Nitroxide-mediated polymerization to form symmetrical ABA triblock copolymers from a bidirectional alkoxyamine initiator

Bidirectional alkoxyamine 2 was synthesized and used as the initiator in the polymerization of styrene (S), n-butyl acrylate (nBA), t-butyl acrylate (tBA), isoprene (I), and dimethylacrylamide (DMA). A variety of symmetrical ABA triblock copolymers were prepared, ranging in size from 5 to 59 kDa. Kinetics studies and gel permeation chromatography (GPC) confirmed the “living” nature of these polymerizations. Trifluoroacetic acid was used to convert the PtBA blocks of these polymers into poly(acrylic acid) (PAA) blocks, forming ABA amphiphilic triblock copolymers. AFM images of PAA-b-PnBA-b-PAA and PAA-b-PS-b-PAA triblock copolymers ionized by the addition of 2,2′-(ethylenedioxy)bis(ethylamine) show evidence of self-assembly.     

pH- and thermo-multi-responsive fluorescent micelles from block copolymers via reversible addition fragmentation chain transfer (RAFT) polymerization

Well-defined pH- and thermo- multi-responsive fluorescent micelles based on the self-assembly of diblock copolymers poly[(N-isopropyl-acrylamide-co-N-vinylcarbazole)-b-2-(dimethylamino)ethyl acrylate], (PNIPAAM-co-PNVC)-b-PDMAEA, are described. The diblock copolymers are prepared via the reversible addition fragmentation chain transfer (RAFT) copolymerization of N-isopropyl-acrylamide (NIPAAM) and N-vinylcarbazole (NVC) followed by chain extension in presence of 2-(dimethylamino)ethyl acrylate) (DMAEA). The micelles are formed in aqueous solutions in a wide range of temperature (25-60 °C), and their sizes increase from 40 to 65 nm when varying pH from basic to acidic. The cross-linking of the PDMAEA-containing shell with 1,2-bis(2-iodoethoxy)ethane (BIEE) results in spherical soft nanoparticles which size is increased by 20-25% when compared to the micelles. The presence of NVC in concentrations as low as 4% in the core of the micelles allow the nanoparticles to be tagged by fluorescence, making them well suited for therapeutic applications.     

Simple and facile synthesis of aryl benzoates from stabilized arenediazonium tetrafluoroborate using a recyclable polymer-supported benzoate ion

Temperature-responsive P(NIPAM-co-HMAM)-b-PEO-b-P(NIPAM-co-HMAM) triblock copolymers were synthesized by an atomic transfer radical polymerization (ATRP) method without freeze?Cpump?Cthaw cycles. The composition, structure, and molecular weight of the synthesized block copolymer were characterized by ¹?H NMR and GPC. The phase transitions induced by temperature for different copolymers in dilute aqueous solutions have been studied using transmittance measurements, laser particle size measurements, viscosity analysis, and surface tension measurement, which showed that the HMAM content and the PEO (or PEG) chain length in the synthesized triblock copolymer affects the copolymer??s lower critical solution temperature (LCST). The micellization behavior of each temperature-responsive triblock copolymer was investigated by fluorescence probe measurements and transmission electron microscopy (TEM), which showed that the triblock copolymers form stable micelles above the LCST. The introduction of the HMAM component and the formation of micelles represent the first steps in the development of an injectable gel that forms in situ through chemical and physical crosslinking.     

Synthesis of comb-shaped copolymers by combination of reversible addition-fragmentation chain transfer polymerization and cationic ring-opening polymerization

Comb-shaped graft copolymers with poly(methyl acrylate) as a handle were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and ring-opening polymerization (ROP) techniques in three steps. First, copolymers of poly(styrene-co-chloromethyl styrene), poly(St-co-CMS), were prepared by RAFT copolymerization of St and CMS using 1-(ethoxycarbonyl)prop-1-yl dithiobenzoate (EPDTB) as RAFT agent. Second, the polymerization of MA using poly(St-co-CMS)-SC(S)Ph as macromolecular chain transfer agent produced block copolymer poly(St-co-CMS)-b-PMA. Third, cationic ring-opening polymerization of THF was performed using poly(St-co-CMS)-b-PMA/AgClO₄ as initiating system to produce comb-shaped copolymers. The structures of the poly(St-co-CMS), poly(St-co-CMS)-b-PMA and final comb-shaped copolymers were characterized by ¹H NMR spectroscopy and gel permeation chromatography (GPC).     

