Synthesis and Aggregation Behaviors of Well‐Defined Thermoresponsive Pentablock Terpolymers With Tunable LCST

A series of thermoresponsive pentablock terpolymers, poly(N‐isopropylacrylamide)‐b‐poly(ethylene oxide)‐b‐poly(propylene oxide)‐b‐poly(ethylene oxide)‐b‐poly(N‐isopropylacrylamide), is prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization. The effect of NIPAM and PPO block lengths on lower critical solution temperature (LCST), critical micelle concentration (cmc), and aggregation number (N_agg) is investigated via UV–Vis spectroscopy and steady‐state fluorescence spectroscopy. The results show that upon increasing the block lengths, LCST and cmc decrease, while N_agg increases. TEM observation shows that associated spherical‐like particles are evidenced below the LCST of the terpolymers, and regular or irregular spherical micelles or even intermicellar aggregates are observed above the LCST.     

Conformational behaviour of linear and crosslinked poly(4-but-3-en-1-ynyl-1-methylpiperidin-4-ol) in solution

The conformational transition expanded coil to compact globule for linear and crosslinked poly(4-but-3-en-1-ynyl-1-methylpiperidin-4-ol), poly{1-[2-(4-hydroxy-1-methyl-4-piperidyl)ethynyl]ethylene}, ( 1 ) in aqueous and aqueous-salt solutions was investigated. The free energy of the conformational transition for linear 1 . n HCl was calculated. It was shown that in aqueous solution 1 is characterized by a lower critical solution temperature (LCST). The collapse of crosslinked 1 on changing the ionization state (aqueous salt solution) and temperature was observed and is similar to a phase transition.     

LCST phase separation in biodegradable polymer blends: poly(D,L‐lactide) and poly(ϵ‐caprolactone)

A lower critical solution temperature (LCST) phase transition is reported for blends of the biodegradable polymers poly(D,L ‐lactide) (PDLA) and poly(ε‐caprolactone) (PCL). From light scattering measurements the cloud point curve is determined to have a critical temperature of 86°C and a critical concentration of mass fraction 36 wt.‐% PCL. Optical microscopy of phase‐separated films indicates a spinodal morphology at the critical concentration, and droplet phases at off‐critical concentrations. After quenching phase separated blends below the melting temperature of PCL (60°C), the crystallization of PCL is used to positively identify PCL‐rich and PDLA‐rich phases. When cystallization of PCL follows LCST phase separation, the size, shape, and distribution of crystalline regions can be adjusted by the degree of PCL/PDLA phase separation. Thus, the LCST phase separation offers a novel method to control microphase structure in biodegradable materials. Applications to control of mechanical and physical properties in tissue engineering scaffolds are discussed in light of the results.     

Hydrogen-bonded polymer gel and its application as a temperature-sensitive drug delivery system

The mixture of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer (F-68) and poly vinyl alcohol (PVA) forms a polymer complex gel by intra/intermolecular interaction via hydrogen bonding in water, which is verified by differential scanning calorimetry. With 30 wt% F-68 aqueous solution and 15 wt% PVA aqueous solution, F-68/PVA complex gel was prepared and its swelling transition was observed at approximately 37 degrees C. Based on the temperature-sensitivity of hydrogen bondings in F-68/PVA complex gel, temperature sensitive drug delivery system has been designed and characterized. For the stability in the aqueous media, F-68/PVA complex gel was prepared with a form of polymeric bead, followed by the encapsulation with poly(lactide-co-glycolide) membrane. With changing the ratio of F-68/PVA, the swelling transition of polymer complex gel was manipulated and pulsatile release of acetoaminophen, used as a model drug, was demonstrated in response to pulsatile change of temperature between 35 degrees C and 40 degrees C.     

