The Temperature‐Responsive Nanoassemblies of Amphiphilic Random Copolymers Carrying Poly(siloxane) and Poly(oxyethylene) Pendant Chains

Novel amphiphilic random copolymers carrying poly(oxyethylene) and poly(siloxane) pendant chains are synthesized by atom transfer radical polymerization starting from either a fluorescent, julolidine‐based initiator, or a nonfluorescent initiator. For both copolymer systems, dynamic light scattering measurements carried out on aqueous solutions as a function of temperature reveal the occurrence of a sharp and fully reversible transition between two different self‐associative states of individual, single‐chain self‐folded nanoassemblies, so‐called unimer micelles, (D_h = 8–10 nm) and collapsed multichain aggregates (D_h = 700–1400 nm) at a critical temperature T_c. Covalently linked julolidine terminal and added ethidium bromide are separately used as fluorescent probes and both prove the temperature‐dependence of the different self‐association of the copolymers in water.     

Molecular Dynamics of Amphiphilic Random Copolymers in the Bulk: A 1H and 19F NMR Relaxometry Study

A set of amphiphilic random copolymers of poly(ethylene glycol) methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) with different compositions synthesized by atom transfer radical polymerization (ATRP) is investigated by ¹H and ¹⁹F NMR relaxometry. In particular, a thorough investigation of T₁ and T₂ relaxation times at variable temperature and copolymer composition provides the first complete and detailed characterization of the dynamics of both the main chain backbone and the side chains of the PEGMA‐co‐FA copolymers. The results highlight an intramolecular segregation of rigid main chain and mobile side chains, and an additional self‐assembling of the PEGMA and FA side chains into distinct nanodomains, driven by the hydrophobic interactions between FA side chains. The obtainment and observation of nanoscale phase separation in random copolymers is a promising achievement to the aim of controlling self‐assembly in the bulk by suitably modulating copolymers composition, which can open novel avenues to easier fabrications and applications in nanotechnologies.     

Thermo‐responsive Poly(methyl methacrylate)‐block‐poly(N‐isopropylacrylamide) Block Copolymers Synthesized by RAFT Polymerization: Micellization and Gelation

Summary: RAFT polymerization was used to prepare PMMA‐b‐PNIPAM copolymers. Two different chain transfer agents, tBDB and MCPDB, were used to mediate the sequential polymerizations. Micellar solutions and gels were prepared from the resulting copolymers in aqueous solution. When heated above T_c of PNIPAM (about 31 °C), DLS revealed that PNIPAM coronas collapsed, resulting in aggregation of the original micelles. The micellar gels underwent syneresis above T_c as water was expelled from the ordered gel structure, the lattice periodicity of which was determined by SANS. A large decrease in lattice spacing was observed above T_c. The gel became more viscoelastic at high temperature, as revealed by shear rheometry which showed a large increase in G″.

     

Study of the compatibility of poly[(styrene)‐co‐ (4‐vinylbenzoic acid)] with poly[(ethyl methacrylate)‐co‐(4‐vinylpyridine)] blends

Binary systems of poly[(ethyl methacrylate)‐co‐(4‐vinylpyridine)] (12.5 mol‐%), PEMAVP‐13, with poly[(styrene)‐co‐4‐(vinylbenzoic acid)] (3.5, 6.5 and 7.4 mol‐%), PSVBA, are investigated by differential scanning calorimetry and Fourier transform infrared spectroscopy. The calorimetric results show that PEMAVP‐13 is miscible with the three PSVBA copolymers in the studied proportions of 2 : 1, 1 : 1 and 1 : 2 by weight. The thermogram of each mixture shows a single composition‐dependent glass transition temperature, T_g. The experimental value of T_g for each blend is higher than the calculated weight average T_g of its components. Such a positive deviation implies the presence of strong specific interactions within these blends. A comparison of the determined Kwei q‐value reveals an increase of the specific interactions with acidic units in PSVBA composition. Fourier transform infrared measurements in the carbonyl stretching vibration region show the occurrence of hydrogen bonding involving the carboxylic acid groups of PSVBA with the carbonyl groups of PEMAVP‐13.     