Suspension polymerization stabilized by triblock copolymer with CdS nanoparticles

In this paper, a new method to prepare polymer colloid particles stabilized by triblock copolymer with CdS nanoparticles was described. Poly(ethylene glycol-block-styrene-block-2-(dimethylamino) ethyl methacrylate) (PEG-b-PS-b-PDMAEMA) triblock copolymer was synthesized by sequential ATRP method. Micelles with CdS nanoparticles in the corona were prepared by “in situ” reaction of hydrogen sulfide with cadmium ion clusters in the corona of the micelles. The size of the CdS nanoparticles is affected by molar ratio of DMAEMA to cadmium ions and polymer concentration in the solution. When introduced into o/w emulsion the micelles reassemble on the surface of styrene oil droplets. PS colloid particles stabilized by triblock copolymer with CdS nanoparticles were achieved by suspension polymerization. TEM image indicates that CdS nanoparticles locate at the surface of the PS colloid particles.     

Synthesis of pH-Responsive Multilayer Micelles for Sustained Release of Folic Acid

Two novel triblock copolymers poly(hydroxypropyl acrylate)-b-poly (methyl methacrylate)-b-poly(N,N-dimethylaminoethyl methacrylate) and poly(hydroxypropyl acrylate)-b-poly(methyl methacrylate)-b-poly(acrylic acid) were successfully synthesized. In acetone media, using the electrostatic interactions between N,N-dimethylaminoethyl methacrylate and acrylic acid units, they could form spherically shaped multilayer micelles with pH-responsive, and have a mean diameter around 110 nm. The critical micelle concentration of it was determined to be 2.42 mg/L. In vitro release experiments, the folic acid-loaded micelles exhibited sustained release behavior and the drug release rate was affected by the pH value of release media. These results indicate that the multilayer micelles may serve as a novel intelligent drug delivery system.     

Self-assembly of amphiphilic di and triblock copolymers of styrene and quaternized 5-(N,N-diethylamino) isoprene in selective solvents

Self-association of highly asymmetric block copolymers of styrene and quaternized 5-(N,N-diethylamino)isoprene was studied. After quaternization with dimethyl sulfate, the di and triblock copolymers consisted of a long block of polystyrene (PS) with a short poly[5-(N,N,N-diethylmethylammonium)isoprene][methyl sulfate](PAI) block at one or both chain ends, respectively. The aggregates were prepared by first dissolving the copolymers in an organic solvent and then adding water to induce the segregation of the PS chains. Pure DMF, THF or dioxane was used as the organic solvent, as well as DMF/THF mixtures. The critical water content (cwc) and the morphologies were studied as a function of the common solvent, initial copolymer concentration and architecture (di or triblock) by static light scattering and by Transmission Electron Microscopy (TEM), respectively. It was found that both, the cwc and the morphologies of the aggregates are most strongly affected by the nature of the common solvent. Some unexpected behaviors were found for the triblock copolymer. Morphologies of a triblock copolymer in various mixtures of DMF and THF, quenched at determined water contents, were investigated in order to study the degree of morphological control that can be achieved solely as function of the organic solvent composition. Multiple morphologies have been found including equilibrium morphologies and kinetically trapped ones. Finally, the stability of primary micelles prepared in DMF was studied by DLS, upon dilution with DMF and water, and a possible mechanism for the destabilization of the aggregates is proposed.     

