Transition In Aqueous Solutions Research Articles

Hydrogen Bonding-Driven Self-Coacervation of Nonionic Homopolymers for Stimuli-Triggered Therapeutic Release.

Inspired by the unique functionalities of biomolecular membraneless organelles (MLOs) formed via liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) and nucleic acids, a great deal of effort has been devoted to devising phase-separated artificial subcellular dynamic compartments. These endeavors aim to unravel the molecular mechanism underlying the formation and intracellular delivery of susceptible macromolecular therapeutics. We report herein pyroglutamic acid (PGA)-based well-defined homopolymers featuring stimuli-tunable reversible self-coacervation ability. The polymer exhibits an upper critical solution temperature (UCST) transition in aqueous solutions and has the propensity to undergo cooling-induced LLPS, producing micrometer-sized liquid droplets. This phase separation phenomenon could be modulated by various factors, including polymer concentration, chain length, solution pH, and types and concentrations of different additives. These micrometer droplets are thermally reversible and encapsulate a wide variety of cargoes, including small hydrophobic fluorescent molecules, hydrophilic anticancer drugs, and fluorophore-labeled macromolecular proteins (bovine serum albumin and lysozyme). The payloads were released by exploiting the thermo/pH-mediated disassembly behavior of the coacervates, preserving the bioactivity of the sensitive therapeutics. This environmentally responsive, simple yet versatile artificial MLO model system will provide insights into the biomolecular nonionic condensates and pave the way for the de novo design of dynamic biomolecule depots.

Study of the Thermal Phase Transition of Poly(N,N-diethylacrylamide-co-N-ethylacrylamide) Random Copolymers in Aqueous Solution.

N-alkyl-substituted polyacrylamides exhibit a thermal coil-to-globule transition in aqueous solution driven by an increase in hydrophobic interactions with rising temperature. With the aim of understanding the role of N-alkyl substituents in the thermal transition, this study focuses on the molecular interactions underlying the phase transition of poly(N,N-diethylacrylamide-co-N-ethylacrylamide) random copolymers. Poly(N,N-diethylacrylamide) (PDEAm), poly(N-ethylacrylamide) (PNEAm), and their random copolymers were synthesized by free radical polymerization and their chemical structure characterized spectroscopically. It was found that the values of the cloud-point temperature increased with PNEAm content, and particle aggregation processes took place, increasing the negative charge density on their surface. The cloud-point temperature of each copolymer decreased with respect to the theoretical values calculated assuming an absence of interactions. It is attributed to the formation of intra- and interchain hydrogen bonding in aqueous solutions. These interactions favor the formation of more hydrophobic macromolecular segments, thereby promoting the cooperative nature of the transition. These results definitively reveal the dominant mechanism occurring during the phase transition in the aqueous solutions of these copolymers.

Synthesis and characterization of polysaccharide carbamates and mixed carbamates with tunable water solubility

Polysaccharide derivatives with two types of functionalities were synthesized; reactive groups for click-chemistry approaches and groups that can tune the water solubility of the products. Xylan phenylcarbonates (XPCs) and cellulose phenylcarbonates (CPCs) with degrees of substitution (DS) ranging from 0.6 to 3.0 were prepared as starting materials. In a modular synthesis approach, these carbonate derivatives were converted with different amines to obtain functional xylan carbamates (XCs) and cellulose carbamates (CCs) with (i) reactive alkynyl- or furfuryl groups and / or (ii) hydrophilic hydroxyalkyl or tertiary amino groups. Both types of functionalities were introduced separately or simultaneously in a convenient one-pot-approach. Mixed polysaccharide carbamates with low, intermediate, and high DS values (0.6 to 2.5) were successfully prepared and characterized. The water solubility of the carbamates and mixed carbamates was tuned by variation of the type and DS of the two hydrophilic substituents. Surprisingly, some of the products showed lower or upper critical solution temperatures (LCSTs, UCSTs). Thus, the thermoreversible phase transition in aqueous solutions was studied. The products obtained in this work are very promising for the preparation of hydrogels through selective covalent crosslinking as well as for the fabrication of thermoresponsive biomaterials.