Activation Energy for Dissociation of Hydrogen‐Bonding Crosslinkers in Phase‐Change Salogels: Dynamic Light Scattering versus Rheological Studies

Dissociation energy of dynamic bonds in thermoresponsive phase‐change salogels is explored using rheology and dynamic light scattering (DLS). The salogels are formed by polyvinyl alcohol (PVA) reversibly crosslinked by hydrogen‐bonding amine‐terminated molecules in an inorganic phase‐change material—lithium nitrate trihydrate (LNH) salt—as a solvent. The crosslinker geometry (linear vs branched) has a strong effect on both the gelation temperature (T_gel) and the crosslinker to polymer ratio at which the gelation occurs. Due to their higher functionality, dendritic crosslinkers are more efficient gelators as compared to their linear counterparts, inducing PVA gelation at a lower concentration of a crosslinker and resulting in salogels with higher T_gel. Both stress relaxation and DLS data can be fitted by the exponential functions with temperature‐independent exponents of ≈0.5 and 2, respectively. For the first time, it is reported that the crosslinker dissociation activation energy determined from the rheological stress relaxation time and DLS slow mode decay time are in very good agreement, comprising ≈130–140 kJ mol^?1 for salogels with both linear and dendritic crosslinkers.     

Hydrolyzed Poly(2‐plenyl‐2‐oxazoline)s in Aqueous Media and Biological Fluids

Hydrolyzed poly(2‐phenyl‐2‐oxazoline)s (PPhOx) are synthesized by partial hydrolysis of PPhOx in order to produce self‐assembling copolymers with chargeable and hydrophobic units. The resulting poly(ethylene imine‐co‐2‐phenyl‐2‐oxazoline) [P(EI‐co‐PhOx)] amphiphilic copolymers contain phenyl‐oxazoline and ethylene imine segments in a random sequence and their chemical structure is confirmed by ¹H NMR and attenuated total reflection‐Fourier transform infrared spectroscopy. Static and dynamic light scattering experiments show that in aqueous solutions the random copolymers associate into aggregates of sizes in the range between 50 and 200 nm depending on the solution conditions and hydrophobic content. The positive charge of the nanoaggregates that is caused by protonation of the amine nitrogen is confirmed by zeta potential measurements. Self‐assembly in phosphate buffered saline results in large aggregates. The aggregates are proved to interact with fetal bovine serum proteins. This investigation shows that hydrolyzed phenyl oxazoline‐based copolymers provide stable amphiphilic nanoparticles able to interact with biological macromolecules for biotechnological and pharmaceutical applications.     

Thermoresponsive Reversible Unimer Micelles of Amphiphilic Fluorinated Copolymers

Amphiphilic fluorinated copolymers PEGMAx-co-FAy and TEGMAx-co-FAy are prepared by activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP). All polymers present a reversible thermoresponsive lower critical solution temperature-type behavior, and a cloud point temperature (T_c) in the range of 30–60 °C strictly dependent on the length of the oxyethylene side chain, the content of the hydrophobic counits, and the concentration of the solution. Combined small angle X-ray scattering (SAXS) and dynamic light scattering measurements are used to study the self-assembly behavior in water, organic solvents (tetrahydrofuran [THF] and dimethylformamide [DMF]), and a fluorinated solvent (hexafluorobenzene [HFB]). SAXS confirms the formation of compact-globular single-chain self-folded unimer micelles in water below T_c, which generally presents small hydrodynamic diameters (D_h ≤ 8 nm) as a result of the folding of the hydrophobic perfluorohexylethyl acrylate counits. The copolymers are also able to form reverse unimer micelle in HFB. The copolymers are not able to self-assemble in unimer micelles in THF or DMF solutions, in which they adopt conventional random coil conformations.     