A new approach in the study of tethered diblock copolymer surface morphology and its tethering density dependence

A poly(l-lactic acid)-block-polystyrene-block-poly(methyl methacrylate) (PLLA-b-PS-b-PMMA) triblock copolymer was synthesized with a crystalline PLLA end block. Single crystals of this triblock copolymer grown in dilute solution could generate uniformly tethered diblock copolymer brushes, PS-b-PMMA, on the PLLA single crystal substrate. The diblock copolymer brushes exhibited responsive, characteristic surface structures after solvent treatment depending upon the quality of the solvent in relation to each block. The chemical compositions of these surface structures were detected via the surface enhanced Raman scattering technique. Using atomic force microscopy, the physical morphologies of these surface structures were identified as micelles in cyclohexane and “onion”-like morphologies in 2-methoxyethanol, especially when the PS-b-PMMA tethered chains were at low tethering density.     

Photophysical properties and self-assembly of triblock copolymer with complexes of positively charged PDMAEMA and oppositely charged chromophores

The self-assembly and photophysical properties of a triblock copolymer with complex mid-block in THF and aqueous solution were investigated in this research. Poly(poly(ethylene glycol) methyl ether methacrylate)-block-poly(2-(dimethylamino ethyl methacrylate)-block- poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA–b–PDMAEMA–b–PPEGMA) triblock copolymer was synthesized by subsequent atom transfer radical polymerizations (ATRP) of DMAEMA and PEGMA. The PDMAEMA blocks were quaternized by a reaction with iodomethane. The complex of the positively charged PDMAEMA chain unit and sodium salt of 1-pyrenebutyric acid was prepared by mixing equimolar amount of the two components in THF/water mixture. Transmission electron microscopy and fluorescence technique results show that the triblock copolymer chains self-assemble into micelles in THF at high concentration. The critical aggregation concentration (CAC) of the triblock copolymer in THF determined by fluorescence technique is 6.8 × 10^?5 M. The triblock copolymer was also able to self-assemble into micelles in water. The value of CAC of the triblock copolymer in water is 2.0 × 10^?5 M. The photophysical properties and self-assembly structures of the triblock copolymer in aqueous solutions were influenced by added sodium chloride. After salt addition, a transition of the assembled structures from micelles to hollow structures was observed.     

Micellization and sol-gel transition of novel thermo- and pH-responsive ABC triblock copolymer synthesized by RAFT

A well-defined thermo- and pH-responsive ABC-type triblock copolymer monomethoxy poly(ethylene glycol)-b-poly(2-(2-methoxyethoxy) ethyl methacrylate-co-N-hydroxymethyl acrylamide)-b-poly(2-(diethylamino) ethyl methacrylate), mPEG-b-P(MEO₂MA-co-HMAM)-b-PDEAEMA, was synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT). The ABC-type triblock copolymer was endowed thermo- and pH-responsive, corresponding to the thermosensitive properties of P(MEO₂MA-co-HMAM) and pH-responsive properties PDEAEMA segments, respectively. The thermo- and pH-responsive properties of copolymer aqueous solutions were studied by UV transmittance measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM). The results showed that the N-hydroxymethyl acrylamide (HMAM) content in triblock copolymer affected the lower critical solution temperature (LCST) of the triblock copolymer aqueous solution. The copolymer self-assembled into core-shell micelles, with the thermoresponsive P(MEO₂MA-co-HMAM) block and the hydrophilic PEG block as the shell, the hydrophobic PDEAEMA block as the core, in alkaline solution at room temperature. While in acidic media, when the temperature above the lower critical solution temperature (LCST) of the triblock copolymer aqueous solution, the copolymer self-assembled into P(MEO₂MA-co-HMAM)-core micelles with mixed hydrophilic PEG and pH-responsive PDEAEMA coronas. Sol-gel transition temperature (T_sol-gel) for the triblock copolymer determined by vial inversion test further indicated that it is dependent on the concentration of the triblock copolymers and solution pH. Copolymer hydrogel loaded with bovine serum albumin (BSA) were used for the sustained release study. The results indicated that the hydrogel was a promising candidate for controlling protein drug delivery.     