Temperature response behavior of poly(1-vinyl-3-methylimidazole dimethyl phosphate-co-N-isopropylacrylamide) in aqueous and ester solutions driven by hydrogen bonding

A series of poly(1-vinyl-3-methylimidazole dimethyl phosphate-co-N-isopropylacrylamide) oligomers was synthesized by reversible addition-fragmentation chain transfer polymerization. The co-oligomers exhibited a pH-tunable lower critical solution temperature (LCST) phase transition in aqueous solutions. By changing the pH of the aqueous solution (HCI), the hydrogen bonding between the internal molecules of the co-oligomers and water molecules was weakened, which effectively reduced the cloud-point temperature. Poly(1-vinyl-3-methylimidazole dimethyl phosphate-co-N-isopropylacrylamide) oligomers exhibit an upper critical solution temperature (UCST) type of phase transition in an ester solution, which is associated with the formation and breaking of hydrogen bonds within the co-oligomers molecules. FT-IR analysis revealed the effect of temperature on hydrogen bonding between the functional groups. Energy decomposition, Electrostatic Potential (ESP), Atoms-in-Molecules (AIM), and Interaction region indicator (IRI) analyses demonstrated the presence of hydrogen bond donors N–H and imidazole ring C–H, and hydrogen bond acceptors C = O and P = O in the co-oligomers. The sites of hydrogen bonding between the co-oligomers and the solvent molecules as well as intermolecular forces were found to be the main factors contributing to the LCST/UCST-type phase transition.

Chlorophyllin-Containing Copolymers and Their Responsive Properties.

Copper-chlorophyllin is a water-soluble derivative of chlorophylls and shows low cytotoxicity and antimutagenic properties in cultured cells. It has multiple applications, including its use as a photosensitizer in photothermal therapy because of its green light-activated photothermal performance. In this work, it was copolymerized with a poly(ethylene glycol) methacrylic monomer to yield random copolymers by free radical polymerization, which showed dual temperature- and pH-dependent phase transitions in aqueous solutions. The cloud points of the copolymer solutions were raised by lowering the pH of the aqueous solutions due to the protonation of the carboxylic groups on the chlorophyllin moieties, which decreased the overall hydrophilicity of the polymers. At low pH values, complete protonation of the carboxylic acid groups of the chlorophyllin moieties led to an irreversible aggregation of the copolymers in water. The incorporation of chlorophyllin in the copolymer improved its stability over its single molecular form.

Nanoscale Structural Phase Transitions in Aqueous Solutions of Organic Molecules

Adiabatic compressibility βS of the 4-methylpyridine + water solution is investigated in a wide concentration and temperature variation interval using Mandelstam–Brillouin scattering spectroscopy. The adiabatic compressibility minimum caused by the microinhomogeneous structure of the solution is experimentally established at the concentration of 0.06 molar fractions of 4-methylpyridine in the solution. The results of the investigations allow the construction of a diagram of possible states caused by a continuous three-dimensional hydrogen bond network of water. The results of experimental study of the excessive hypersound absorption in acetone + water and 3-methylpyridine + water solutions are discussed based on the conclusions of the theory of high-frequency sound scattering near the critical point (developed by Chaban) and the Landau theory. These results are described within the framework of the Landau and Chaban theories and explained by the existence of two different states with minimum thermodynamic stability in the solution.

Modification of Thermoresponsive Poly(<i>N</i>-Isopropylacrylamide) End-Group with Hydrophilic and/or Hydrophobic Compounds Tuned the LCST

