Zwitterionic Diblock Copolymers Research Articles

Pronounced Cold Crystallization and Hydrogen Bonding Distortion of Water Confined in Microphases of Double Zwitterionic Block Copolymer Aqueous Solutions.

Advanced materials leveraging water control are garnering considerable interest, with the state of water emerging as a critical aspect of material design. This study explored the impact of microphase separation on water using aqueous solutions of double zwitterionic diblock copolymers, specifically poly(carboxybetaine methacrylate) and poly(sulfobetaine methacrylate) (PCB2-b-PSB4). These copolymers form a mesoscale periodic ordered lattice structure consisting of two distinct aqueous phases. Through differential scanning calorimetry and X-ray emission spectroscopy, it was found that water in these PCB2-b-PSB4 aqueous solutions exhibits pronounced cold crystallization and subtle distortions in hydrogen-bonding configurations.

Preparation of Water-Soluble Polyion Complex (PIC) Micelles with pH-Responsive Carboxybetaine Block.

A dual zwitterionic diblock copolymer (M100C100) consisting of poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC, M) and poly(3-((2-(methacryloyloxy)ethyl) dimethylammonio) propionate) (PCBMA, C) is synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. A double hydrophilic diblock copolymer (M100S100) consist of PMPC and anionic poly(3-sulfopropyl methacrylate potassium salt) (PMPS, S) is synthesized via RAFT. The degrees of polymerization of each block are 100. The charges of PMPC are neutralized intramolecularly. At neutral pH, the charges in PCBMA are also neutralized intramolecularly due to its carboxybetaine structure. Under acidic conditions, PCBMA exhibits polycation behavior as the pendant carboxy groups become protonated, forming cationic tertiary amine groups. PMPS shows permanent anionic nature independent of pH. Charge neutralized mixture of cationic M100C100 and anionic M100S100 in acidic aqueous solution forms water-soluble polyion complex (PIC) micelle owing to electrostatic attractive interactions. The core is composed of the cationic PCBMA and anionic PMPS blocks, with the PMPC blocks serving as shells that covered the core surface, forming spherical core-shell PIC micelles. Above pH 4 the pendant carboxy groups in PCBMA undergo deprotonation, transitioning to a zwitterionic state, thereby eliminating the cationic charge in PCBMA. Therefore, above pH 4 the PIC micelles are dissociated due to the disappearance of the charge interactions.

Phase Behavior of Double Zwitterionic Block Copolymers in Water: Morphology Transition through Concentration Dependent Selectivity of Water Partitioning

AbstractPhase behavior of double zwitterionic diblock copolymers composed of a poly(carboxybetaine methacrylate) (PCB2) and a poly(sulfobetaine methacrylate) (PSB4) (PCB2n‐b‐PSB4m) has been mapped out in aqueous solutions. Phase diagrams are constructed with polymer concentration, ϕ, ranging from 0.08 to 0.80 and PSB4 volume fraction in the PCB2n‐b‐PSB4ms, fPSB4, ranging from 0.23 to 0.93 at 25 °C. PCB2n‐b‐PSB4m aqueous solutions show symmetric phase diagram above ϕ = 0.55, indicating that water is nearly neutral with respect to PCB2 and PSB4. The morphology transforms from columnar with PCB2 cylinders to lamellar to columnar with PSB4 cylinders with decreasing ϕ, and the phase boundaries exhibit a negative slope below ϕ = 0.45. The morphology transition is rationalized in terms of interfacial curvature modulation through the volume expansion of the PCB2 phase due to the selective water partitioning. The lyotropic mesophase of double hydrophilic block copolymers is a unique molecular compartment for hydrophilic molecules with low interfacial tension.

Modulation of Double Zwitterionic Block Copolymer Aggregates by Zwitterion-Specific Interactions.