Thermally Stable and Well‐Defined Pentadiene‐Derived Copolymers Prepared by Anionic Alternating Copolymerization and Subsequent Controlled Postmodification

Thermally stable and well‐defined hydrocarbon polymers prepared via anionic alternating copolymerization of 1,3‐pentadiene (P monomer: trans (TP) and cis (CP) mixture) and styrene derivatives (S monomer: styrene (St) and 1,1‐diphenylethylene (DPE)) and subsequent hydrogenation and cationic cyclization modifications are reported. The TP/S/CP terpolymerization reveals that an incorporation of S‐alt‐CP sequence into the alternating chain is more favorable, while the S‐alt‐TP insertion is also possible especially under high temperature owing to their competitive energy barriers and thermodynamic properties. Then the resultant copolymers with equimolar amount of the two monomers and predominant linear units are intramolecularly cyclized with CF₃SO₃H, or hydrogenated with p‐toluenesulfonyl hydrazide, to afford soluble and thermally stable hydrocarbon polymers with controlled Mns and narrow ?_Ms. The T_g of cylized polymer increases dramatically (ΔT_g > 100 °C) on cyclization between the adjacent C?C bond in the P structure and the aromatic ring of S unit through the intramolecular Friedel–Crafts alkylation. On the other hand, the T_g of hydrogenated product slightly decreases (ΔT_g ≈ 10 °C) after 98% hydrogenation due to the increasing flexibility of the saturated main‐chain, while the Td increases about 60 °C due to the loss of C?C bonds under oxygen atmosphere.     

N‐Isopropylacrylamide/2‐Hydroxyethyl Methacrylate Star Diblock Copolymers: Synthesis and Thermoresponsive Behavior

Summary: Tri‐arm star diblock copolymers, poly(2‐hydroxyethyl methacrylate)‐block‐poly(N‐isopropylacrylamide) [P(HEMA‐b‐NIPAAm)] with PHEMA and PNIPAAm as separate inner and outer blocks were synthesized via a two‐step ATRP at room temperature. The formation, molecular weight and distribution of polymers were examined, and the kinetics of the reaction was monitored. The PDI of PHEMA was shown to be lower, indicating well‐controlled polymerization of trifunctional macro‐initiator and resultant star copolymers. The thermoresponsive behavior of diblock copolymer aqueous solution were studied by DSC, phase diagrams, temperature‐variable ¹H NMR, TEM and DLS. The results revealed that introducing a higher ratio of HEMA into copolymers could facilitate the formation of micelles and the occurrence of phase transition at lower temperatures. TEM images showed that I‐(HEMA₄₀‐NIPAAm₃₂₀)₃ solutions developed into core‐shell micelles with diameters of approximately 100 nm. I‐(HEMA₄₀‐NIPAAm₃₂₀)₃ was used as a representative example to elucidate the mechanism underlying temperature‐induced phase transition of copolymer solution. In this study we proposed a three‐stage transition process: (1) separately dispersed micelles state at ≈17–22 °C; (2) aggregation and fusion of micelles at ≈22–29 °C; (3) sol‐gel transition of PNIPAAm segments at ≈29–35 °C, and serious syneresis of shell layers.

Molecular architecture of Poly(HEMA‐b‐NIPAAm).     

Crystalline Structure and Thermal Behavior of Water‐Soluble Copolymers with Pendant Terthiophenes

The water‐soluble copolymers having pendant terthiophene, poly(AA3T‐co‐AA), were synthesized by radical copolymerization of [(2,2′ : 5′,2′′‐terthiophen‐5‐yl)methyl acrylate] (AA3T) and acrylic acid (AA), and their molecular structures and thermal behaviors were studied. X‐ray diffraction study showed that the copolymers containing a certain amount of AA3T can form the crystals with monolayer structure, while incorporation of too many AA units into the copolymers disrupted this structure. Possible mechanism of self‐doping on heating was discussed in terms of interaction between AA3T unit with AA unit in the copolymers.     