Poly (N-isopropylacrylamide) (PNIPAAm) is one of the most well-known thermoresponsive polymers that exhibits a reversible coil-to-globule transition in aqueous solution at lower critical solution temperature (LCST) (32°C). PNIPAAm behave as an extended coil form in an aqueous solution below the LCST, meanwhile, above the LCST, it shrinks into a globule form. The LCST of PNIPAAm could be tune when it is chemically modified with hydrophilic and/or hydrophobic compound. In this study, modifications of PNIPAAm end-group with maleimide or phenyl maleimide compounds were prepared and their LCST behaviours were investigated. One end-group of synthesized poly (N-isopropylacrylamide)-chain transfer agent (PNIPAAm-CTA) was modified with maleimide or phenyl maleimide compound through aminolysis reaction to form PNIPAAm-Maleimide (PNIPAAm-M) and PNIPAAm-Phenyl maleimide (PNIPAAm-PhM). Maleimide is a hydrophilic compound, and phenyl maleimide is a slight hydrophobic compound were used in this study. The modification with hydrophilic compound will higher the LCST of PNIPAAm. The slight hydrophobic of phenyl maleimide compound will decrease the LCST. In this study, the successfulness of aminolysis process of PNIPAAm-CTA were determined through the fourier transform infrared (FTIR). Moreover, the LCST behavior of PNIPAAm-CTA, PNIPAAm-M and PNIPAAm-PhM were determined through light scattering intensity analysis. The results indicated that upon heating the solutions of PNIPAAm-CTA, PNIPAAm-M and PNIPAAm-PhM in 10 mM HEPES solution pH 7.4 at 25°C–40°C, PNIPAAm-CTA, and PNIPAAm-PhM solutions started to increase their light intensities at 35°C and PNIPAAm-M at 36°C, respectively. To conclude, modification of PNIPAAm end-group with hydrophobic and/or hydrophilic compound could tune their LCST.

Supramolecular Surface Coatings with Acetylated Polyrotaxane-Based Triblock Copolymers for Thermal Regulation of Cell Adhesion and Fabrication of Cell Sheets.

Polyrotaxanes (PRXs) containing acetylated α-cyclodextrins exhibit a temperature-dependent phase transition in aqueous solutions across their lower critical solution temperature (LCST) of approximately 26.6 °C. To gain insights into the interactions of acetylated PRXs (Ac-PRXs) with biological components, thermoresponsive supramolecular surfaces were prepared by coating tissue culture polystyrene (TCPS) surfaces with Ac-PRX triblock copolymers, and their surface properties across the LCST were evaluated. The wettability and protein adsorption of Ac-PRX-coated surfaces changed significantly between 10 and 37 °C, whereas the uncoated TCPS and unmodified PRX-coated surfaces did not alter the wettability and protein adsorption at 10 and 37 °C. The adhesion, proliferation, morphology, and adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces were found to be similar to those of the uncoated and unmodified PRX-coated surfaces. However, the adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces decreased drastically at 10 °C. Consequently, the cells spontaneously detached from the Ac-PRX-coated surfaces without enzymatic treatment. Additionally, when incubating confluent cells at 10 °C, the cells detached from Ac-PRX-coated surfaces as cell sheets while retaining extracellular matrix proteins. The findings of this study provide new directions for the design of thermoresponsive supramolecular biointerfaces for applications in bioseparation and cell manipulation.

Synthesis of a Degradable Hydrogel Based on a Graft Copolymer with Unexpected Thermoresponsiveness

AbstractIncorporating multiple pyridyl disulfide (PDS) moieties into polymer chains allows the fabrication of a chemically cross‐linked hydrogel through the rapid thiol–disulfide exchange reaction. By aminolysis in the presence of 2,2′‐dithiodipyridine (DTP), the end groups of polymers synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization can readily be converted into PDS‐groups. In this contribution, a RAFT‐synthesized graft copolymer with thermoresponsive poly[di(ethylene glycol) methyl ether methacrylate] forming the backbone and hydrophilic poly(N,N‐dimethylacrylamide) as the side chains is presented. The copolymer chains exhibit surprisingly a two‐step lower critical solution temperature transition in aqueous solutions. After modification of the end groups of the backbone and side chains, the PDS‐terminated chains can react with a dithiol cross‐linker to form a thermoresponsive hydrogel. In a reducing environment, the cleavable disulfide linkages lead to on‐demand dissolution of the hydrogel. The resulting thiol‐terminated chains undergo a reversible sol–gel transition in response to redox variations, expanding the potential application areas of such a polymer system.

