2,6‐Diaminopyridine and Acrylamide‐Based Copolymers with Upper Critical Solution Temperature‐type Behavior in Aqueous Solution

Novel amphiphilic diblock copolymers bearing acid-labile oxazolidine moieties: Synthesis, self-assembly and responsive behavior in aqueous solution

A new family of the thermo-responsive polymers based on poly[N-(4-vinylbenzyl)-N,N-dialkylamine] with the pendent amine group as well as the doubly thermo-responsive triblock copolymer were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. These polymers showed the lower critical solution temperature (LCST) and/or the upper critical solution temperature (UCST) in alcohol and in the alcohol/water mixture. The polymer molecular weight, the polymer concentration, the cosolvent/nonsolvent and the deuterated solvent affecting the LCST and/or UCST were investigated, and their great influence on the LCST/UCST was demonstrated. The origin of the phase transition of poly[N-(4-vinylbenzyl)-N,N-dialkylamine] at LCST upon heating was investigated and the possible reason was proposed. The doubly thermo-responsive triblock copolymer of PVMA53-b-PVEA108-b-PVMA53 underwent phase transition at two LCST temperatures. The PVEA108 block underwent the initial phase transition at the first LCST of 32.5 °C to form core–corona micelles, and then the subsequent phase transition of the PVMA53 block took place at the second LCST of 54.5 °C to produce corona-collapsed micelles. The proposed polymers based on poly[N-(4-vinylbenzyl)-N,N-dialkylamine] are anticipated to broaden the thermo-responsive polymer range and will be useful in polymer science.

A novel monomer, N‐(2‐((3‐morpholine‐3‐isopropyl)thio)ethyl)methacrylamide (MTMA), is synthesized and polymerized by reversible addition‐fragmentation chain transfer (RAFT) polymerization to give a thermoresponsive polymer poly[N‐(2‐((3‐morpholino‐3‐oxopropyl)thio)ethyl)methacrylamide] (PMTMA). PMTMA exhibits reversible thermoresponsive phase transitions of the lower critical solution temperature (LCST) type in water and the upper critical solution temperature (UCST) type in ethanol and methanol. The degree of polymerization and concentration of PMTMA, and solvent type have a significant influence on the transition temperature. PMTMA shows complicated thermoresponse in water–alcohol mixtures. In water–ethanol mixtures, the phase diagram of PMTMA can be divided into three regions according to ethanol volume percentages, φ: 0 ≤ φ < 15% for an LCST region; 15% ≤ φ < 91.5% for a complete dissolution region; 91.5% ≤ φ ≤ 100% for a UCST region. At high water content, the LCST increases with increasing ethanol content; and at high ethanol content, the UCST decreases with increasing water content. In water–methanol mixtures, PMTMA shows more complex thermoresponse. In the range of 0–50 °C, the phase diagram can be divided into five regions, depending on the methanol volume percentages φ: 0 ≤ φ < 15% for LCST region; 15% ≤ φ < 25% for immiscible region; 25% ≤ φ < 85% for UCST region; 85% ≤ φ < 95% for fully dissolved region; 95% ≤ φ ≤ 100% for another UCST region.

"Schizophrenic" diblock copolymers containing nonionic and zwitterionic blocks were prepared with well-controlled molecular weights via atom-transfer radical polymerization (ATRP). In this work, we report a systematic study of how morphological changes of poly(N-isopropylacrylamide)-block-poly(sulfobetaine methacrylate) (PNIPAAm-b-PSBMA) copolymers affect hemocompatibility in human blood solution. The "schizophrenic" behavior of PNIPAAm-b-PSBMA was observed by (1)H NMR, dynamic light scattering (DLS), and turbidity measurement with double morphological transition, exhibiting both lower critical solution temperature (LCST) and upper critical solution temperature (UCST) in aqueous solution. Below the UCST of PSBMA block, micelles were obtained with a core of insoluble PSBMA association and a shell of soluble PNIPAAm, whereas the opposite micelle structure was observed above the LCST of PNIPAAm block. In between the UCST and LCST, unimers with both soluble blocks were detected. Hydrodynamic size of prepared polymers and copolymers is determined to illustrate the correlations between intermolecular nonionic/zwitterionic associations and blood compatibility of PNIPAAm, PNIPAAm-b-PSBMA, and PSBMA suspension in human blood. Human fibrinogen adsorption onto the PNIPAAm-b-PSBMA copolymers from single-protein solutions was measured by DLS to determine the nonfouling stability of copolymer suspension. The new nonfouling nature of PNIPAAm-b-PSBMA copolymers was demonstrated to show extremely high anticoagulant activity and antihemolytic activity in human blood over a wide range of explored temperatures from 4 to 40 °C. The temperature-independent blood compatibility of nonionic/zwitterionic block copolymer along with their schizophrenic phase behavior in aqueous solution suggests their potential in blood-contacting applications.

