Synthesis and characterization of shell cross-linked micelles with hydroxy-functional coronas: a pragmatic alternative to dendrimers?

Shell cross-linked (SCL) micelles with hydroxy-functional coronas have been constructed in aqueous solution by exploiting the micellar self-assembly behavior of a new thermoresponsive ABC triblock copolymer. This copolymer was prepared via atom transfer radical polymerization in a convenient one-pot synthesis and comprised a thermoresponsive core-forming poly(propylene oxide) (PPO) block, a cross-linkable central poly(2-(dimethylamino)ethyl methacrylate) (DMA) block, and a hydroxy-functional outer block based on poly(glycerol monomethacrylate) (GMA). DMF GPC analysis confirmed a unimodal molecular weight distribution for the PPO-PDMA-PGMA triblock copolymer precursor, with an M(n) of 12 100 and a polydispersity of approximately 1.26. This copolymer dissolved molecularly in aqueous solution at 5 degrees C but formed micelles with hydroxy-functional coronas above a critical micelle temperature of around 12 degrees C, which corresponded closely to the cloud point of the PPO macroinitiator. Cross-linking of the DMA residues using 1,2-bis(2-iodoethoxy)ethane produced SCL micelles that remained intact at 5 degrees C, i.e., below the cloud point of the core-forming PPO block. Dynamic light scattering studies confirmed that the SCL micelle diameter could be varied depending on the temperature employed for cross-linking: smaller, more compact SCL micelles were formed at higher temperatures, as expected. Since cross-linking involved quaternization of the DMA residues, the SCL micelles acquired cationic surface charge as judged by aqueous electrophoresis studies. These cationic SCL micelles were adsorbed onto near-monodisperse anionic silica sols, which were used as a model colloidal substrate. Thermogravimetric analyses indicated a SCL micelle mass loading of 2.5-4.4%, depending on the silica sol diameter and the initial micelle concentration. Aqueous electrophoresis measurements confirmed that surface charge reversal occurred after adsorption of the SCL micelles, and scanning electron microscopy studies revealed a uniform coating of SCL micelles on the silica particles.     

Aqueous chromatographic system for separation of biomolecules using thermoresponsive polymer modified stationary phase

We have investigated a new method for HPLC using packing materials modified with a functional polymer, such as thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm). PNIPAAm-modified silica exhibits temperature-controlled hydrophilic-hydrophobic surface property changes in aqueous systems. Temperature-responsive chromatography is performed with an aqueous mobile phase without using an organic solvent. We designed ternary copolymers of NIPAAm introduced 2-(dimethyl-amino) ethyl methacrylate (DMAEMA) as a cationic monomer and butyl methacrylate (BMA) as a hydrophobic monomer. A cationic thermoresponsive hydrogel grafted surface would produce an alterable stationary phase with both thermally regulated hydrophobicity and charge density for separation of bioactive compounds. In this study, we achieved successful separation of lysozyme without the loss of bioactivity by temperature-responsive chromatography. The electrostatic and hydrophobic interactions could be modulated simultaneously with the temperature in an aqueous mobile phase, thus the separation system would have potential applications in the separation of biomolecules.     

Synthesis and in situ atomic force microscopy characterization of temperature-responsive hydrogels based on poly(2-(dimethylamino)ethyl methacrylate) prepared by atom transfer radical polymerization

Well-defined copolymers of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and benzophenone methacrylate (BPMA) with different compositions were synthesized via atom transfer radical polymerization. The molecular weights of these copolymers were Mn approximately 30 000 g/mol, while the BPMA content varied from 2.5 to 10 mol %. The copolymers with a low content of BPMA (2.5 and 5 mol %) exhibited a sharp thermal transition at 33-36 degrees C in aqueous solution. A hydrogel was immobilized and patterned on a silicon wafer via UV treatment of the spin-coated polymer layer using a photomask technique. The thermoresponsive behavior of the patterned polymer gel was quantitatively investigated by variable temperature in situ contact mode atomic force microscopy, which revealed the presence of two lower critical solution temperature regions. One region was between 25 and 30 degrees C, corresponding to the topmost layer of the hydrogel film, and the other region, around 40 degrees C, corresponded to the bulk of the hydrogel. Concurrent lateral force microscopy measurements revealed that, just above the transition temperature, the bulk region exhibited enhanced friction.     