One‐Step Preparation of Reduction‐Responsive Biodegradable Polymers as Efficient Intracellular Drug Delivery Platforms

Reduction‐responsive biodegradable polymeric micelles based on functional 2‐methylene‐1,3‐dioxepane (MDO) copolymers are developed and investigated for triggered doxorubicin (DOX) release. The MDO‐based copolymers P(MDO‐co‐PEGMA‐co‐PDSMA) are synthesized via the simple one‐step radical ring‐opening copolymerization of MDO, poly(ethylene glycol) methyl ether methacrylate (PEGMA), and pyridyldisulfide ethylmethacrylate (PDSMA). The copolymers can self‐assemble to form micelles in aqueous solution. DOX, a model anticancer drug, is loaded into the micelles with the drug loading content (DLC) of 11.3%. The micelles can be disassembled under a reductive environment (10 × 10^?3m glutathione), which results in a triggered drug release behavior. The glutathione‐mediated intracellular drug release of DOX‐loaded micelles is investigated against A549 cells. Confocal laser scanning microscopy (CLSM) results demonstrated that DOX‐loaded micelles exhibits faster drug release in glutathione monoester (GSH‐OEt)‐pretreated A549 cells, compared with untreated and buthionine sulfoximine (BSO)‐pretreated A549 cells. Based on the facile synthetic strategy, the reduction‐sensitive biodegradable micelles with triggered intracellular drug release are promising for anticancer drug delivery.

     

Synthesis of Amphiphilic Poly(ethylene oxide‐co‐glycidol)‐graft‐polyacrylonitrile Brush Copolymers and their Self‐assembly in Aqueous Media

An amphiphilic copolymer brush poly(ethylene oxide‐co‐glycidol)‐graft‐polyacrylonitrile [poly(EO‐co‐Gly)‐g‐PAN], is successfully prepared for the first time by a combination of anionic polymerization and redox free radical polymerization. The final products and intermediates are characterized by NMR and GPC. Aggregates made from the brush copolymers, poly(EO‐co‐Gly)‐g‐PAN, with a long hydrophobic graft length in water are studied by TEM and DLS. The effects of hydrophobic graft length and water content on the morphologies are discussed. Some rare morphologies of aggregates are observed, such as lamellae, bicontinuous networks, bowls or nanosheets, and large compound rods with a brittleness that can be ascribed to the orientation of high content semi‐crystalline PAN segments.     

Synthesis,Characterization and In Vitro Cytotoxicity of Poly[(5‐benzyloxy‐trimethylene carbonate)‐co‐(trimethylene carbonate)]

The ring‐opening copolymerization of 5‐benzyloxy‐trimethylene carbonate (BTMC) with trimethylene carbonate (TMC) was described. The polymerization was carried out in bulk at 150°C using stannous octanoate as initiator. The influence of reaction conditions such as polymerization time and initiator concentration on the yield and molecular weight of the copolymers were investigated. The poly(BTMC‐co‐TMC)s obtained were characterized by FT‐IR, ¹H NMR, ¹³C NMR, GPC and DSC. NMR results of copolymer showed no evidence for decarboxylation occurring during the propagation. The relationship between the copolymer glass transition temperature and composition was in agreement with the Fox equation. The in vitro cytotoxicity studies of the poly(BTMC‐co‐TMC) (50 : 50) using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay demonstrated that the copolymer has low cytotoxicity compared to poly[(lactic acid)‐co‐(glycolic acid)] (75 : 25).     

Temperature and pH Dual‐Responsive Behavior of Dendritic Poly(N‐isopropylacrylamide) with a Polyoligomeric Silsesquioxane Core and Poly(2‐hydroxyethyl methacrylate) Shell

Novel temperature and pH dual‐responsive dendritic polyoligomeric silsesquioxane (POSS)–poly(N‐isopropylacrylamide) (PNIPAm)–poly(2‐hydroxyethyl methacrylate) (PHEMA) copolymers are prepared via atom transfer radical polymerization and click reactions. The cloud points (T_c) decrease with decreasing pH from 10.0 to 5.0 due to the weakened inter‐molecular interactions and enhanced intra‐molecular hydrogen bonding, whereas the T_c exhibits a small increase from pH 5.0 to 4.0 because of the better solvation of PHEMA at highly acidic conditions. The above findings are corroborated by the different sizes of aggregates observed by dynamic light scattering. The encapsulation of a fluorescent dye and stimulated release by temperature and pH changes are also demonstrated.     

