SET‐LRP Synthesis of Well‐Defined Light‐Responsible Block Copolymer Micelles

Herein, the synthesis of well‐defined light‐sensitive amphiphilic diblock copolymers consisting of UV‐responsive poly(2‐nitrobenzyl acrylate) (PNBA) and hydrophilic poly(ethylene oxide) (PEO) blocks is reported. This is achieved by a single electron transfer living radical polymerization (SET‐LRP) of 2‐nitrobenzyl acrylate monomer initiated by PEO‐containing macroinitiator. Despite several reports on PEO‐b‐PNBA copolymers, this is the first time the PNBA block is synthesized by a controlled radical polymerization leading to the copolymers with low dispersity (Ð = 1.10). In water, the copolymers self‐assemble into well‐defined micelles with a hydrodynamic diameter of 25 nm. Upon irradiation with UV‐light, the PNBA units degrade to hydrophilic poly(acrylate) resulting in disassembly of the micelles. Considering the robustness of the reported synthetic protocol, the prepared polymers represent an interesting platform for the construction of new stimuli‐responsive drug delivery systems.     

Flower‐Like Multicompartment Micelles with Janus‐Core Self‐Assembled from Fluorocarbon‐Terminated Pluronics

Multicompartment micelles (MCMs), whose cores have at least two compartments, show potential applications in various areas, but the synthesis of polymers for preparing MCMs is usually tedious and time‐consuming. In this work, two well‐defined telechelic fluorocarbon‐terminated triblock copolymers, F₈‐PEO₁₀₀‐PPO₆₅‐PEO₁₀₀‐F₈ (F₈‐F127‐F₈) and F₈‐PEO₁₃₂‐PPO₅₀‐PEO₁₃₂‐F₈ (F₈‐F108‐F₈), are synthesized via a single‐step coupling reaction of Pluronics F127 or F108 with perfluoro‐1‐octanesulfonyl fluoride and characterized by Fourier‐transform infrared and NMR spectroscopies, as well as gel permeation chromatography and surface tensiometry. Both of these fluorocarbon‐terminated Pluronics can self‐assemble into spherical MCMs with Janus‐core in aqueous solution, as evidenced by transmission electron microscopy imaging. Since the lipophilic block (PPO) and fluorophilic segments (F₈) are separated by the hydrophilic blocks (PEO), these fluorocarbon‐terminated Pluronics will loop to give rise to flower‐like MCMs, and the calculations based on thermodynamics and dynamics support the formation of such unique aggregates. A “pre‐self‐assembly” mechanism is proposed to explain the formation process of flower‐like MCMs with Janus‐core prepared by these telechelic fluorocarbon‐terminated triblock copolymers.     

Controlled ROMP Synthesis of Ferrocene‐Containing Amphiphilic Dendronized Diblock Copolymers as Redox‐Controlled Polymer Carriers

Novel well‐defined redox‐responsive Ferrocene (Fc)‐containing amphiphilic dendronized diblock copolymers are synthesized by the ring‐opening metathesis polymerization technique using Grubbs’ third‐generation olefin metathesis catalyst as the initiator. These dendronized block copolymers can self‐assemble into spherical micelles in aqueous solution. The size of self‐assembled micelles can be modulated by the composition (namely, the ratio of hydrophobic and hydrophilic segments) and concentration of the dendronized copolymers. The obtained micelles show reversible redox‐controlled self‐assembly behaviors using FeCl₃ as oxidant and glutathione as reductant. Furthermore, the model molecule Rhodamine B is successfully loaded in these micelles, and the oxidation‐triggered controllable release is achieved by changing the type of oxidants (FeCl₃ and H₂O₂) and their concentrations. This is the first example of redox‐responsive micelles self‐assembled by novel amphiphilic dendronized Fc‐containing block copolymers, and the present micelles are visualized to be potential candidates in many fields, especially in stimuli‐responsive drug delivery systems.     

