology is characterized by electron microscopy and light scattering, while encapsulation efficiency () is quantified using nuclear magnetic resonance diffusometry. Increasing the PA loading shifts the nanoparticle morphology from spherical micelles cylindrical micelles vesicles. At a 32 mg/ml PA loading, maximizes at ~80%. Increasing the PHPMA degree of polymerization minimally impacts . The invariance of toward core block length suggests that PA binds to the nanoparticle corona, highlighting the importance of the hydrophilic block for drug encapsulation during PISA.

Lactate and glucose responsive boronic acid-substituted amphiphilic block copolymer nanoparticles of high aspect ratio

The establishment of conditions for formation of higher order morphologies (e.g. rods and worms) is important, as such nanoparticles are more efficient than spheres in drug delivery. Glucose-binding of core–shell nanoparticles comprising of boronic acid (BA) moieties occurs under basic conditions at above the pKa of the BA (pH 8.7). The resulting increased solubility of the core-forming BA-containing block is utilised in the delivery of therapeutics to diabetics. In contrast, the binding of the key anaerobic metabolite lactate to the BA moiety of amphiphilic block copolymers is unreported, despite occurring at lower physiological neutral pH 7.4. Herein, for the first time, high aspect ratio nanoparticles are observed for (unprotected) BA-substituted amphiphilic block copolymers in water, achieved by incorporating a non-stimuli responsive hydrophobic (tert-butylacrylamide) block. Amphiphilic diblock (Mn = 24,100 and 27,700 gmol−1) and triblock copolymers (Mn = 21,500 and 25,200 gmol−1) with relatively narrow molecular weight distributions (ᴆ = 1.31–1.48) were prepared by reversible addition-fragmentation chain transfer (RAFT) solution polymerizations. Aggregates formed upon dialysis with lactate at pH 7.4 were generally similar to those formed upon self-assembly with glucose at pH 8.7. Spherical nanoparticles for poly(N,N-dimethylacrylamide, DMA)28-b-(3-(acrylamidophenyl)boronic acid, 3-BAPhA)84-TTC (trithiocarbonate) decreased in size from Dh = 259 nm to mostly 100–150 nm upon ionization of BA-moieties with lactate, base, and glucose. Poly(DMA)96-b-(3-BAPhA)62 gave ∼ 500 nm long worms and lamellae under basic conditions, which transitioned to irregular spheres and rods upon addition of glucose. Self-assembly for triblock copolymers with BA-binding gave worms and fused spherical micelle rod-like structures.

Single-ion nano-features formed by a Li-containing block copolymer synthesized via PISA

Synthesis of lithium-containing block copolymer nanoparticles via PISA and their use in the formation of structured thin films.

Continuous synthesis of block copolymer nanoparticlesviatelescoped RAFT solution and dispersion polymerisation in a miniature CSTR cascade

Miniaturised continuous-flow reactors offer an economical and scalable route to explore the synthesis of block copolymersviaRAFT mediated polymerisation-induced self-assembly (PISA).

Novel ferrocene-containing amphiphilic block copolymer nanoparticles as high-capacity charge carriers in aqueous redox flow systems

Size-exclusion polymer electrolytes are promising charge carriers to diminish the crossover and allowing commercially available low-cost porous membranes in redox flow batteries. Boosting the solubility in water and maximizing the number of redox sites to enhance the capacity of these polymeric systems is challenging. New highly water dispersed amphiphilic diblock copolymers are reported here, with an average concentration value of 1.7 10−3 mmol of Ferrocene (Fc)-linked moieties per mg of polymer, determined by total X-ray reflection fluorescence. These redox amphiphilic block copolymers are stabilized in water as spherical nanoparticles (20 nm) by using a simple phase solvent inversion procedure. We evidence a maximum polymer dispersibility value of 6 g/L in water, for long-term stable polymer nanoparticle suspensions, yielding a theoretical capacity value of 4.78 mAh at 10.5 mM Fc. Further adjustment of the ionic conductivity and pH of these stable redox block copolymer suspensions has rendered a conductivity value of 44.5 mS/cm at pH values close to a neutral one, by adding a variety of salt supports. Studies using a 3-electrode configuration cell reveal an efficient charge transport between each of the Fc motifs in the polymer nanoparticle. A capacity value of 3.1 mAh with no transient of the polymer nanoparticles crosswise the cheap porous membrane is evidenced when cycled as polycatholyte material in a Zn hybrid aqueous redox flow battery. The particle size and electronic changes of these novel amphiphilic redox block copolymer electrolytes during consecutive redox cycles have also been monitored by dynamic light scattering and ultraviolet-visible spectroscopy, respectively. The analysis of the results enables the understanding of the main mechanisms behind their non-fully reversible capacity. Among them, aggregation and sedimentation, along with retention inside the graphite felt electrode acting the latter as a filter. These insights will aid the design of future polymer electrolyte materials and redox flow battery components with better performance and cost.