Lipase-catalyzed synthesis of pH-responsive poly(β-thioether ester)-b-poly(ethylene glycol)-b-poly(β-thioether ester) amphiphilic triblock copolymers for drug delivery

Novel amphiphilic triblock copolymers poly(β-thioether ester)-b-poly(ethylene glycol)-b-poly(β-thioether ester) (PTE-b-PEG-b-PTE) were designed for the first time and used as carriers for the sustained release of the hydrophobic drug curcumin (Cur). These BAB-type triblock copolymers were synthesized via one-step enzymatic polycondensation with catalysis by immobilized lipase B from Candida antarctica (CALB). The copolymers could self-assemble to form flower-like nanosized micelles in aqueous solution. The pH-triggered disassembly behaviors of the micelles were evaluated from the changes of the micellar size and molecular weight due to the acid-degradable β-thiopropionate groups in the hydrophobic PTE core. Cur was encapsulated into the micelles and showed faster release at pH 5.0 than pH 7.4. In vitro experiments indicated that the copolymers were non-cytotoxic, while the Cur-loaded micelles effectively inhibited the proliferation of HeLa cells. All these findings demonstrated the potential of PTE-b-PEG-b-PTE triblock copolymers as a promising pH-responsive nanocarrier for controlled drug delivery.     

Synthesis and characterization of copolymers of 5,6-benzo-2-methylene-1,3-dioxepane and n-butyl acrylate

The ATRP copolymerization of 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) with n-butyl acrylate (nBA) was studied by using ethyl 2-bromoisobutyrate (EBriBu) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA)/Cu(I)Br as the initiator and catalyst, respectively. The reactivity ratios of the monomers in the copolymerization were determined using the Kelen-Tüdõs method and were found to be r_BMDO=0.08 and r_nBA=3.7. The copolymer yield decreased with higher amounts of BMDO in the initial feed. The structure of these copolymers was thoroughly characterized by 1D and 2D NMR techniques and quantitative ring opening of BMDO in its copolymerization was demonstrated. The hydrolytic degradation behavior of the BMDO/nBA copolymers was also studied.     

Synthesis of thermoresponsive poly(N-isopropylmethacrylamide) and poly(acrylic acid) block copolymers via post-functionalization of poly(N-methacryloxysuccinimide)

Polymers exhibiting a thermoresponsive, lower critical solution temperature (LCST) phase transition have proven to be useful for many applications as “smart” or “intelligent” materials. A series of poly(N-isopropylmethacrylamide) (PNIPMAM) polymer, poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PNIPMAM-b-PAA) diblock, and poly(acrylic acid)-b-poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PAA-b-PNIPMAM-b-AA) triblock copolymer samples were synthesized via ATRP. A facile post-functionalization route was developed that uses an activated ester functionality to convert poly(N-methacryloxysuccinimide) (PMASI) blocks to LCST capable polyacrylamide, while poly(t-butyl acrylate) (PtBA) blocks were converted to water-soluble poly(acrylic acid) (PAA). The post-functionalization was monitored via ¹H NMR and ATR-FTIR. The aqueous solution properties were explored and the PNIPMAM polymers were shown to have a LCST phase transition varying from 35 to 60 °C. The ability to synthesize block copolymers that are thermoresponsive and water-soluble will be of great benefit for broader applications in drug delivery, bioengineering, and nanotechnology.     

Self-assembly behavior of rod–coil–rod polypeptide block copolymers

Self-assembly behavior of rod–coil–rod poly(γ-benzyl-l-glutamate)-b-poly(ethylene glycol)-b-poly(γ-benzyl-l-glutamate) (PBLG-b-PEG-b-PBLG) triblock copolymers with various PBLG block lengths in aqueous solution was investigated. The PBLG-b-PEG-b-PBLG triblock copolymers are able to self-assemble into vesicles when PBLG block length is relatively short. Meanwhile, the initial polymer concentration was found to have influence on the self-assembly. Giant vesicles can be observed when the initial concentration is high. Dissipative particle dynamics (DPD) simulations about the vesicles revealed that the rigid rod blocks could be aligned parallelly with each other to form the monolayer vesicles wall. When the PBLG block length in the PBLG-b-PEG-b-PBLG triblock copolymers increases, the aggregate morphologies were observed to transform from vesicles to spherical micelles. Based on the experimental and simulation results, we proposed a possible mechanism of the morphological transitions of the rod–coil–rod triblock copolymer aggregates.     