Thermally reversible pluronic/heparin nanocapsules exhibiting 1000-fold volume transition

Novel Pluronic/heparin composite nanocapsules that exhibit a thermally responsible swelling and deswelling behavior were synthesized. Pluronic F-127 preactivated with p-nitrophenyl chloroformate at its two terminal hydroxyl groups was dissolved in a methylene chloride phase. The organic phase was dispersed in an aqueous phase containing heparin. At an organic/aqueous interface, Pluronic-cross-linked heparin nanocapsules were produced. They exhibited a 1000-fold volume transition (ca. 336 nm at 25 degrees C; ca. 32 nm at 37 degrees C), and a reversible swelling and deswelling behavior when the temperature was cycled between 20 and 37 degrees C. The reversible volume transition of Pluronic nanocapsules was caused by micellization and demicellization of cross-linked Pluronic polymer chains within the nanocapsule structure in response to temperature. The morphological characters were investigated with transmission electron microscopy and small angle neutron scattering. Pluronic/heparin nanocapsules had an aqueous fluid-filled hollow interior with a surrounding shell layer below the critical temperature, but they became a collapsed core/shell structure similar to that of Pluronic micelles above it.     

Aggregation and thermoresponsive properties of new star block copolymers with a cholic acid core

Poly(allyl glycidyl ether) (PAGE) and poly(ethylene glycol) (PEG) blocks were sequentially grown via anionic polymerization to form four block copolymer arms on a cholic acid (CA) core, yielding star block copolymers (CA(AGE(8)-b-EG(n))(4)) with low polydispersities (ca. 1.05). The introduction of PAGE segments into CA(PEG)(4) significantly reduced their crystallinity. The polymers can aggregate in water at room temperature above their critical aggregation concentration. The copolymers are thermoresponsive; their behavior in aqueous solutions was studied by the use of UV-visible spectroscopy, dynamic light scattering, and transmission electron microscopy. Their cloud points vary from 13 to 55 °C with increasing length of the PEG segments. Double thermoresponsive behavior was observed with short PEG segments because of a two-step transition process: small micelles are formed upon heating and then further aggregate into micellar clusters through the association of PEG chains.     

Selective synthesis of double temperature-sensitive polymer-peptide conjugates

A novel synthetic route has been developed to couple selectively a modified octa-peptide, that is able to gel at low temperature, to the prototypical thermoresponsive polymer poly(N-isopropylacrylamide) to give a bioconjugate that exhibits double thermoresponsiveness.     

Synthesis and applications of shell cross-linked thermoresponsive hybrid micelles based on poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(methyl methacrylate)

Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.     

Modifying the thermosensitivity of copolymers of sodium styrene sulfonate and<Emphasis Type="Italic"> N</Emphasis>-isopropylacrylamide with dodecyltrimethylammonium chloride

The interactions between copolymers of sodium styrene sulfonate (SSS) and N-isopropylacrylamide (NIPAM), anionic polyelectrolytes, and dodecyltrimethylammonium chloride (DTAC), a cationic surfactant, were studied in aqueous solutions of various ionic strengths. The copolymers were found to be thermoresponsive, showing a lower critical solution temperature (LCST). The influence of the polymer composition, the surfactant concentration, and the ionic strength on the LCST was studied. The surfactant was found to interact strongly with the polymer, forming mixed polymer-surfactant micelles. The critical aggregation concentration (cac) of the polymer-surfactant system was found from fluorescence spectroscopy using pyrene as a fluorescent probe. A strong dependence of the anionic polyelectrolyte-cationic surfactant interactions on the structure of the ionic comonomer was observed.     

Triphenylphosphane-functionalised amphiphilic copolymers: tailor-made support materials for the efficient and selective aqueous two-phase hydroformylation of 1-octene

Amphiphilic copolymers (random P1 and block P2) based on 2-oxazolines were synthesised with triphenylphosphane ligands covalently linked to the polymers by means of a metal-free synthesis route. The resulting macroligands were used in the aqueous two-phase hydroformylation of 1-octene. The influence of the polymer architecture (random and block copolymers) on activity and selectivity of the hydroformylation reaction was investigated and compared with that of nonfunctionalised copolymers (random P3 and block P4) and Rh(I)/triphenylphosphane trisulfonate as a water-soluble catalyst. The highest activities were observed for the random copolymer P1 (p=50 bar, T=100 degrees C, c=8 x 10(-4) mol L(-1)) with a turnover frequency (TOF) of 3700 h(-1), whereas the corresponding block copolymer P2 reached TOF numbers of 1630 h(-1). Additionally, both macroligands indicated efficient suppression of isomerisation and led to almost constant n/iso selectivities of about 3 after complete substrate conversion. Copolymers P3 and P4 showed, under identical reaction conditions, strong isomerisation after 40-60 % conversion (n/iso approximately 0.7) and maximum activities of 1560 h(-1) (P3) and 1330 h(-1) (P4) at a concentration of 5 x 10(-3) mol L(-1).     