Synthesis and Self‐Assembly Behavior of Organic–Inorganic Poly(ethylene oxide)‐block‐Poly(MA POSS)‐block‐Poly(N‐isopropylacrylamide) Triblock Copolymers

In this work, the synthesis of 3‐methacryloxypropylheptaphenyl POSS, a new POSS macromer (denoted MA‐POSS) is reported. The POSS macromer is used to synthesize PEO‐b‐P(MA‐POSS)‐b‐PNIPAAm triblock copolymers via sequential atom transfer radical polymerization (ATRP). The organic‐inorganic, amphiphilic and thermoresponsive ABC triblock copolymers are characterized by means of nuclear magnetic resonance spectroscopy (NMR) and gel permeation chromatography (GPC). Differential scanning calorimetry (DSC) and atomic force microscopy (AFM) show that the hybrid ABC triblock copolymers are microphase‐separated in bulk. Cloud point measurements show that the effect of the hydrophiphilic block (i.e. PEO) on the LCSTs is more pronounced than the hydrophobic block (i.e. P(MA‐POSS)). Both transmission electron microscopy (TEM) and dynamic light scattering (DLS) show that all the triblock copolymers can be self‐organized into micellar aggregates in aqueous solutions. The sizes of the micellar aggregates can be modulated by changing the temperature. The temperature‐tunable self‐assembly behavior is interpreted using a combination of the highly hydrophobicity of P(MA‐POSS), the water‐solubility of PEO and the thermoresponsive property of PNIPAAm in the triblock copolymers.     

Disassembly of Crystalline Platelets of an Amphiphilic Triblock Copolymer Mediated by Varying pH and Organic Diacids

Regulation of crystalline micelles is difficult to achieve because of the strong solidification of crystallization. In this present work, an amphiphilic triblock copolymer poly(ethylene oxide)‐b‐poly(ε‐caprolactone)‐b‐poly(4‐vinylpyridine) (PEO‐b‐PCL‐b‐P4VP) is prepared, in which the P4VP block serves as an H‐bonding acceptor. It is originally self‐assembled into crystalline lamellar micelles in aqueous solution. Subsequently, the effect of varying pH and organic diacids on morphological transition is investigated in detail. Lamellae‐to‐cylinder‐to‐sphere transitions are observed after decreasing the pH or with the addition of organic diacids with different chain spacers. The decreasing pH causes increasing hydrophilicity of the P4VP block, while adding organic diacids results in an increasing corona swelling of the P4VP segment, both of which lead to a decreasing crystallinity of the poly(ε‐caprolactone) core. Consequently, morphological variety changing from lamellar to worm‐like to spherical micelles can be achieved.     

Micro‐ and Macrophase Separation in Phenolic Resol Resin/PEO‐PPO‐PEO Block Copolymer Blends: Effect of Hydrogen‐Bonded PEO Length

We demonstrate microphase‐separated thermosets based on blends of phenolic resol resin and poly(ethylene oxide)‐block‐poly(propylene oxide)‐block‐poly(ethylene oxide) (PEO‐PPO‐PEO), i. e., so‐called Pluronics. Three triblock copolymers are used (PE 9200, PE 10300 and PE 9400) where the molecular weights of the PPO blocks are nearly equal and the weight fractions of the PEO blocks f_PEO are 0.20, 0.30 and, 0.40, respectively. The blends are prepared in a particularly straightforward way using aqueous solutions and thermal crosslinking. Structure formation is characterized using transmission electron microscopy and small‐angle X‐ray scattering. PPO turns out to be sufficiently repulsive to allow microphase separation in the bulk crosslinked phase and the tendency for macrophase separation upon curing is reduced due to the hydrogen bonding between the PEO and resol. The weight fraction of PEO‐PPO‐PEO in the present blends has been limited to a relatively small value, i. e., 20 wt.‐%, and spherical microphase‐separated structure is observed for f_PEO = 0.40 with a long period of the order 120 Å. Macrophase separation manifests upon curing if the weight fraction of the PEO blocks is smaller, i. e., f_PEO = 0.30 or f_PEO = 0.20. In addition, in order to prevent macrophase separation, the molecular weights of PEO blocks and resol resin before curing are of the same order. In that respect, the system behaves qualitatively similar to the corresponding thermoplastic homopolymer/block copolymer blends.     