Transformable double hydrophilic block copolymer assemblies are valid as a biocompatible smart macromolecular system. The molecular mechanisms in the spontaneous assembly of double zwitterionic diblock copolymers composed of a poly(carboxybetaine methacrylate) (PCB2) and a poly(sulfobetaine methacrylate) (PSB4) chains (PCB2-b-PSB4) were investigated by the modulation of the aggregates in response to nondetergent zwitterions. The PCB2-b-PSB4 diblock copolymers with a high degree of polymerization PSB4 block produced aggregates in salt-free water through "zwitterion-specific" interactions. The PCB2-b-PSB4 aggregates were dissociated by the addition of nondetergent sulfobetaine (SB4) and carboxybetaine (CB2) molecules, while the aggregates showed different aggregation modulation processes for SB4 and CB2. Zwitterions with different charged groups from SB4 and CB2, glycine and taurine, hardly disrupted the PCB2-b-PSB4 aggregates. The PCB2-b-PSB4 aggregate modulation efficiency of SBs associated with the intercharge hydrocarbon spacer length (CSL) rather than the symmetry with the SB in the PSB chain. These zwitterion-specific modulation behaviors were rationalized based on the nature of zwitterions including partial charge density, dipole moment, and hydrophobic interactions depending on the charged groups and CSL.

Bio-inspired zwitterionic polymeric chelating assembly for treatment of copper-induced cytotoxicity and hemolysis

We developed a hemocompatible, bio-inspired, multivalent, polymeric-chelating assembly based on the poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(serinyl acrylate) (PMPC-b-PserA) zwitterionic diblock copolymer. Functional PMPC-b-PserA was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization to catch and encapsulate free copper ions (Cu2+) in a solution. PMPC with an identical polar group to phospholipids exhibits high hydrophilicity and fouling resistance against non-specific adsorption, and inertness to the metal ions. On the other hand, PserA with pendant groups of amino acids possesses a strong capability to react with Cu2+ by coordination interaction. Therefore, when PMPC-b-PserA was brought into contact with Cu2+, a hydrophobic core with multiple coordination “bridges” between polymers and Cu2+ was formed, leading to self-assembly of core-shell polymer-metal nanoparticles. As a result, free Cu2+ ions can be removed from the solution to prevent damage to cells and tissues. The synthesis and chemical structure of PMPC-b-PserA were characterized, and the formation of self-assembled polymer-Cu2+ nanoparticles and colloidal stability were analyzed. More importantly, the detoxification of PMPC-b-PserA in presence of Cu2+ with fibroblast cells was demonstrated by increased cell viability >80%. In addition, the hemolysis, which occurred due to disruption of RBC membranes by free Cu2+, was effectively suppressed by adding PMPC-b-PserA. The bio-inspired and biocompatible chelating agent of PMPC-b-PserA provides a new treatment approach to encapsulate and detoxify heavy metals in complex media for chelation therapy.

Lyotropic Morphology Transition of Double Zwitterionic Diblock Copolymer Aqueous Solutions

AbstractPolymer concentration‐dependent aqueous lyotropic morphology transition of a double zwitterionic diblock copolymer composed of a poly(carboxybetaine methacrylate) (PCB) and poly(sulfobetaine methacrylate) (PSB) is unraveled employing small‐angle X‐ray scattering. Salt‐free aqueous solutions of the well‐defined diblock copolymer produce ordered periodic structure and the morphology transforms from hexagonally close‐packed cylinder to lamellar with decreasing the polymer concentration. The morphology transition is induced by the preferential distribution of water molecules into the PCB domains below threshold polymer concentration because of the limited water capacity of the PSB network domains. The volume fraction modulation causes the instability of phase boundary curvature urging the morphology transition. The precise ordered nanostructure control of the highly biocompatible double zwitterionic block copolymers is valid for responsive biocompatible molecular design in biomaterials.

Aqueous one-pot synthesis of well-defined zwitterionic diblock copolymers by RAFT polymerization: an efficient and environmentally-friendly route to a useful dispersant for aqueous pigments

An atom-efficient, wholly aqueous one-pot synthesis of zwitterionic diblock copolymers has been devised. Such copolymers can serve as highly effective aqueous dispersants for nano-sized transparent yellow iron oxide particles.