Temperature sensitive dopamine-imprinted (N,N-methylene-bis-acrylamide cross-linked) polymer and its potential application to the selective extraction of adrenergic drugs from urine

A temperature sensitive dopamine-imprinted polymer was prepared in 80% aqueous methanol solution by free-radical cross-linking co-polymerisation of methacrylic acid and acrylamide at 60 degrees C in the presence of N,N-methylene-bis-acrylamide as the cross-linker and dopamine hydrochloride as template molecule. The resulting molecularly imprinted polymer (MIP) formed temperature responsive materials, which could be used for the selective separation of appropriate dopamine and adrenergic compounds from a liquid matrix at ambient temperatures. The thermoresponsive MIP exhibited a swelling-deswelling transition in 80% aqueous methanol solution at about 35 degrees C. The capacity of the thermoresponsive MIP to recognise the template molecule when present in aqueous methanol solution changed with temperature, with the highest selectivity found at 35 degrees C. Additionally, binding parameters obtained from Scatchard analyses indicate that increasing temperature resulted in an increased affinity and binding capacity of specific binding sites, but had less effect on non-selective binding sites. Subsequently, the thermoresponsive MIP was tested for its application as a sorbent material, utilisable in the selective solid-phase extraction (SPE) of dopamine and other adrenergic compounds (epinephrine, isoproterenol, salbutamol and serotonin) from urine samples. It was shown that the compounds that were structurally related to dopamine could be removed by elution, while dopamine and serotonin, the analytes of interest, remained strongly adsorbed to the adsorbent during SPE applications. The thermoresponsive MIP displayed different efficiency in clean-up and enrichments using the SPE protocol at different temperatures.     

Thermoresponsive gene carriers based on polyethylenimine-graft-poly[oligo(ethylene glycol) methacrylate

A family of thermoresponsive cationic copolymers (TCPs) that contain branched PEI 25 K as the cationic segment and poly(MEO(2)MA-co-OEGMA(475)) as the thermosensitive block (TP) is prepared. The DNA binding capability, physicochemical properties, and biological performance of the TCPs are studied. All of these TCPs can condense DNA to form polyplexes with diameters of 150-300 nm and zeta potentials of 7-32 mV at N/P ratios between 12 and 36. The length of TP block is a key factor for shielding the positive surface charge of the polyplexes and protecting them against protein adsorption. TCPs with a higher TP content have a lower cytotoxicity while the best transfection performance is achieved by the TCPs with longest TP length, reaching a level of the intact PEI 25 K in the presence of serum.     

水溶性荧光增强共轭聚合物的合成及性能研究

通过Suzuki反应将1,2-二[4-(6-溴己氧基)苯基]-1,2-二(4-溴苯基)乙烯与1,4-对苯二硼酸丙二醇酯共聚得到含有四苯乙烯基团的共轭聚合物P-0,通过后功能化得到了具有良好水溶性的聚合物P-1.通过1H-NMR、MALDI-TOF、MS和凝胶渗透色谱(GPC)对其结构进行表征.测定了P-1在水溶液中的紫外吸收光谱、荧光发射光谱以及荧光量子产率.通过P-1与小分子化合物MC-1的对比,P-1的荧光增强灵敏度优于MC-1.在P-1的溶液中分别加入沉淀剂或带有负电荷的生物大分子,两者的紫外吸收光谱与荧光发射光谱有很大的差异,通过结果对比,初步探讨了聚集诱导荧光增强的机理,经过静电作用限制苯环内旋转可以实现荧光强度的线型增长.     

Thermoresponsive micelles from Jeffamine-b-poly(L-glutamic acid) double hydrophilic block copolymers

Double hydrophilic block copolymers (DHBC) consisting of a Jeffamine block, a statistical copolymer based on ethylene oxide and propylene oxide units possessing a lower critical solution temperature (LCST) of 30 degrees C in water, and poly(L-glutamic acid) as a pH-responsive block were synthesized by ring-opening polymerization of gamma-benzyl-L-glutamate N-carboxyanhydride using an amino-terminated Jeffamine macroinitiator, followed by hydrolysis. This DHBC proved thermoresponsive as evidenced by dynamic light scattering and small-angle neutron scattering experiments. Spherical micelles with a Jeffamine core and a poly(L-glutamic acid) corona were formed above the LCST of Jeffamine. The size of the core of such micelles decreased with increasing temperature, with complete core dehydration being achieved at 66 degrees C. Such behavior, commonly observed for thermosensitive homopolymers forming mesoglobules, is thus demonstrated here for a DHBC that self-assembles to generate thermoresponsive micelles of high colloidal stability.     