Polymer nanoparticles pass the plant interface

As agriculture strives to feed an ever-increasing number of people, it must also adapt to increasing exposure to minute plastic particles. To learn about the accumulation of nanoplastics by plants, we prepared well-defined block copolymer nanoparticles by aqueous dispersion polymerisation. A fluorophore was incorporated via hydrazone formation and uptake into roots and protoplasts of Arabidopsis thaliana was investigated using confocal microscopy. Here we show that uptake is inversely proportional to nanoparticle size. Positively charged particles accumulate around root surfaces and are not taken up by roots or protoplasts, whereas negatively charged nanoparticles accumulate slowly and become prominent over time in the xylem of intact roots. Neutral nanoparticles penetrate rapidly into intact cells at the surfaces of plant roots and into protoplasts, but xylem loading is lower than for negative nanoparticles. These behaviours differ from those of animal cells and our results show that despite the protection of rigid cell walls, plants are accessible to nanoplastics in soil and water.

H2O2-Responsive Nanocarriers Prepared by RAFT-Mediated Polymerization-Induced Self-Assembly of N-(2-(Methylthio)ethyl)acrylamide for Biomedical Applications

H2O2-sensitive block copolymer nanoparticles (NPs) composed of a hydrophilic macro-chain transfer agent (macro-CTA) and a hydrophobic thioether-bearing block were prepared by polymerization-induced self-assembly (PISA) approach. The PISA process first involved the chain extension of poly((poly(ethylene glycol) methyl ether methacrylate)-co-(poly(ethylene glycol) methacrylate)) macro-CTA with a H2O2-responsive N-(2-(methylthio)ethyl)acrylamide (MTEAM) monomer, which self-assembled into P((PEGMA-co-PEGMAOH)-b-PMTEAM) block copolymer NPs. The polymerization kinetics indicated the evolution of particle size and morphology from spherical micelles, fused micelles, to vesicles over time. Upon incubation with 0.1 to 10 mM H2O2, spheres were fragmented due to the oxidation of the PMTEAM cores, thus transforming the hydrophobic thioethers into hydrophilic sulfoxides and disassociating the nanocarriers. 43% of the hydrophobic Nile red dye was encapsulated into the spherical micelles and demonstrated a controlled release in H2O2 incubation. Spherical micelles and vesicles displayed no cytotoxicity in MCF-7, DU145, and 22Rv1 cells. Both spheres and vesicles were efficiently internalized into MCF-7 cells, with spheres showing a higher level of uptake than vesicles due to the smaller sizes. In summary, PISA of P((PEGMA-co-PEGMAOH)-b-PMTEAM) allowed the direct formation and loading of hydrophobic dye into spherical micelles, which showed a controlled drug release in H2O2.

Carbohydrate-based block copolymer nanoparticles: Novel nanocarrier for delivery of chlorine-aluminum phthalocyanine for use in photodynamic therapy

The development of third-generation photosensitizers for use in photodynamic therapy (PDT) is one of the most promising directions in current cancer therapy. Nanoparticles based on the block copolymer maltoheptaose-b-poly (methyl methacrylate) (MH-b-PMMA) containing the photosensitizer chlorine-aluminum phthalocyanine (ClAlPc) were developed for application in PDT. The MH-b-PMMA@ClAlPc nanoparticles showed a hydrodynamic radius of 41 nm, low polydispersity index, negative zeta potential, high encapsulation efficiency, and optimal stability. Furthermore, MH-b-PMMA@ClAlPc nanoparticles were able to generate cytotoxic singlet oxygen (1O2), showing singlet oxygen quantum yields (ΦΔ) values close to free ClAlPc. The drug release profile from MH-b-PMMA@ClAlPc was described by a biphasic model, consisting of fast release at early time, followed by a sustained release profile. The nanoparticles were mainly located in the intestinal surrounding cells and did not induce lethality to Caenorhabditis elegans at low concentrations. Our findings highlight that glyconanoparticles have potential to be employed as novel nanocarriers for hydrophobic photosensitizers in PDT.