Preparation of Responsive Zwitterionic Diblock Copolymers Containing Phosphate and Phosphonate Groups

In this study, novel zwitterionic diblock copolymers, namely poly(2-(N-morpholino)ethyl methacrylate))-block-poly(2-(methacryloyloxy)ethyl phosphate) (PMEMA-b-PMOEP) and poly(2-(N-morpholino)ethyl methacrylate))-block-poly ((methacryloyloxy)methyl phosphonic acid) (PMEMA-b-PMOMP), were synthesized via reversible addition-fragmentation chain transfer controlled radical polymerization. Solution properties of these phosphorus-based diblock copolymers were investigated using dynamic light scattering, transmission electron microscopy and proton nuclear magnetic resonance spectroscopy. Since the PMEMA block has both salt- and thermo-responsive properties, PMEMA-b-PMOEP and PMEMA-b-PMOMP diblock copolymers formed core-shell micelles in basic aqueous media as the PMEMA block formed insoluble micelle core with the addition of Na2SO4 or an increase in temperature in basic solution. Additionally, PMEMA-b-PMOMP diblock copolymers interacted strongly with calcium cations and yielded reverse micellar structures via complexation of phosphate with metal cation in aqueous media.

IR780-loaded zwitterionic polymeric nanoparticles with acidity-induced agglomeration for enhanced tumor retention

The tumor-targeted delivery of near infrared (NIR)-triggered photothermal therapy (PTT) by varied nanocarriers has captured substantial attention. In order to boost the antitumor efficacy of PTT by promoting cellular uptake and tumor retention of PTT-carrying nanoparticles, the surface charge-changeable polymeric nanoparticles comprising poly(lactic-co-glycolic acid) (PLGA) cores covered with zwitterionic diblock copolymers, methoxypoly(ethylene glycol)-b-poly(methacrylic acid-co-histamine methacryamide), mPEG-b-P(MAA-co-HMA), were developed as vehicles of IR780. Due to the acid-triggered protonation of imidazole groups, the resulting positively charged HMA residues tend to form electrostatic complexes with negatively charged MAA residues, thus facilitating the embedding of outer PEG segments into the neutral and gel-like surfaces and thus the formation of inter-particle aggregation. Taking advantage of the weak acidity of tumor extracellular matrix, the IR780-loaded nanoparticles undergoing acidity-elicited dramatic structural transformation showed appreciably enhanced cellular uptake by TRAMP-C1 cells and prolonged tumor retention time.

Synthesis of Zwitterionic Diblock Copolymers with Cleavable Biotin Groups at the Junction Points and Fabrication of Bioconjugates by Biotin–Streptavidin Coupling

Combinations of synthetic polymers and natural proteins provide a route to the synthesis of new biomaterials. The bioconjugates combining tunable properties of polymers with functionalities of proteins have found broad applications. One of the most challenging problems in this research field is the self-assembly behaviors of responsive polymer–protein bioconjugates. In this research, synthesis and self-assembly of bioconjugates composed of zwitterionic block copolymer and streptavidin were investigated. Block copolymers of poly(ethylene glycol) (PEG) and poly[3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate] (PDMAPS) with cleavable biotin groups at the junction points were synthesized. The zwitterionic block copolymers exhibit phase transitions with upper critical solution temperatures (UCSTs) in aqueous solutions. The concentration of sodium chloride exerts a significant influence on the UCST. The zwitterionic block copolymer chains self-assemble into vesicles in aqueous solution at a temperatur...

Colouring crystals with inorganic nanoparticles

A simple, one-pot method is presented whereby gold nanoparticles coated with a zwitterionic diblock copolymer are incorporated within single crystals of calcite. This may provide a versatile alternative to dyeing crystal with organic molecules and could be extended to create a series of new nanocomposite crystals with novel properties.