Synthesis of Thermoresponsive Diblock Copolymer Nano-Objects via RAFT Aqueous Emulsion Polymerization of Hydroxybutyl Methacrylate

We recently reported that the reversible addition–fragmentation chain transfer (RAFT) aqueous emulsion polymerization of hydroxybutyl methacrylate (HBMA) using a relatively short non-ionic poly(glycerol monomethacrylate) (PGMA) precursor enables convenient preparation of diblock copolymer nano-objects with spherical, worm-like, or vesicular morphologies. We postulated that the relatively high aqueous solubility of HBMA (∼25 g dm–3 at 50 °C) was likely to be a key parameter for overcoming the problem of kinetically trapped spheres that is observed for many RAFT aqueous emulsion polymerization formulations. In this study, we revisit the RAFT aqueous emulsion polymerization of HBMA using a poly(ethylene glycol) (PEG) precursor as a steric stabilizer block. Remarkably, the resulting PEG45–PHBMA20 diblock copolymer nanoparticles exhibit thermoreversible morphological transitions in aqueous solution. More specifically, transmission electron microscopy and small-angle X-ray scattering studies confirmed that spheres are formed at 25 °C, worms at 58 °C, and vesicles at 65 °C. This is the first time that such behavior has been reported for nano-objects prepared by RAFT aqueous emulsion polymerization. Moreover, variable temperature dynamic light scattering and oscillatory rheology studies confirmed that these transitions are highly reversible at 0.1 and 10% w/w, respectively. Variable temperature 1H NMR studies indicated that (i) the PEG stabilizer block undergoes dehydration on heating and (ii) the apparent degree of hydration of the hydrophobic PHBMA block increases on heating from 25 to 65 °C. This suggests that the change in copolymer morphology is best explained in terms of a uniform plasticization mechanism.

Association with Imidazole in the Cooperative Order-Disorder Transition in Aqueous Solution of Schizophyllan.

Schizophyllan, a triple helical polysaccharide, exhibits cooperative order-disorder transition (CODT) in aqueous solutions. The transition transforms the ordered structure (triple helix I) formed between the branched side chains and solvent molecules into the disordered structure (triple helix II) without dissociation of the triple helix. The CODT behaviors in H2O-imidazole mixtures containing HCl with different molar ratios of imidazole/HCl were investigated by adiabatic calorimetry and differential scanning calorimetry on two schizophyllan solutions with different molar masses. The transition temperature (Tr) and the transition enthalpy (ΔHr) significantly depended on both of the mole fractions of imidazole and imidazole/HCl. The composition dependences of Tr and ΔHr in H2O-imidazole mixtures were analyzed with linear cooperative transition theory for the solvent-stabilizing effect in the mixture with active compounds. Theoretical analyses confirmed that both imidazole and imidazolium ions in the solutions competitively interact with the side chain of the triple helix.

Thermoresponsive polymers in non-aqueous solutions

Polymers does not only show phase transition in aqueous solutions but they also do in organic solvents, which is the focus of this review article.

Zwitterionic nanogels with temperature sensitivity and redox-degradability for controlled drug release

Zwitterionic polymers play an attractive role in the application of stealthy nanocarriers for their excellent antifouling property. Herein, a zwitterionic nanogel with temperature sensitivity and redox-responsive degradability prepared by copolymerization of N-vinylcaprolactam (VCL) and 2-(methacryloyloxy) ethyldimethyl-(3-sulfopropyl) ammonium hydroxide (DMAPS) via aqueous precipitation polymerization. The prepared nanogels own ultra-high colloidal stability and non-specific protein adsorption resistance as a result of the incorporation of zwitterionic groups. Meanwhile, they exhibit sensitive temperature-induced swelling/collapse transition in aqueous solution and excellent redox-degradability ascribed to the presence of disulfide bonds. The nanogels loaded with anticancer drug doxorubicin (DOX) exhibit low leakage of DOX under physiological conditions (merely 23.8 % within 24 h), whereas striking release amount of DOX under reducing conditions combined with elevated temperature (93.4 % within 24 h). The measurement of cell viability showed that the cytotoxicity of blank nanogels to tumor cells (HeLa cells) was negligible, while the nanogels loaded with DOX had a prominent inhibitory impact on tumor cells.