A hemicyanine-conjugated copolymer as a highly sensitive fluorescent thermometer

A simple-structured copolymer, poly(NIPAM-co-HC), consisting of N-isopropylacrylamide (NIPAM) and 4-(4-dimethylaminostyryl)pyridine (hemicyanine, HC) units as thermoresponsive and fluorescent signaling parts, respectively, has been synthesized. This copolymer dissolved in water shows very weak fluorescence at <25 degrees C, while showing fluorescence enhancement at >25 degrees C. The fluorescence intensity increases with a rise in temperature and saturates at >40 degrees C, enabling temperature detection at 25-40 degrees C. The fluorescence enhancement is driven by a heat-induced phase transition of the polymer from coil to globule state. The HC units within the coil state polymer exist as the nonfluorescent benzenoid form; however, the less polar domain formed inside the globule state polymer leads to transformation of the HC unit to the fluorescent quinoid form, resulting in heat-induced fluorescence enhancement. The fluorescence intensity measured at 40 degrees C is >20-fold higher than the intensity at <25 degrees C, which is the highest enhancement value among the fluorescent thermometers proposed so far. The polymer shows reversible fluorescence enhancement/quenching, regardless of the heating/cooling process. In addition, the polymer shows high reusability with a simple recovery process.     

Preparation of biodegradable and thermoresponsive enzyme–polymer conjugates with controllable bioactivity via RAFT polymerization

The preparation of biodegradable and thermoresponsive enzyme–polymer bioconjugates with controllable enzymatic activity via reversible addition−fragmentation chain transfer (RAFT) polymerization and amidation conjugation reaction is presented. A new 2-mercaptothiazoline ester functionalized RAFT agent with intra-disulfide linkage was synthesized and used as chain transfer agent (CTA) to generate a biocompatible homopolymer, poly(ethyleneglycol) acrylate (polyPEG-A) and a thermoresponsive copolymer of poly(ethyleneglycol) acrylate with di(ethyleneglycol)ethyl ether acrylate [poly(PEG-A-co-DEG-A)]. These biodegradable and thermoresponsive polymers were then conjugated to the surface of glucose oxidase (GOx) under mild condition to afford the biodegradable and thermoresponsive enzyme–polymer conjugates. Cleavage of the polymer chains from the GOx surface obviously recovered the enzymatic activity. The thermoresponsive test of GOx-poly(PEG-A-co-DEG-A) revealed that the bioconjugate exhibited regular enzymatic activity fluctuation upon the temperature change below or above the lower critical solution temperature (LCST). The as-prepared enzyme–polymer conjugates were also characterized using ¹H NMR, UV–vis spectroscopy, polyacrylamide gel electrophoresis (PAGE) and biocatalytic activity tests. These smart enzyme–polymer conjugates would envision promising applications in biotechnology and biomedicine.     

Synthesis and characterization of a novel paramagnetic macromolecular complex [Gd(TTDASQ-protamine)

Adenocarcinomas in rats and humans frequently contain perivascular, degranulating mast cells that release heparin. Protamine is a low-molecular weight, cationic polypeptide that binds to heparin and neutralizes its anticoagulant properties. A novel magnetic resonance imaging (MRI) contrast agent containing protamine was synthesized. TTDASQ, the derivative of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), was also synthesized and the kinetic stability of [Gd(TTDASQ)]- chelate containing phosphate buffer and ZnCl2 to measure the relaxation rate (R1) at 20 MHz was studied by transmetallation with Zn(II). The water-exchange rate (k(ex)298) of [Gd(TTDASQ)]- is 6.4 x 10(6) s(-1) at 25.0 +/- 0.1 degrees C which was obtained from the reduced 17O relaxation rates (1/T(1r) and 1/T(2r)) and chemical shift (omega(r)) of H(2)17O, and it is compared with that previously reported for the other gadolinium(III) complex, [Gd(DO3ASQ)]. The binding affinity assay showed that the (TTDASQ)3-pro19 has higher activity toward heparin. On the other hand, the effect of heparin on the relaxivity of the [Gd(TTDASQ)3-pro19] conjugate shows the binding strength (K(A)) is 7669 dm3 mol(-1) at pH 7.4 and the relaxivity (r(b)1) of the [Gd(TTDASQ)3-pro19]-heparin adduct is 30.9 dm3 mmol(-1) s(-1).     