We rationally designed a monomer that when polymerized formed a well-defined nonionic polymer [poly(2-(methacryloyloxy) ethylureido glycinamide), PMEGA] by reversible addition fragmentation chain transfer with a flat and tunable upper critical solution temperature (UCST) in water. The monomer was made in one pot from commercially available compounds and with ease of purification. Strong hydrogen-bonding side groups on the polymer produced sharp coil-to-globule transitions upon cooling below its UCST. Ideal random copolymers produced with butyl methacrylate also showed flat UCST profiles, in which the UCST increased with a greater butyl methacrylate copolymer composition from 7 to 65 °C. In the presence of NaCl, the UCST decreased linearly with NaCl concentration due to the "salting-in" effect, and it was found that the slopes from the linear decrease of UCST were nearly identical for all copolymer compositions. This new polymer and its copolymers support the hypothesis that strong hydrogen bonding between the side groups allowed the flat UCST to be readily tuned with a high level of predictability. We postulate that this polymer system may provide wide biological applicability similar to that found for the well-used flat lower critical solution temperature (LCST) of poly(N-isopropylacrylamide).

Well-defined diblock copolymers comprising thermosensitive poly(N-isopropyl acrylamide) (PNIPAM) and poly(n-butylacrylate) (PBA) blocks were synthesized by macromolecular design by interchange of xanthates (MADIX)/reversible addition−fragmentation chain transfer polymerization (RAFT) using a xanthate-type mediating agent. Their behavior in aqueous solution as a function of temperature was studied by scattering and microscopy techniques. The cloud point temperature values were strongly correlated to the hydrophobic content of the copolymers. Moreover, above the cloud point, the block copolymer structure led to the formation of large reversible aggregates with well-defined sizes. Those polymers were then used to study the synthesis and stability of gold nanoparticles (AuNPs) dispersions either by coating preformed AuNPs or by in situ preparation. In this latter case, we showed that the appropriate choice of polymer concentration allows one to control the size of the AuNPs. Furthermore, the AuNPs were embedded within globules of diblock copolymers, this type of architecture providing long-term stability as well as a thermosensitivity to the AuNPs.

We describe the one-pot synthesis of temperature-responsive branched polymer nanoparticles. Reversible addition–fragmentation chain transfer (RAFT) polymerisation has been utilised to synthesise ultra-high molecular weight sulfobetaine polymers (up to ca. 500 kDa) with good control over molecular weight (Mn) and dispersity (Mw/Mn). The UCST cloud points of these linear polymers were found to increase with both Mn and concentration, and represent one of the few recent descriptions of polymers exhibiting UCST behaviour in aqueous solution. The incorporation of difunctional monomers results in branched polymers which display vastly reduced transition temperatures compared to their linear counterparts. Furthermore, the incorporation of a permanently hydrophilic monomer results in the formation of stable core–shell particles which no longer exhibit a cloud point in water, even at very high concentrations (ca. 50 mg mL−1). The branched polymers are shown to form discrete well-defined nanoparticles in aqueous solution, and these have been characterised by DLS, SLS, TEM and DOSY. Their reversible swelling behaviour in response to temperature is also demonstrated.