pH‐Responsive Double‐Hydrophilic Block Copolymers: Synthesis and Drug Delivery Application

A novel double‐hydrophilic block copolymer P(MEO₂MA‐co‐OEGMA)‐b‐PAMA has been successfully synthesized by two‐step RAFT polymerization. Then, the amino groups of PAMA blocks in the copolymers react with 1‐pyrenecarboxaldehyde via a “Schiff‐base” reaction, and the resulting copolymers are self‐assembled to form spherical micelles in aqueous solution. Because the “Schiff‐base” linkage is pH sensitive, the release rate of pyrene depends upon the pH of solution. Complete release is achieved at pH 1, and the control release is much faster at pH 5.5 than that at pH 7.4. With progress of pyrene release, the micelles are disassembled gradually and disappeared completely at last. This double‐hydrophilic copolymer is a promising candidate of drug carrier for the aldehyde‐ containing hydrophobic drugs.     

Crystallization in ABC Triblock Copolymers with Two Different Crystalline End Blocks: Influence of Confinement on Self‐Nucleation Behavior

The influence of different confinements active during crystallization within polybutadiene‐block‐polyisoprene‐block‐poly(ethylene oxide) (PB‐b‐PI‐b‐PEO) and the corresponding hydrogenated polyethylene‐block‐poly(ethylene‐alt‐propylene)‐block‐poly(ethylene oxide) (PE‐b‐PEP‐b‐PEO) triblock copolymers on the self‐nucleation behavior of the crystallizable PEO and PE blocks is investigated by means of differential scanning calorimetry (DSC). In triblock copolymers with PEO contents ≤ 20 wt.‐% crystallization of PEO is confined within small isolated microdomains (spheres or cylinders), and PEO crystallization takes place exclusively at high supercoolings. Self‐nucleation experiments reveal an anomalous behavior in comparison to the classical self‐nucleation behavior found in semicrystalline homopolymers. In these systems, domain II (exclusive self‐nucleation domain) vanishes, and self‐nucleation can only take place at lower temperatures in domain III_SA, when annealing is already active. The self‐nucleation behavior of the PE blocks is significantly different compared with that of the PEO blocks. Regardless of the low PE content (10–25 wt.‐%) in the investigated PE‐b‐PEP‐b‐PEO triblock copolymers a classical self‐nucleation behavior is observed, i.e., all three self‐nucleation domains, usually present in crystallizable homopolymers, can be located. This is a direct result of the small segmental interaction parameter of the PEP and PE segments in the melt. As a consequence, crystallization of PE occurs without confinement from a homogeneous mixture of PE and PEP segments.

Self‐nucleation regimes of a block copolymer showing confined crystallization by means of DSC.     

Structure of polystyrene-block-poly(ethylene oxide) diblock copolymer micelles in water

Micellization in water of two homologous series of AB-type diblock copolymers, composed of polystyrene (PS) as the A block and poly(ethylene oxide) (PEO) as the B block, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS). The copolymers have molecular weights M _n in the range 2 000—34 800, and have in a given series, the same number of repeating units of the PS block, (N_PS = 10 and 38), and a variable number of repeating units of the PEO block (N_PEO values in the range 23–704). In order to avoid secondary association of micelles, a dialysis technique was used to prepare the micellar systems, in the case of copolymers having high M _n values of the PS block. The experimental micelle properties such as the core radius R_c and the aggregation number N of non-equilibrium structures, so called “frozen micelles”, obtained by dialysis, were found to be independent of the copolymer characteristics. However, for equilibrium structures, obtained by direct solubilization of the copolymers (N_PS = 10) in water, R_c and N were found to decrease with increasing N_PEO for the homologous series.     