The Effect of Topology on Block Copolymer Nanoparticles: Linear versus Star Block Copolymers in Toluene.

Linear and star block copolymer (BCP) nanoparticles of (polystyrene-block-poly(4-vinylpyridine))n (PS-b-P4VP)n with arm numbers of 1, 2, 3, and 4 were prepared by two methods of polymerization-induced self-assembly (PISA) and general self-assembly of block copolymers in the low-polar organic solvent, toluene. The effect of the arm number on the size and/or morphology of the (PS-b-P4VP)n nanoassemblies synthesized by the two methods in toluene and on the polymerization kinetics was investigated in detail. Our results show that in toluene, a low-polar solvent, the topology not only affected the morphology of the BCP nanoparticles prepared by PISA, but also influenced the BCP nanoparticles synthesized through general self-assembly.

Gaining Structural Control by Modification of Polymerization Rate in Ring-Opening Polymerization-Induced Crystallization-Driven Self-Assembly.

Polymerization-induced self-assembly (PISA) has become an important one pot method for the preparation of well-defined block copolymer nanoparticles. In PISA, morphology is typically controlled by changing molecular architecture and polymer concentration. However, several computational and experimental studies have suggested that changes in polymerization rate can lead to morphological differences. Here, we demonstrate that catalyst selection can be used to control morphology independent of polymer structure and concentration in ring-opening polymerization-induced crystallization-driven self-assembly (ROPI-CDSA). Slower rates of polymerization give rise to slower rates of self-assembly, resulting in denser lamellae and more 3D structures when compared to faster rates of polymerization. Our explanation for this is that the fast samples transiently exist in a nonequilibrium state as self-assembly starts at a higher solvophobic block length when compared to the slow polymerization. We expect that subsequent examples of rate variation in PISA will allow for greater control over morphological outcome.

Regioselective Seeded Polymerization in Block Copolymer Nanoparticles: Post‐Assembly Control of Colloidal Features

AbstractPost‐assembly modifications are efficient tools to adjust colloidal features of block copolymer (BCP) particles. However, existing methods often address particle shape, morphology, and chemical functionality individually. For simultaneous control, we transferred the concept of seeded polymerization to phase separated BCP particles. Key to our approach is the regioselective polymerization of (functional) monomers inside specific BCP domains. This was demonstrated in striped PS‐b‐P2VP ellipsoids. Here, polymerization of styrene preferably occurs in PS domains and increases PS lamellar thickness up to 5‐fold. The resulting asymmetric lamellar morphology also changes the particle shape, i.e., increases the aspect ratio. Using 4‐vinylbenzyl azide as co‐monomer, azides as chemical functionalities can be added selectively to the PS domains. Overall, our simple and versatile method gives access to various multifunctional BCP colloids from a single batch of pre‐formed particles.

Regioselective Seeded Polymerization in Block Copolymer Nanoparticles: Post-Assembly Control of Colloidal Features.

Post‐assembly modifications are efficient tools to adjust colloidal features of block copolymer (BCP) particles. However, existing methods often address particle shape, morphology, and chemical functionality individually. For simultaneous control, we transferred the concept of seeded polymerization to phase separated BCP particles. Key to our approach is the regioselective polymerization of (functional) monomers inside specific BCP domains. This was demonstrated in striped PS‐b‐P2VP ellipsoids. Here, polymerization of styrene preferably occurs in PS domains and increases PS lamellar thickness up to 5‐fold. The resulting asymmetric lamellar morphology also changes the particle shape, i.e., increases the aspect ratio. Using 4‐vinylbenzyl azide as co‐monomer, azides as chemical functionalities can be added selectively to the PS domains. Overall, our simple and versatile method gives access to various multifunctional BCP colloids from a single batch of pre‐formed particles.