This manuscript serves as the starting point for in-depth research of multicomponent, statistical, methacrylate-based copolymers that potentially mimic the behavior of proteins in aqueous solutions. These synthetic macromolecules are composed of specially chosen comonomers: methacrylic acid (MAA), oligoethylene glycol methyl ether methacrylate (OEGMA475), 2-(dimethylamino)ethyl methacrylate (DMAEMA) and benzyl methacrylate (BzMA). Monomer choice was based on factors such as the chemical nature of pendant functional groups, the polyelectrolyte/polyampholyte and amphiphilic character and the overall hydrophobic-hydrophilic balance (HLB) of the obtained quaterpolymers. Their synthesis was achieved via a one-pot reversible addition fragmentation chain transfer (RAFT) polymerization in two distinct compositions and molecular architectures, linear and hyperbranched, respectively, in order to explore the effects of macromolecular topology. The resulting statistical quaterpolymers were characterized via 1H-NMR and ATR-FTIR spectroscopies. Their behavior in aqueous solutions was studied by dynamic (DLS) and electrophoretic light scattering (ELS) and fluorescence spectroscopy (FS), producing vital information concerning their self-assembly and the structure of the formed aggregates. The physicochemical studies were extended by tuning parameters such as the solution pH and ionic strength. Finally, the quaterpolymer behavior in FBS/PBS solutions was investigated to test their colloid stability and biocompatibility in an in vivo-mimicking, biological fluid environment.

Fouling on filtration membranes is induced by the nonspecific interactions between the membrane surface and the foulants, and effectively hinders their efficient use in various applications. Here, we established a facile method for the coating of membrane surface with a dual stimuli-responsive antifouling microgel system enriched with a high polyzwitterion content. Different poly(sulfobetaine) (PSB) zwitterionic polymers with defined molecular weights and narrow dispersities were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and integrated onto poly(N-vinylcaprolactam) (PVCL) microgels via a controlled dosage of a cross-linker, adapting a precipitation polymerization technique to obtain a core-shell microstructure. Increasing the PSB macro-RAFT concentration resulted in a shift of both upper critical solution temperature and lower critical solution temperature toward higher temperatures. Cryogenic transmission electron microscopy at different temperatures suggested the formation of a core-shell morphology with a PVCL-rich core and a PSB-rich shell. On the other hand, the significant variations of different characteristic proton signals and reversible phase transitions of the microgel constituents were confirmed by temperature-dependent 1H NMR studies. Utilizing a quartz crystal microbalance with dissipation monitoring, we have been able to observe and quantitatively describe the antipolyelectrolyte behavior of the zwitterionic microgels. The oscillation frequency of the sensor proved to change reversibly according to the variations of the NaCl concentration, showing, in fact, the effect of the interaction between the salt and the opposite charges present in the microgel deposited on the sensor. Poly(ethersulfone) membranes, chosen as the model surface, when functionalized with zwitterionic microgel coatings, displayed protein-repelling property, stimulated by different transition temperatures, and showed even better performances at increasing NaCl concentration. These kinds of stimuli-responsive zwitterionic microgel can act as temperature-triggered drug delivery systems and as potential coating materials to prevent bioadhesion and biofouling as well.

Study on the performance of polycarboxylate-based superplasticizers synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization

Polystyrene, poly(methylacrylate) and poly(methyl methacrylate) four and three-arm stars were synthesized by Reversible Addition Fragmentation chain-Transfer (RAFT) polymerization by using two new dithioester-derived chain transfer agents [CTA or R-S-(C = S)Z]), CTA-1 and CTA-2. CTA-1 is a four arm CTA while CTA-2 is a three-arm CTA. These were easily synthesized from commercially available reagents and were characterized by spectroscopic techniques such as 1H-NMR, 13C-NMR, IR and mass spectrometry. It is demonstrated that the two new CTAs enable the growth of arms away from the core (i.e., core first approach). An attempt has been made to study the effect of the structure of the R-group, which is present as the core in the CTA, on the polymerization, by analyzing the detailed kinetics. This study suggests that CTA-2, with a benzylic R group, enables the controlled star polymerization of styrene while CTA-1, with a R group similar in structure to the propagating radical derived from the polymerization of methyl acrylate (MA), enables the controlled polymerization of MA although to a lesser extent. This study also reveals that the temperature of free radical initiated RAFT (star) polymerization should be chosen in such a way that it is a compromise between reasonable rate of homolysis of the initiator and the CTA (R-group).

Asymmetrical flow field-flow fractionation (AsFIFFF) was used to determine the hydrodynamic particle sizes, molar masses, and phase transition behaviour of various poly(N-isopropylacrylamide) (PNIPAM) samples synthesised by reversible addition--fragmentation chain transfer (RAFT) and conventional free radical polymerisation processes. The results were compared with corresponding data obtained by dynamic light scattering (DLS) and size exclusion chromatography (SEC). Agreement between the three methods was good except at higher molar masses, where the molar mass averages obtained by SEC were much lower than those obtained by AsFIFFF and light scattering. The aggregation of the polymers, which are thermally sensitive, was studied by DLS and AsFIFFF at various temperatures. In deionised water there was an abrupt change in the particle size due to phase separation at approximately equal to 32-35 degrees C. The critical temperatures determined by AsFIFFF were 3-5 degrees C higher than those obtained by DLS.