β‐Cyclodextrin‐Based Star Amphiphilic Copolymers: Synthesis,Characterization, and Evaluation as Artificial Channels

14‐arm amphiphilic star copolymers are synthesized according to different strategies. First, the anionic ring polymerization of 1,2‐butylene oxide (BO) initiated by per(2‐O‐methyl‐3,6‐di‐O‐(3‐hydroxypropyl))‐β‐CD (β‐CD’OH₁₄) and catalyzed by t‐BuP₄ in DMF is investigated. Analyses by NMR and SEC show the well‐defined structure of the star β‐CD’‐PBO₁₄. To obtain a 14‐arm poly(butylene oxide‐b‐ethylene oxide) star, a Huisgen cycloaddition between an α‐methoxy‐ω‐azidopoly(ethylene oxide) and the β‐CD’‐PBO₁₄,whose end‐chains are beforehand alkyne‐functionalized, is performed. In parallel, 14‐arm star copolymers composed of butylene oxide‐b‐glycidol arms are successfully synthesized by the anionic polymerization of ethoxyethylglycidyl ether (EEGE) initiated by β‐CD’‐PBO₁₄ with t‐BuP₄. The deprotection of EEGE units is then performed to provide the polyglycidol blocks. These amphiphilic star polymers are evaluated as artificial channels in lipid bilayers. The effect of changing a PEO block by a polyglycidol block on the insertion properties of these artificial channels is discussed.     

Self‐Assembled Acrylic ABA Triblock Copolymer Hydrogels with Various Block Compositions: Water Absorbency,Rheology, and SAXS

A series of well‐defined symmetric poly(methyl methacrylate)‐b‐poly(sodium methacrylate)‐b‐poly(methyl methacrylate) (PMMA‐b‐PSMA‐b‐PMMA) triblock copolymers with various block compositions is synthesized. The amphiphilic ABA triblock copolymers form polyelectrolyte hydrogels in water by self‐assembly. The hydrophobic PMMA endblocks act as physical cross‐links in the form of frozen micelles, while the hydrophilic PSMA midblocks span the 3D network. The influence of various synthetic parameters on the self‐assembly and the macroscopic properties of these hydrogels is systematically investigated by water absorbency, oscillatory shear rheology, and small‐angle X‐ray scattering. The polymer concentration during the hydrogel formation affects the ratio between looping and bridging chains. The number of MMA units per endblock (n_A) determines the size and the relaxation rates of the physical cross‐links and thus, the mechanical stability of the hydrogels. More SMA units in the midblock (n_B) increase the water absorbency, while the mechanical moduli decrease. Even lower G‐moduli are achieved by partly exchanging the symmetric ABA triblock with AB diblock copolymers, which can only form non‐elastic dangling ends.     

Preparation and identification of di-block copolymer composed of crystalline poly(ethylene oxide) and noncrystalline poly(vinyl acetate) with well-defined structure

A block copolymer of ethylene oxide (EO) and vinyl acetate (VAc) was prepared by sequential anionic and photo-induced charge transfer polymerization (CTP) using UV sensible p-aminophenoxy end groups on PEO (PEO_a). The structure and composition of this block copolymer (PEO-b-PVAc) were identified in detail. The relationship between polymerization rate (R_p) and the concentrations of benzophenone (BP) and monomer, and the effect of the concentration and molecular weight of PEO_a on the polymerization of VAc, are discussed; the relationship R_p ∝ [PEO_a-11000]^0.33 [VAc]^0.28 [BP]^0.47 using benzene as a solvent was derived. The dependence of the thermal properties of PEO-b-PVAc on the length of the PVAc block is described. It turned out that the PEO and PVAc blocks are compatible.     

Folate‐Conjugated Poly(N‐(2‐hydroxypropyl) methacrylamide)‐block‐Poly(benzyl methacrylate): Synthesis,Self‐Assembly,and Drug Release

Well‐defined amphiphilic diblock copolymers of poly(N‐(2‐hydroxypropyl)methacrylamide)‐block‐poly(benzyl methacrylate) (PHPMA‐b‐PBnMA) are synthesized using reversible addition–fragmentation chain transfer polymerization. The terminal dithiobenzoate groups are converted into carboxylic acids. The copolymers self‐assemble into micelles with a PBnMA core and PHPMA shell. Their mean size is <30 nm, and can be regulated by the length of the hydrophilic chain. The compatibility between the hydrophobic segment and the drug doxorubicin (DOX) affords more interaction of the cores with DOX. Fluorescence spectra are used to determine the critical micelle concentration of the folate‐conjugated amphiphilic block copolymer. Dynamic light scattering measurements reveal the stability of the micelles with or without DOX. Drug release experiments show that the DOX‐loaded micelles are stable under simulated circulation conditions and the DOX can be quickly released under acidic endosome pH.     