Synthesis of biodegradable pentaarmed star-block copolymers via an asymmetric BIS-TRIS core by combination of ROP and RAFT: From star architectures to double responsive micelles

Biodegradable star-shaped poly(?-caprolactone) and poly(?-caprolactone-b-l-lactide) (5sPCL-b-PLLA) with five arms were synthesized by ring-opening polymerization (ROP) from an asymmetric BIS-TRIS core via “core-first” strategy. Subsequently, a series of amphiphilic and double responsive star-block copolymers were synthesized by Z-RAFT star polymerization of N,N-dimethylamino-2-ethyl methacrylate (DMAEMA) from the star-shaped macro-RAFT agent, which was prepared by attaching 3-benzylsulfanylthiocarbonylthiocarbonylsufanylpropionic acid (BSPA) to 5sPCL-b-PLLA using a simple two-step reaction sequence. GPC and ¹H NMR data demonstrated the polymerization courses are under control. The molecular weight of 5sPCL-b-PLLA-b-DMAEMA increased with the monomer conversion, and the molecular weight distribution was in the range of 1.19-1.37. The spherical micelles with degradable core and pH/thermo-double sensitive shell had been prepared from the aqueous medium of the amphiphilic star-shaped copolymers by dialysis method. Both pH and thermal-responsive behaviours of copolymer micelles obtained in this study were investigated. The micelle size and morphology were measured by DLS, AFM and TEM.     

Synthesis and physical gels of pH- and thermo-responsive tertiary amine methacrylate based ABA triblock copolymers and drug release studies

A series of novel pH-responsive ABA triblock copolymer gelators have been synthesized by using poly[2-(diisopropylamino)ethyl methacrylate] (PDPA) as the A block and poly[2-(dimethylamino)ethyl methacrylate] (PDMA) as the B block via group transfer polymerization. While the PDPA-b-PDMA-b-PDPA triblock copolymers are molecularly soluble in acidic aqueous media due to protonation of all tertiary amine groups, they formed either gels by the chain-end hydrophobic interactions with relatively high polymer concentration (10 wt%) or near monodisperse “flower” micelles with low polymer concentration at neutral and basic aqueous solutions. The hydrophobic model drug release was studied in a sustained manner from the gels at pH 7.4 by varying the polymer concentration, the polymer molecular weight and the temperature of the medium. Preliminary studies indicate that both slow, sustained release and fast, triggered release of a model hydrophobic drug, dipyridamole, can be achieved by tuning the solution pH, polymer concentration, polymer molecular weight and temperature of the gel.     

Synthesis and characterization of biodegradable amphiphilic triblock copolymers methoxy-poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-lactic acid)

Starting from MPEG-NH₂, a series of amphiphilic triblock copolymers MPEG-b-PLL-b-PLA were synthesized through PEG-NH₂-initiated ring-open polymerization of N ^ε-benzyloxycarbonyl-L-lysine, followed by acylation coupling between the amino-terminated MPEG-b-PZLL-NH₂ and carboxyl-terminal PLA and the deprotection of amines. The block copolymers were characterized by FT-IR, ¹H NMR, GPC, DSC and TEM. The copolymer functional groups, molecular and block structures were verified by FT-IR, ¹H NMR and DSC, respectively. The GPC results indicate that the chain lengths of each block can be controlled by varying the feed ratios of the monomer and initiator, providing the polymer samples with a narrow molecular weight distribution (M _w /M _n = 1.10 ~ 1.25). The TEM analysis shows that the triblock polymers can self-assemble into polymeric micelles in aqueous solution with spherical morphology. The cell-cytotoxicity assay indicates that the triblock polymers show no obvious cytotoxicity against Bel7402 human hepatoma cells.     