Phase diagrams of temperature-responsive copolymers p(MEO2MA-co-OEGMA) in water

Random copolymers of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) have a temperature-induced phase transition in aqueous solutions, which can be tuned for different temperatures from ca. 20 °C to 90 °C, by changing their monomer ratio. Here, we explore a novel approach combining UV–Vis measurements (light scattering) with standard and modulated-temperature differential scanning calorimetry (DSC), to obtain the phase diagrams of copolymers with different compositions over an unprecedented wide concentration range (0.7–800 mg/mL). We used three copolymers synthesized by RAFT polymerization with very low size dispersity, and containing 6, 8 and 11 mol% of OEGMA. The change in their phase transition temperature with concentration show that they reach different lower critical solution temperature (LCST) in the concentration interval 20–30 mg/mL. Our results offer new insights on the influence of concentration, in particular for high concentrations, on the temperature, the reversibility and the kinetics of the phase transition. This information can be used to assist the design of copolymers with predetermined temperature response.

Searching for Aquamelt Behavior among Silklike Biomimetics during Fibrillation under Flow.

In this paper, we elucidate a generic mechanism behind strain-induced phase transition in aqueous solutions of silk-inspired biomimetics by atomistic molecular dynamics simulations. We show the results of modeling of homopeptides polyglycine Gly30 and polyalanine Ala30 and a heteropeptide (Gly-Ala-Gly-Ala-Gly-Ser)5, i.e., the simplest and yet relevant sequences that could mimic the behavior of natural silk under stress conditions. First, we analyze hydrophobicities of the sequences by calculating the Gibbs free energy of hydration and inspecting the interchain hydrogen bonding and hydration by water. Second, the force-extension profiles are scanned and compared with the results for poly(ethylene oxide), the synthetic polymer for which the aquamelt behavior has been proved recently. Additionally, the conformational transitions of oligopeptides from coiled to extended states are characterized by a generalized order parameter and by the dependence of the solvent-accessible surface area of the chains on applied stretching. Fibrillation itself is surveyed using both the two-dimensional interchain pair correlation function and the SAXS/WAXS patterns for the aggregates formed under stress. These are compared with experimental data found in the literature on fibril structure of silk composite materials doped with oligoalanine peptides. Our results show that tensile stress introduced into aqueous oligopeptide solutions facilitates interchain interactions. The oligopeptides display both a greater resistance to extension as compared to poly(ethylene oxide) and a reduced ability for hydrogen bonding of the stretched chains between oligomers and with water. Fiber formation is proved for all simulated objects, but the most structured one is made of a heteropeptide (Gly-Ala-Gly-Ala-Gly-Ser)5: For this sequence, we obtain the highest degree of the secondary structure motifs in the fiber. We conclude that this is the most promising candidate among considered sequences to find the aquamelt behavior in further experimental studies.

The solution-gel phase transition in aqueous solutions of agarose

Thermal hysteresis and stability of agarose–water gelling systems were studied by the spectrophotometer for different concentrations at different temperatures. Gelation temperature depends on the concentration of agarose. With the increase in the concentration of agarose gelation temperature, strength of agarose increases too. With the increase in the concentration of polymer solvent–gel phase transition, gel melting happens at higher temperatures. The price of enthalpy was determined (150.0127 KC/mol). In gelation process, the phase separation is completed and in this process, the value of this [Formula: see text] equally increases.

Molecular Weight-Dependent, Flexible Phase Behaviors of Amphiphilic Block Copolymer/Additive Complexes in Aqueous Solution.