NMR Study of Thermoresponsive Block Copolymer in Aqueous Solution

Temperature behavior of D₂O solutions of poly(ethylene oxide) (PEO)₁₁₄‐block‐poly(N‐isopropylacrylamide) (PNIPAm)₁₀₉ is characterized by NMR methods. At temperatures above the lower critical solution temperature (LCST) transition of PNIPAm component, ¹H NMR spectra are consistent with existence of micelles where immobilized PNIPAm blocks form rather compact core and mobile PEO blocks form a shell of micelles. The transition of PNIPAm component shifts toward lower temperatures with increasing polymer concentration. 2D nuclear Overhauser effect spectroscopy spectra which can provide information on proton groups in close spatial contact (<0.5 nm) show an increase in intensity of cross‐peaks between PEO protons and main chain CH and CH₂ protons, and isopropyl CH protons of PNIPAm units after increasing the temperature from 292.7 to 301.6 K. The fact that this change occurs at temperature, which is still below the LCST transition of PNIPAm component evidences certain conformation changes in the PEO‐b‐PNIPAm block copolymer already in the pretransition region.

     

Phase diagram and structural study of polystyrene — poly(ethylene oxide) block copolymers, 1. Systems polystyrene/poly(ethylene oxide)/diethyl phthalate

By means of low angle X-ray scattering and differential scanning calorimetry, we have drawn the phase diagrams of poly(ethylene oxide)-polystyrene block copolymers in the presence of diethyl phthalate as a preferential solvent of polystyrene. Such systems exhibit two liquid-cristalline structures in terms of temperature and solvent concentration. At temperatures below about 50°C, a lamellar structure (LC) with crystallized poly(ethylene oxide) chains exists. Between 50 and about 170°C, we find a structure with melted poly(ethylene oxide) chains. Like for amorphous block copolymers, the type of the latter structure is governed by the copolymer composition. We have shown that in the LC structure, the poly(ethylene oxide) chains crystallize folding in two superposed layers, and we have studied the number of folds and the crystallinity of the poly(ethylene oxide) blocks as a function of solvent concentration, composition and rel. mol. mass of the copolymer, and of the crystallization temperature.     

The Aggregation Behavior of Poly(ethylene oxide)‐Poly(methyl methacrylate) Diblock Copolymers in Organic Solvents

Poly(ethylene oxide)‐poly(methyl methacrylate) and poly(ethylene oxide)‐poly(deuteromethyl methacrylate) block copolymers have been prepared by group transfer polymerization of methyl methacrylate (MMA) and deuteromethyl methacrylate (MMA‐d₈), respectively, using macroinitiators containing poly(ethylene oxide) (PEO). Static and dynamic light scattering and surface tension measurements were used to study the aggregation behavior of PEO‐PMMA diblock copolymers in the solvents tetrahydrofuran (THF), acetone, chloroform, N,N‐dimethylformamide (DMF), 1,4‐dioxane and 2,2,2‐trifluoroethanol. The polymer chains are monomolecularly dissolved in 1,4‐dioxane, but in the other solvents, they form large aggregates. Solutions of partially deuterated and undeuterated PEO‐PMMA block copolymers in THF have been studied by small‐angle neutron scattering (SANS). Generally, large structures were found, which cannot be considered as micelles, but rather fluctuating structures. However, ¹H NMR measurements have shown that the block copolymers form polymolecular micelles in THF solution, but only when large amounts of water are present. The micelles consist of a PMMA core and a PEO shell.     

A DSC study of the miscibility of poly(ethylene oxide)-block-poly(DL-lactide) copolymers with poly(DL-lactide).