pH‐Sensitive Poly(ethylene glycol)/Poly(ethoxyethyl glycidyl ether) Block Copolymers: Synthesis,Characterization, Encapsulation,and Delivery of a Hydrophobic Drug

Curcumin is a natural polyphenolic compound known for its numerous pharmacological properties. However, its low water solubility and instability at neutral pH are serious drawbacks preventing its use as an oral drug. Well‐defined amphiphilic poly(ethylene glycol)‐block‐poly(ethoxyethyl glycidyl ether) (PEG‐b‐PEEGE) block copolymers carrying acid‐labile acetal groups are synthesized by anionic ring‐opening polymerization and investigated as potential pH‐sensitive nano‐carriers for delivery of curcumin to cancer cells. The nanoparticles, resulting from copolymer self‐assembly in aqueous media, are characterized by dynamic light scattering and cryo‐transmission electron microscopy. The nanoparticles’ stabilities are evaluated in three different phosphate buffers (pH = 7.2, 6.4, and 5.3). The stability decreases at lower pH and a complete disappearance of the nanoparticles is noticed after 4 days at pH 5.3. Curcumin is encapsulated in hydrophobic core of mPEG₄₀‐b‐PEEGE₂₅ nanoparticles allowing significant enhancements of curcumin solubility in water and lifetime at neutral pH. In vitro curcumin release is studied at different pH by UV‐spectroscopy and high‐performance liquid chromatography (HPLC). The cytotoxicity of curcumin and curcumin encapsulated in micelles is evaluated by cell viability 3‐(4,5‐Dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay on MDA‐MB‐231 human breast cancer cells.     

Self‐Assembly and Responsive Behavior of Poly(peptide)‐Based Copolymers

Well‐defined copolymers synthesized by combining poly(ethylene glycol) (PEG) and amino acid based building blocks are investigated with regard to their helical rigidity and self‐assembly. Optical active block copolymers reported here are designed to have a pendant amino acid and polymerizable group, that is, isonitrile in order to induce helix formation and reduce the mobility of polymer chains by forming a hydrogen bond network so that a helix with reasonable rigidity can be obtained. Due to the amphiphilicity and a relatively shorter PEG as a coil, these polymers form micelles as observed under transmission electron microscopy in which copolymers PEG₁₀₈‐b‐PPIC₇₆₄ and PEG₁₀₈‐b‐PPIC₁₀₂₀ appear to be evolving into nanoparticles with a size distribution of 100–200 nm. Circular dichroism spectroscopy is employed to study the nature of the helix and its rigidity. The folding and unfolding of polymer helix as a result of the ability of a selective solvent to form/disrupt hydrogen bonds with the peptide linkage is also discussed to highlight the responsive nature of the polymer.     

Synthesis and characterization of new ABA triblock copolymers with poly[3(S)-isobutylmorpholine-2,5-dione] and poly(ethylene oxide) blocks

ABA type block copolymers with poly[3(S)-isobutylmorpholine-2,5-dione] (PIBMD, A) and poly(ethylene oxide) (M_n = 6 000, PEO, B) blocks, PIBMD-b-PEO-b-PIBMD, were synthesized via ring-opening polymerization of 3(S)-isobutylmorpholine-2,5-dione in the presence of hydroxytelechelic poly-(ethylene oxide) with stannous octoate as a catalyst. M_n of the resulting copolymers increases with increasing 3(S)-isobutylmorpholine-2,5-dione content in the feed at constant mole ratio of monomer (M) to catalyst (C) (M/C = 125). No racemization of the leucine residue takes place during both homopolymerization of IBMD and polymerization of IBMD in the presence of PEO and Sn(Oct)₂. The melting temperature of the PIBMD segments in the block copolymers depends on the length of the PIBMD blocks. The melting temperature of the PEO blocks is lower than that of the homopolymer, and the crystallinity of the PEO block decreases with increasing length of the PIBMD blocks. The PIBMD block crystallizes first upon cooling from the melt. This leads to only imperfect crystallization or no crystallization of the PEO blocks.     