Pluronic amphiphilic block copolymers, well known to have a phase behavior can be controlled by external conditions, have a wide range of potential for applications such as nanotemplates or nanobuilding blocks. However, the phase behaviors of Pluronic block copolymer/additive complexes with highly ordered phases have not been fully investigated. Here, we report the unusual molecular weight-dependent self-assembly of Pluronic block copolymer/additive complexes. Depending on the temperature and additive, Pluronic P65 block copolymer with a lower molecular weight showed the closed loop-like (CLL) phase behavior with the disorder-order-disorder-order phase transition in aqueous solution, whereas Pluronic P105 and P85 block copolymers with higher molecular weights underwent highly ordered continuous phase transitions with face centered cubic (FCC), hexagonal, and lamellar phases. It is expected that the specific phase behavior of the block copolymer/additive complex can be applied in optical devices such as nanotemplates or optical sensors for a highly ordered superlattice. Furthermore, this study provides a new route to control the phase behavior of the block copolymers without a complicated process.

Temperature sensitive self-assembling hydroxybutyl chitosan nanoparticles with cationic enhancement effect for multi-functional applications

Hydroxybutyl chitosan (HBC) with different degree of substitution (DS) were prepared using a homogeneous reaction system (KOH/urea), which could achieve temperature-dependent reversible morphological transition in aqueous solution. During hydrophobic assembly, amino groups on HBC chains exposed on the surface of nanoparticles formed a poly-cationic structure. The structure of HBCs was characterized by FTIR, 13C NMR, XRD, TGA and rheology. The morphology and assembly mechanism of HBC nanoparticles were studied by TEM, AFM and DLS. Also, the results of coagulation, bacteriostatic, superoxide anion clearance and anionic contaminant removal tests suggested that HBC nanoparticles had excellent flocculation and removal effect of anionic composites. Moreover, the cytocompatibility test indicated that HBC could effectively promote proliferation and division of mouse fibroblast, mouse embryonic fibroblast and rat bone marrow mesenchymal stem cells. These cationic HBC nanoparticles exhibited great potential in multi-functional applications.

Protoporphyrin IX copolymer with poly(ethylene glycol) methacrylate and its thermoresponsive properties

Porphyrins and their derivatives have been widely used in catalysis, energy conversion, photonics, and biomedicine; however, their use in biological applications is restricted by their limited solubility in aqueous systems. We have prepared a water-soluble copolymer containing moieties of naturally occurring protoporphyrin IX using direct copolymerization of a poly(ethylene glycol) (PEG) methacrylate monomer with protoporphyrin IX via free-radical polymerization. The content of protoporphyrin IX in the copolymer was determined by 1H NMR and UV–vis absorption spectroscopies. Their solution properties and the photostability of the protoporphyrin IX moiety in the copolymer provide direct evidence of the covalent incorporation of protoporphyrin IX within the copolymer. The copolymer showed a reversible phase transition in aqueous solution due to the lower critical solution temperature (LCST). The phase transition temperature varies with the pH of the solutions because of the protonation of the carboxylic acid groups. This copolymer may be useful as an alternative thermoresponsive material for biomedical applications.

Concentration Dependences of Macromolecular Sizes in Aqueous Solutions of Albumins

On the basis of experimental data for the shear viscosity in the aqueous solutions of ovine serum albumin and using the cellular model describing the viscosity in aqueous solutions, the concentration dependences of the effective radius of ovine serum albumin macromolecules in the aqueous solutions within a concentration interval of 3.65–25.8 wt% and a temperature interval of 278–318 K at the constant pH = 7.05 are calculated. The concentration and temperature dependences of the effective radii of ovine, bovine, and human serum albumin macromolecules are compared. It is shown that they are partially similar for the solutions of ovine and human serum albumins within concentration intervals of 0.12–0.49 vol% and 0.18–0.48 vol%, respectively, provided an identical acid-base balance (pH) in those solutions. The following conclusions are drawn: (i) the concentration dependences of the effective radii of structurally similar macromolecules of various albumins are similar, but provided an identical pH, and (ii) the dependence of the volume concentration of aqueous albumin solutions on the temperature at the constant radius of a macromolecule confirms the hypothesis about the existence of a dynamic phase transition in aqueous solutions at a temperature of 42 ∘C, at which the thermal motion of water molecules significantly changes.