Diblock copolymers of poly[2-(dimethylamino)ethyl methacrylate]-block-poly[di(ethylene glycol) methyl ether methacrylate], PDMAEMA-b-PDEGMA, were synthesized by reversible addition–fragmentation chain transfer polymerization. The block ratio was varied to study the influence on the lower critical solution temperature and the corresponding phase transition in water. Therefore, turbidimetry, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and laser Doppler velocimetry were applied. Additionally, asymmetric flow field-flow fractionation (AF4) coupled to DLS and multiangle laser light scattering (MALLS) was established as an alternative route to characterize these systems in terms of molar mass of the polymer chain and size of the colloids after the phase transition. It was found that AF4–MALLS allowed accurate determination of molar masses in the studied range. Nevertheless, some limitations were observed, which were critically discussed. The cloud point and phase transition of all materials, as revealed by turbidimetry, could be confirmed by DSC. For block copolymers with block ratios in the range of 50:50, a thermo-induced self-assembly into micellar and vesicular structures with hydrodynamic radii (Rh) of around 25 nm was observed upon heating. At higher temperatures, a reordering of the self-assembled structures could be detected. The thermo-responsive behavior was further investigated in dependence of pH value and ionic strength. Variation of the pH value mainly influences the solubility of the PDMAEMA segment, where a decrease of the pH value increases the transition temperature. An increase of ionic strength leads to a reduction of the cloud point due to the screening of electrostatic interactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 924–935

Well-defined polymers with carbohydrate residues pendant to the main chain (glycopolymers) were prepared by reversible addition fragmentation chain transfer (RAFT) polymerisation. Excellent control over molecular weight and narrow polydispersities (1.1-1.2) were achieved over a range of molecular weights. In addition, efficient synthesis of block copolymers by sequential monomer addition with both hydrophilic and hydrophobic non-carbohydrate blocks was demonstrated. The aqueous solution behaviour of amphiphilic block glycopolymers was investigated, revealing the formation of multivalent carbohydrate-bearing aggregates in solution with the capability for the solubilisation of hydrophobic species (a water-insoluble dye). One such amphiphilic glycopolymer shows by TEM the formation of a worm-like micelle phase. Further investigations of these novel bioactive macromolecular assemblies are underway.

Reversible addition–fragmentation chain transfer (RAFT) polymerization was used to generate well-defined pH-responsive biofunctional polymers as potential ‘smart’ gene delivery systems. A series of five poly(dimethylamino ethyl methacrylate-co-cholesteryl methacrylate) P(DMAEMA-co-CMA) statistical copolymers, with similar molecular weights and varying cholesterol content, were prepared. The syntheses, compositions and molecular weight distributions for P(DMAEMA-co-CMA) were monitored by nuclear magnetic resonance (NMR), solid-state NMR and gel permeation chromatography (GPC) evidencing well-defined polymeric structures with narrow polydispersities. Aqueous solution properties of the copolymers were investigated using turbidimetry and light scattering to determine hydrodynamic diameters and zeta potentials associated with the phase transition behaviour of P(DMAEMA-co-CMA) copolymers. UV-Visible spectroscopy was used to investigate the pH-responsive behaviour of copolymers. Hydrodynamic radii were measured in the range 10–30 nm (pH, temperature dependent) by dynamic light scattering (DLS). Charge studies indicated that P(DMAEMA-co-CMA) polymers have an overall cationic charge, mediated by pH. Potentiometric studies revealed that the buffering capacity and pKa values of polymers were dependent on cholesterol content as well as on cationic charge. The buffering capacity increased with increasing charge ratio, overall demonstrating transitions in the pH endosomal region for all five copolymeric structures. Cell viability assay showed that the copolymers displayed increasing cytotoxicity with decreasing number of cholesterol moieties. These preliminary results show the potential of these well-defined P(DMAEMA-co-CMA) polymers as in vitro siRNA delivery agents.