Surface self-assembled zwitterionization of poly(vinylidene fluoride) microfiltration membranes via hydrophobic-driven coating for improved blood compatibility

A facile surface self-assembled zwitterionization process is presented, aiming at improving the blood compatibility of poly(vinylidene fluoride) (PVDF) membranes. Zwitterionic diblock copolymers containing hydrophobic propylene oxide and hydrophilic sulfobetaine methacrylate blocks were prepared with well controlled molecular weights via atom-transfer radical polymerization (ATRP). Poly(propylene oxide)-block-poly(sulfobetaine methacrylate) (PPO-b-PSBMA) copolymers with varying zwitterionic PSBMA lengths were coated by self-assembling process onto the surface of PVDF microfiltration membranes in order to enhance their surface hydrophilicity and protein resistance. A systematic study regarding the effect of block lengths of PPO-b-PSBMA copolymers on the hemocompatibility of zwitterionic PVDF membranes in human blood solution was then performed. Protein adsorption from single-protein solutions and 100% blood plasma solutions was measured on the PVDF surfaces covered with PPO-b-PSBMA brushes. If the increase in PPO content in copolymer increased the efficiency of coating on the membrane, resistance to human fibrinogen adsorption was enhanced when increasing the PSBMA content. The control of the anchoring structures of zwitterionic copolymer layers highly regulates the adsorption of plasma proteins, the adhesion of platelets, and the coagulation of human plasma. PVDF membranes coated with PPO-b-PSBMA containing a high amount of zwitterionic SBMA units presented a high hydration capability, believed to allow improving significantly the hemocompatible character of PVDF membranes. This work suggests that the hemocompatible nature of self-assembled zwitterionic brushes gives them a great potential in the molecular design of antithrombogenic membranes for use in human blood applications.

Neutral, anionic, cationic, and zwitterionic diblock copolymers featuring poly(2-methoxyethyl acrylate) “hydrophobic” segments

Amphiphilic diblock copolymers incorporating “hydrophobic” poly(2-methoxyethyl acrylate) (PMEA) and hydrophilic neutral poly(ethylene glycol) monomethyl ether (mPEG), anionic poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA), cationic poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), and zwitterionic poly(3-(N-(2-methacryloyloxyethyl)-N,N-dimethylammonio)propane sulfonate) (PDMAPS) blocks are constructed. mPEG, poly(tert-butyl acrylate) (PtBA), and poly(tert-butyl methacrylate) (PtBMA) macroinitiators are chain extended with 2-methoxyethyl acrylate (MEA) employing copper-mediated atom transfer radical polymerization (ATRP) garnishing well-defined diblock copolymers with narrow polydispersities (1.11–1.30). Selective cleavage of the tert-butyl esters affords PAA-b-PMEA and PMAA-b-PMEA. ATRP of 2-dimethylaminoethyl methacrylate (DMAEMA) from the PMEA macroinitiator results in PMEA-b-PDMAEMA while the betainisation of the latter provides zwitterionic diblock amphiphile PMEA-b-PDMAPS. Inspection of these macromolecular architectures by NMR spectroscopy and size exclusion chromatography (SEC) confirms a fairly high degree of control over the reactions emphasizing flexibility and precision of the approach.

Preparation of Biocompatible Zwitterionic Block Copolymer Vesicles by Direct Dissolution in Water and Subsequent Silicification within Their Membranes

The facile preparation of block copolymer vesicles in pure water and their subsequent stabilization by sol-gel chemistry within the vesicle membrane is described. An amphiphilic biocompatible zwitterionic diblock copolymer, poly(epsilon-caprolactone)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine], PCL-b-PMPC, was synthesized by (i) ring-opening polymerization of epsilon-caprolactone, (ii) end-group modification by esterification, and (iii) atom transfer radical polymerization (ATRP) of 2-(methacryloyloxy)ethyl phosphorylcholine (MPC). Unusually, block copolymer vesicles were formed instantly upon adding dried copolymer powder into hot water without using organic cosolvents, pH adjustment, or even stirring. This protocol is much more convenient than previously reported methods such as solvent-switching and film rehydration. The PCL vesicle membrane is moderately hydrophobic and fully biodegradable. The highly biocompatible PMPC chains are expressed on both the exterior and interior surface of the membrane. These vesicles can be stabilized by aqueous sol-gel chemistry within the hydrophobic PCL vesicle membrane by using tetramethyl orthosilicate (TMOS) as the silica precursor in the absence of any external catalyst. The water-immiscible TMOS precursor is initially solubilized within the hydrophobic membrane prior to its in situ transformation into silica. The vesicles were characterized by 1H NMR spectroscopy, atomic force microscopy, transmission electron microscopy, and dynamic light scattering.