Synthesis of Amphiphilic Comb‐Shape Copolymers Via Ring‐Opening Polymerization of a Macromonomer

Amphiphilic comb‐shape copolymers PCL‐co‐P(MTC‐mPEG₁₆) (where PCL, MTC, and mPEG refer to poly(ε‐caprolactone), 2‐methyltrimethylene carbonate, and methoxy poly(ethylene glycol), respectively) are synthesized by ring‐opening polymerization of ε‐caprolactone and cyclic carbonate‐terminated PEG macromonomer (MTC‐mPEG₁₆) with benzyl alcohol as an initiator and Sn(Oct)₂ as a catalyst. Amphiphilic copolymers PCL‐co‐P(MTC‐mPEG₁₆) can form micelles in aqueous solution by self‐assembly. The diameters of PCL‐co‐P(MTC‐mPEG₁₆) micelles characterized by dynamic light scattering area few dozens of nanometers with a narrow size distribution and the morphology of the micelles observed through transmission electron microscopy are nanosized spheres. The in vitro drug release of comb‐shape copolymer PCL‐co‐P(MTC‐mPEG₁₆) micelles is more stable and sustained than that of linear block copolymers mPEG‐b‐PCL.

     

Effects of A‐B Block Copolymer Additives on Interfacial Tension of A/B Polymer Blends Near the Critical Temperature: Comparison of Mean‐Field Calculations with Experiments

A simple square‐gradient theory (SGT) for the interfacial tension of homopolymer‐A/homopolymer‐B blends with A‐B diblock copolymer additives near the critical solution temperature, T_c, has been proposed to describe the experimental finding that, as the temperature changes away from T_c, the interfacial tension γ increases, and then decreases, exhibiting a maximum. Dynamic mean‐field calculations (DMF) of a self‐consistent field treatment are also performed to describe it and are compared with those of the proposed SGT. Both of SGT and DMF reasonably describe the γ‐maximum behavior and the additive‐concentration dependence of the location of γ‐maximum in γ‐T relation. Agreements of SGT with DMF results are quite satisfactory, although SGT, in general, gives thinner adsorbed layers of block copolymers than those evaluated by DMF.     

Fiber‐Like Micelles from the Crystallization‐Driven Self‐Assembly of Poly(3‐heptylselenophene)‐block‐Polystyrene

The crystallization‐driven self‐assembly (CDSA) of crystalline‐coil polyselenophene diblock copolymers represents a facile approach to nanofibers with distinct optoelectronic properties relative to those of their polythiophene analogs. The synthesis of an asymmetric diblock copolymer with a crystallizable, π‐conjugated poly(3‐heptylselenophene) (P3C7Se) block and an amorphous polystyrene (PS) coblock is described. CDSA was performed in solvents selective for the PS block. Based on transmission electron microscopy (TEM) analysis, P3C7Se₁₈‐b‐PS₁₂₅ formed very long (up to 5 μm), highly aggregated nanofibers in n‐butyl acetate (nBuOAc) whereas shorter (ca. 500 nm) micelles of low polydispersity were obtained in cyclohexane. The micelle core widths in both solvents determined from TEM analysis (≈ 8 nm) were commensurate with fully‐extended P3C7Se₁₈ chains (estimated length = 7.1 nm). Atomic force microscopy (AFM) analysis provided characterization of the micelle cross‐section including the PS corona (overall micelle width ≈ 60 nm). The crystallinity of the micelle cores was probed by UV–vis and photoluminescence (PL) spectroscopy and wide‐angle X‐ray scattering (WAXS).     