Tunable,concentration‐independent,sharp, hysteresis‐free UCST phase transition from poly(N‐acryloyl glycinamide‐acrylonitrile) system

Poly(N‐acryloylglycinamide‐co‐acrylonitrile) (poly(NAGA‐AN)) copolymers were synthesized using reversible‐addition‐fragmentation transfer polymerization. In contrast to poly(NAGA) the thermoresponsive behavior of poly(NAGA‐AN) shows a narrow cooling/heating hysteresis in water with a tunable cloud point, depending on the acrylonitrile amount in polymer. Furthermore, we showed that there is no significant effect of the solution concentration on the cloud point and stable phase transition behavior in electrolyte solutions, which is presumable controlled by forming stable micellar like structures as a result of the block/graft‐copolymer structure. This is in contrast to poly(NAGA) which shows a strong concentration dependent cloud point in aqueous solution with a broad cooling/heating hysteresis. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 274–279     

Closed-loop sol-gel transition of PEG-PEC aqueous solution

We are reporting an unusual closed-loop phase behavior of poly(ethylene glycol)-beta-poly(ethyl-2-cyanoacrylate) (PEG-PEC) aqueous solutions. As the temperature increased from 0 to 60 degrees C, the aqueous polymer solution (12 wt %) underwent sol-to-gel and gel-to-syneresis transitions. However, the polymer aqueous solution persisted as a sol phase below 4.0 wt % as well as above 16 wt % in the same temperature range, thus forming a closed-loop gel domain in the phase diagram. The closed-loop gel domain is suggested to be a result of the balance between the aggregation and the stabilization of micelles in specific temperature and concentration ranges.     

Palladium-catalyzed Mizoroki-Heck reactions in water using thermoresponsive polymer micelles

Palladium-catalyzed Mizoroki-Heck reactions were carried out in water using thermoresponsive polymer micelles. The micelles were generated from thermoresponsive block copolymers consisting of a poly(N-isopropylacrylamide) (PNIPAAm) segment and a hydrophilic segment such as nonionic poly(ethylene glycol) (PEG) (2) and anionic poly(sodium p-styrenesulfonate) (PSSNa) (9). These copolymers exhibited lower critical solution temperature (LCST) behavior at ca. 40–50?°C and showed thermal stimuli-induced formation and dissociation of micelles. The copolymers formed micelles in aqueous solution at higher temperature, where catalytic reactions proceeded. At lower temperature, the micelles dissociated to form a clear solution, enabling efficient extraction of the products from aqueous reaction mixture. In the presence of these copolymers, palladium complexes catalyzed the coupling reactions between aryl iodides and alkene compounds inside the hydrophobic micelle cores in water under relatively milder conditions. Extraction of the products from the aqueous solution of 2 or 9 was found to be efficient enough in comparison with conventional surfactants.     

Poly(bis-2,2,2-trifluoroethoxymethyl oxetane): enhanced surface hydrophobicity by crystallization and spontaneous asperity formation

We report a spontaneous increase in the contact angle (104 degrees --> 136 degrees +/- 4 degrees ) for a semicrystalline polyoxetane with symmetrical CF3CH2OCH2 side chains. Poly(bis-trifluoroethoxymethyl)oxetane, P(B-3FOx), Mn = 21 kDa, was prepared by a modification of conventional cationic ring opening polymerization. At ambient temperature, the polymer is between Tg (-39 degrees C) and Tm (approximately 70 degrees C). Tapping mode atomic force microscopy (TM-AFM) revealed an interesting process-dependent topology. Coatings that were melted and slow-cooled displayed increasing roughness over the course of 4-6 weeks at 25 degrees C. The result was a topology characterized by sharp micrometer-scale ridges and asperities. The heat of fusion increases from an initial value of 21.9 J/g after slow cooling (non-isothermal melt crystallization) to 28 J/g after 6 weeks (non-isothermal melt crystallization plus isothermal melt crystallization). The coating appearance changes from transparent with a slight haze to translucent. The changing topology was accompanied by a 30 degrees increase in the water contact angle, up to 140 degrees , attributed to an asperity-rich surface yielding a discontinuous three-phase contact line and to a change in the proportions of crystalline and amorphous area fractions accompanying crystallization.