Solution Self‐Assembly of Poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane: Formation of Spherical Micelles with an Organometallic Poly(ferrocenylphenylphosphine) Core

The novel organometallic‐inorganic diblock copolymer, poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane (PFP‐b‐PDMS), with narrow molecular weight distribution has been synthesized by living anionic polymerization through sequential monomer addition. These block copolymers self‐assemble into “star‐like” spherical micelles in hexane with a dense organometallic PFP core surrounded by a swollen corona of the PDMS chains. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize these micellar aggregates. It was found that the block copolymer micelles have a relatively narrow core size distribution, but an overall broader distribution of hydrodynamic size in hexane. Significantly, the preparation method of the micelle solution was also found to have an influence on the size and size distribution of the resulting micellar structures.     

Calcium Alcoholates of Hydroxytelechelic Poly(ethylene oxide)s as Initiators for the Ring‐Opening Polymerization of 3‐(S)‐Isopropylmorpholine‐2,5‐dione

Block copolymers with poly[3‐isopropylmorpholine‐2,5‐dione] (PIPMD) and poly(ethylene oxide) (M̄_n = 6 000, PEO) blocks, PIPMD‐b‐PEO‐b‐PIPMD, were synthesized via the ring‐opening polymerization of 3‐(S)‐isopropylmorpholine‐2,5‐dione (IPMD) in the presence of the calcium alcoholate of hydroxytelechelic poly(ethylene oxide) as an initiator at 140°C within 24 or 96 h. The number‐average molecular weight (M̄_n) of the resulting copolymers increases with increasing IPMD content in the feed and with reaction time. According to ¹H NMR spectroscopic analysis, about 40% of IPMD is racemized during polymerization within 96 h at 140°C, while about 12% is racemized within 24 h. The melting temperature of the PEO block upon first heating is lower than that of pure PEO homopolymer, and the melting endotherm decreases with increasing length of the PIPMD block upon second heating.     

The Aggregation Behavior of Poly(ethylene oxide)‐Poly(methyl methacrylate) Diblock Copolymers in Organic Solvents

Poly(ethylene oxide)‐poly(methyl methacrylate) and poly(ethylene oxide)‐poly(deuteromethyl methacrylate) block copolymers have been prepared by group transfer polymerization of methyl methacrylate (MMA) and deuteromethyl methacrylate (MMA‐d₈), respectively, using macroinitiators containing poly(ethylene oxide) (PEO). Static and dynamic light scattering and surface tension measurements were used to study the aggregation behavior of PEO‐PMMA diblock copolymers in the solvents tetrahydrofuran (THF), acetone, chloroform, N,N‐dimethylformamide (DMF), 1,4‐dioxane and 2,2,2‐trifluoroethanol. The polymer chains are monomolecularly dissolved in 1,4‐dioxane, but in the other solvents, they form large aggregates. Solutions of partially deuterated and undeuterated PEO‐PMMA block copolymers in THF have been studied by small‐angle neutron scattering (SANS). Generally, large structures were found, which cannot be considered as micelles, but rather fluctuating structures. However, ¹H NMR measurements have shown that the block copolymers form polymolecular micelles in THF solution, but only when large amounts of water are present. The micelles consist of a PMMA core and a PEO shell.     

Janus Micelle Formation Induced by Protonation/Deprotonation of Poly(2‐vinylpyridine)‐block‐Poly(ethylene oxide) Diblock Copolymers

A novel approach to amphiphilic polymeric Janus micelles based on the protonation/deprotonation process of poly(2‐vinylpyridine)‐block‐poly(ethylene oxide) (P2VP‐b‐PEO) diblock copolymers in THF is presented. It is found that addition of HCl to the micelles solution of P2VP‐b‐PEO copolymers leads to the formation of vesicles. Subsequently mixing a small amount of hydrazine monohydrate with the vesicle solution can induce the dissociation and reorganization of the vesicles into Janus micelles. When HCl is replaced by HAuCl₄ precursors, composite Janus particles containing gold in P2VP blocks are obtained.