Kinetics of pH-Induced Formation and Dissociation of Polymeric Vesicles Assembled from a Water-Soluble Zwitterionic Diblock Copolymer

The kinetics of pH-induced formation and dissociation of vesicles self-assembled from a biocompatible zwitterionic diblock copolymer, poly(2-(methacryloyloxy)ethyl phosphorylcholine)-b-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC- b-PDPA), was investigated in detail via a combination of stopped-flow light scattering and laser light scattering (LLS). Upon jumping from pH 2 to 10, stopped-flow light scattering reveals three distinct relaxation processes for the early stages of vesicle self-assembly (0-40 s). Kinetic sequences associated with the obtained three characteristic relaxation times have been tentatively proposed. Moreover, the kinetics of vesicle formation in the later stage (from 3 min onward) was investigated by dynamic LLS. It was found that both the intensity-averaged hydrodynamic radius, R h, and the polydispersity, mu2/Gamma (2), decrease exponentially, yielding a characteristic relaxation time of approximately 350 s. To our knowledge, this is the first report on the kinetics of the unimer-to-vesicle transition of a stimulus-responsive diblock copolymer. The kinetics of vesicle dissociation for a pH jump from 12 to 2 was also investigated. The breakdown of polymeric vesicles is extremely fast and is independent of polymer concentration; it is complete within approximately 5 ms and is in marked contrast to the much slower rate of vesicle formation.

Adsorption characteristics of zwitterionic diblock copolymers at the silica/aqueous solution interface

The adsorption of a zwitterionic diblock copolymer, poly(2-(diethylamino)ethyl methacrylate)– block–poly(methacrylic acid) (PDEA 59–PMAA 50), at the silica/aqueous solution interface has been characterised as a function of pH. In acidic solution, this copolymer forms core–shell micelles with the neutral PMAA chains being located in the hydrophobic cores and the protonated PDEA chains forming the cationic micelle coronas. In alkaline solution, the copolymer forms the analogous inverted micelles with anionic PMAA coronas and hydrophobic PDEA cores. The morphology of the adsorbed layer was observed in situ using soft-contact atomic force microscopy (AFM): this technique suggests the formation of a thin adsorbed layer at pH 4 due to the adsorption of individual copolymer chains (unimers) rather than micelle aggregates. This is supported by the remarkably low dissipation values and the relatively low degrees of hydration for the adsorbed layers, as estimated using a combination of quartz crystal microbalance with dissipation monitoring (QCM-D) and optical reflectometry (OR). In alkaline solution, analysis of the adsorption data suggests a conformation for the adsorbed copolymers where one block projects normal to the solid/liquid interface; this layer consists of a hydrophobic PDEA anchor block adsorbed on the silica surface and an anionic PMAA buoy block extending into the solution phase. Tapping mode AFM studies were also carried out on the silica surfaces after removal from the copolymer solutions and subsequent drying. Interestingly, in these cases micelle-like surface aggregates were observed from both acidic and alkaline solutions. The lateral dimension of the aggregates seen is consistent with the corresponding hydrodynamic diameter of the copolymer micelles in bulk solution. The combination of the in situ and ex situ AFM data provides evidence that, for this copolymer, micelle aggregates are only seen in the ex situ dry state as a result of the substrate withdrawal and drying process. It remains unclear whether these aggregates are caused by micelle deposition at the surface during the substrate withdrawal from the solution or as a result of unimer rearrangements at the drying front as the liquid recedes from the surface.