Allyl functionalized telechelic linear polymer and star polymer via RAFT polymerization

Reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene using bisallyl trithiocarbonate as a chain transfer agent (CTA) was studied. The polymerization exhibited first-order kinetics and the molecular weight increased linearly with increase of monomer conversion. Well defined allyl-functionalized telechelic polystyrene (PS), poly(tert-butyl acrylate) (PtBA) and corresponding triblock copolymers, polystyrene-b-poly(n-butyl acrylate)-b-polystyrene (PS-b-PnBA-b-PS) and poly(tert-butyl acrylate)-b-polystyrene-b-poly(tert-butyl acrylate) (PtBA-b-PS-b-PtBA) were prepared as characterized with GPC and NMR analysis. The allyl-end groups of the telechelic PS have been switched to 1,2-dibromopropyl groups quantitatively by bromine addition reaction, further substitution of the bromide with azide was also made. Furthermore, star PS with allyl-end-functionalized arms was synthesized by RAFT polymerization of divinyl benzene using allyl-functionalized PS as a macro-CTA via arm-first approach. Star polymer with a thiol-functionalized core was generated by aminolysis reaction of the star polymer and ethylenediamine. As a result, difunctionalized star polymer with allyl and thiol groups was obtained and was used as a stabilizer for the formation of gold nanoparticles.     

pH-responsive PMAA-b-PEG-b-PMAA triblock copolymer micelles for prednisone drug release and release kinetics

pH-sensitive hydrophilic poly(methacrylic acid)-b-poly(ethylene glycol)-b-poly(methacrylic acid) (PMAA-b-PEG-b-PMAA) triblock copolymers were synthesized through atom transfer radical polymerization, and were characterized by FT-IR, ¹H NMR, and GPC. The as-synthesized polymers can self-assemble into stable and almost spherical nanomicelles in aqueous solution with an average size range from 18 to 89?nm, depending on the micellar concentrations, while they assumed well-defined spherical morphologies in PBS solutions. The micellization behavior in different media was investigated by a fluorescence spectroscopy technique, UV–Vis transmittance, and dynamic light scattering measurements. The critical micelle concentration and size of the micelles decrease with the increasing the length or molecular weights of PEG and PMAA chains. A pH-dependent phase transition behavior produces at a pH value of about 5.2, and the stable pH micellization behavior varied within a narrow pH range from ca. 4.8 to 7.4. These triblock copolymers are generally low cytotoxicity at a micellar concentration below 400?mg?L^?1, as revealed by the MTT assay. The prednisone release and release kinetics studies disclosed that these pH-sensitive polymeric micelles are good carriers for the drug delivery.     

Poly[N-(2-hydroxypropyl)methacrylamide-block-n-butyl acrylate] micelles in water/DMF mixed solvents

Three diblock copolymers of poly[N-(2-hydroxypropyl)methacrylamide] (poly(HPMA)) and poly(n-butyl acrylate) (poly(BA)) with varying lengths of blocks were prepared by atom transfer radical polymerization. All copolymers were found to be soluble in dimethylformamide (DMF) and poorly soluble or insoluble in water. In water and mixed DMF/H₂O solvents, the copolymers were dispersed in micellar form by controlled addition of water to DMF solutions of copolymers under continuous intensive stirring. The micellar solutions in water were prepared by dialysis of solutions in DMF/H₂O (95 vol% of H₂O) against water. Solution properties of diblock copolymers of poly(HPMA) and poly(BA) were studied using static and dynamic laser light scattering to characterize the behavior of the copolymers at the supramolecular level. The effects of preparation mode, organic solvent (DMF) and copolymer chemical composition on the formation of micelles were studied. While a slower mixing procedure was optimal for copolymers with short poly(HPMA) blocks, a faster mixing was more suitable for copolymers having longer poly(HPMA) blocks. Finally, the dimensions of micelles in water were evaluated. The most compact micelles were prepared from copolymers having short hydrophilic poly(HPMA) blocks. On the other hand, the copolymer with the longest poly(HPMA) block formed micelles with the smallest size and the lowest density.