Thermoresponsive Properties of Sugar Sensitive Copolymer of N‐Isopropylacrylamide and 3‐(Acrylamido)phenylboronic Acid

Summary: The copolymer of N‐isopropylacrylamide and 3‐(acrylamido)phenylboronic acid (82:18, = 47 000 g · mol^?1) was prepared by free radical polymerization. The copolymer showed typical thermal precipitation behavior in aqueous solutions, its precipitation temperature (T_P) being increased from 23 to 32 °C by increasing the pH from 6.5 to 9.7, because of ionization of the phenylboronate units. The pK_a was evaluated as 8.9 ± 0.1 from the effect of pH on T_P. At pH > 9, i.e., in the anionic form of the copolymer, T_P was affected by a very low concentration of glucose (5.6 μM , ΔT_P = 1–1.5 °C), because of complex formation with a high binding constant. At a higher concentration of polyols (560 μM , pH > 8) the increase of T_P was maximal for the copolymer complexes with fructose (7–10 °C) and decreased in the order: fructose > glucose ≈ mannitol > pentaerythritol > galactose > Tris >glycerol. Di‐ and oligosaccharides (lactose, sucrose, and dextran) caused a slight increase of T_P at pH 7.5–8.7 while no effect was observed at pH > 9. Isothermal dissolution of the copolymer suspension in water (27 °C, pH 8.5) was possible in the presence of fructose or mannitol but required higher concentrations (1.4–3.6 × 10³ μM ) as compared to those which enabled the shift of T_P in the soluble copolymer. The dissolution rate increased with fructose concentrations.

Effect of pH on T_P of poly(NIPAAM‐co‐AAPBA) in the presence of various monosaccharides.     

pH‐Responsive Double‐Hydrophilic Block Copolymers: Synthesis and Drug Delivery Application

A novel double‐hydrophilic block copolymer P(MEO₂MA‐co‐OEGMA)‐b‐PAMA has been successfully synthesized by two‐step RAFT polymerization. Then, the amino groups of PAMA blocks in the copolymers react with 1‐pyrenecarboxaldehyde via a “Schiff‐base” reaction, and the resulting copolymers are self‐assembled to form spherical micelles in aqueous solution. Because the “Schiff‐base” linkage is pH sensitive, the release rate of pyrene depends upon the pH of solution. Complete release is achieved at pH 1, and the control release is much faster at pH 5.5 than that at pH 7.4. With progress of pyrene release, the micelles are disassembled gradually and disappeared completely at last. This double‐hydrophilic copolymer is a promising candidate of drug carrier for the aldehyde‐ containing hydrophobic drugs.     

Emulsion Self‐Assembly Synthesis of Chitosan/Poly(lactic‐co‐glycolic acid) Stimuli‐Responsive Amphiphiles

An amphiphilic graft copolymer using chitosan (CS) as a hydrophilic main chain and poly(lactic‐co‐glycolic acid) (PLGA) as a hydrophobic side chain is prepared through an emulsion self‐assembly synthesis. CS aqueous solution is used as a water phase and PLGA in chloroform is served as an oil phase. A water‐in‐oil (W/O) emulsion is fabricated in the presence of the surfactant span‐80. The self‐assembly reaction is performed between PLGA and CS under the condensation of EDC. Fourier transform IR (FTIR) spectroscopy reveals that PLGA is grafted onto the backbone of CS through the interactions between end carboxyl and amino groups of the two components. ¹H NMR spectroscopy directly indicates the grafting content of PLGA in the CS‐graft‐PLGA (CS‐g‐PLGA) copolymer is close to 25%. X‐ray diffraction (XRD) confirms that the copolymer exhibits an amorphous structure. The CS‐g‐PLGA amphiphile can self‐assemble to form micelles with size in the range of ≈100–300 nm, which makes it easy to apply in various targeted‐drug‐release and biomaterial fields.