Esterification of hydroxylated polymers with 2-sulfobenzoic acid cyclic anhydride: A facile approach for the synthesis of near-monodisperse strong acid homopolymers and diblock copolymers

A convenient two-step route was developed to prepare a range of low polydispersity strong acid homopolymers and several examples of well-defined diblock copolymers. Atom transfer radical polymerization (ATRP) of either 2-hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate or glycerol monomethacrylate afforded the corresponding near-monodisperse hydroxylated homopolymers, while several diblock copolymer precursors were prepared by either (1) the one-pot ATRP of 2-hydroxypropyl methacrylate and 2-(diethylamino)ethyl methacrylate using sequential monomer addition or (2) the ATRP of either 2-hydroxypropyl methacrylate or glycerol monomethacrylate using a poly(ethylene oxide)-based macro-initiator. Excess 2-sulfobenzoic acid cyclic anhydride was used to fully esterify the hydroxy groups of these homopolymers and diblock copolymers under mild conditions. The resulting zwitterionic diblock copolymers undergo micellar self-assembly on adjusting the pH of the solution, while one of the anionic poly(ethylene oxide)-based diblock copolymers formed colloidal polyelectrolyte complexes in aqueous solution when mixed with a cationic poly(ethylene oxide)-based diblock copolymer.

Synthesis of Zwitterionic Diblock Copolymers without Protecting Group Chemistry

A versatile new route to zwitterionic diblock copolymers that avoids protecting group chemistry is reported. Various tertiary amine methacrylates are block copolymerized with 2-hydroxyethyl methacrylate to produce hydroxy-functional diblock precursors via sequential monomer addition. These low-polydispersity precursors are then treated with succinic anhydride under mild conditions to produce a range of new near-monodisperse zwitterionic diblock copolymers in which both blocks are weak polyelectrolytes. Thus, the final copolymers exhibit complex aqueous solution behavior (isoelectric points, schizophrenic micellization behavior, etc.) depending on the solution pH.

Micelle Formation and Inversion Kinetics of a Schizophrenic Diblock Copolymer

It is known that the zwitterionic diblock copolymer, poly(4-vinylbenzoic acid)-b-poly(N-(morpholino)ethyl methacrylate) (VBA-b-MEMA), exhibits interesting “schizophrenic” micellization behavior (see: Liu, S.; Armes, S. P. Langmuir 2003, 19, 4432−4438). The kinetics of the pH-induced formation and dissociation of VBA−core micelles, the salt-induced formation and dilution-induced dissociation of MEMA−core micelles at pH 10, and the pH-induced micellar inversion between VBA− and MEMA−core micelles in the presence of 0.8 M Na2SO4 were studied in detail using stopped-flow apparatus equipped with a light scattering detector. A pH jump from 12 to 2 in the absence of salt leads to the formation of VBA−core micelles; upon a pH jump from 2 to 12, the breakup of VBA−core micelles into unimers occurs within the dead time of the stopped-flow apparatus (∼ 2−3 ms). At pH 10, addition of Na2SO4 (> 0.6 M) induces the formation of MEMA−core micelles. Compared to the pH-induced formation and dissociation of VBA−core micell...

A brief review of ‘schizophrenic’ block copolymers

Recent progress in the synthesis of so-called ‘schizophrenic’ water-soluble block copolymers is reviewed. The original report in this new sub-field involved a tertiary amine methacrylate-based AB diblock copolymer synthesized by group transfer polymerization that was both pH- and salt-responsive, allowing the formation of either A-core or B-core micelles in aqueous solution. A second example involved a poly(propylene oxide)-tertiary amine methacrylate diblock copolymer synthesized via atom transfer radical polymerization (ATRP) that exhibited both pH- and thermo-responsive behavior. More recently, several examples of wholly pH-responsive zwitterionic diblock copolymers (prepared via ATRP, usually using protecting group chemistry) have been reported, with their aqueous solution behavior being characterized with varying degrees of precision. The synthesis and characterization of purely thermo-responsive diblock copolymers is also discussed, along with the first example of an ABC triblock copolymer that is capable of forming a ‘trinity’ of micelles in aqueous solution at 20 °C simply by adjusting the solution pH. In this remarkable final example, the cores of the three types of micelles are formed by hydrophobic forces, polyion complexation and hydrogen bonding, respectively.