The purpose of this study was to examine the miscibility of poly(ethylene oxide)-block-poly(DL-lactide) copolymers with poly (DL-lactide). The copolymers L7E73L7 and L17E78L17 (L = carbonyloxymethylmethylene unit, OCOCH(CH3); E = oxyethylene unit, OCH2CH2) were synthesised by non-catalysed anionic polymerisation and characterised by gel permeation chromatography and 13C NMR. Blends of each of the copolymers with poly(DL-lactide) with compositions over the range from 10 to 90 wt% copolymer were cast as thin films and examined by differential scanning calorimetry (DSC) to determine glass transition temperatures (Tg) and melting temperatures (Tm). The phase diagram showed a region of miscibility above the melting point of the copolymer in the system (approx. 35-40 degrees C). Within this region the system was glassy at low mass fractions of oxyethylene in the copolymer (wE < or = 0.1) and rubbery at higher mass fractions. Below Tm a mechanically compatible glassy blend existed at low wE whilst quenching of systems of higher wE led to phase separation, the biphasic region consisting of crystalline Em-sequences of copolymer separated from non-crystalline poly(DL-lactide). The phase diagram resulting from this study provides the means for the design of drug delivery systems based on blends of poly(DL-lactide) and poly(ethylene oxide)-containing components. The crystal melt boundary can be lowered by the use of block copolymers with short poly(ethylene oxide) blocks permitting the preparation of blends which are miscible at room temperature and rubbery or glassy according to composition.     

Gelation Behavior of Bioabsorbable Hydrogels Consisting of Enantiomeric Mixtures of A–B–A Tri‐block Copolymers of Polylactides (A) and Poly(ethylene glycol) (B)

A–B–A tri‐block copolymers of poly(L ‐lactide) (PLLA: A) and poly(ethylene glycol) (PEG: B) and those of poly(D ‐lactide) (PDLA: A) and PEG (B) were prepared and suspended in saline. Mixing suspensions consisting of the enantiomeric copolymers with identical block compositions induced a temperature‐dependent sol‐to‐gel transition. It was found that the composition window of the copolymers that allowed the spontaneous sol–gel transition around body temperature was considerably narrow, being affected by how easily the PLLA and PDLA blocks of the copolymers can form the stereocomplex in the mixed suspensions. The gelation rate and gel strength also depended on the copolymer composition and concentration at a constant gelation temperature of 37 °C.     

Polyhedral Oligosilsesquioxane (POSS) Nanoparticle Localization in Ordered Structures Formed by Solvated Block Copolymers

The coassembly of polyhedral oligosilsesquioxanes (POSS) of two different surface chemistries is considered, one hydrophilic, poly(ethylene oxide) (PEO), and the other hydrophobic, isobutyl (iB), in cylindrical structures formed by hydrated poly(ethylene oxide)‐poly(propylene oxide)‐poly(ethylene oxide) block copolymer, Pluronic P105 (EO₃₇PO₅₆EO₃₇). Incorporation of PEO‐POSS by replacing an equal mass of water results in an increase in the lattice parameter (d), which is attributed to an increase in the degree of block segregation. In the case of adding PEO‐POSS at a fixed Pluronic P105/water ratio, d ~ φ_polymer^‐0.7, which suggests that PEO‐POSS particles are located inside the hydrated PEO domains. Incorporation of iB‐POSS in the water‐in‐xylene cylindrical structure causes an order‐to‐order phase transition to a bicontinuous cubic structure, which suggests that iB‐POSS decreases the degree of block segregation by locating at the PEO‐PPO interfacial regions. The nanoparticle versus molecule nature of POSS is discussed by comparing POSS effects to those of 10.6 nm diameter deprotonated silica nanoparticles and of glycerol or glucose.

     

Double Hydrophilic Poly(ethylene oxide)‐block‐Poly(dehydroalanine) Block Copolymers: Comparison of Two Different Synthetic Routes

Two different synthetic pathways give access to the amphiphilic block copolymer poly(ethylene oxide)‐block‐poly(tert‐butoxycarbonylaminomethylacrylate). In the first approach, two end‐functionalized segments are linked via click chemistry; and in the second approach, a poly(ethylene oxide) (PEO) based macroinitiator is chain extended via atom transfer radical polymerization (ATRP). In both cases the linking unit consists of an amide group, which is necessary to effectively deprotect the corresponding polymer precursor without cleavage of both segments. For this, amide‐containing ATRP initiators are employed and successful synthesis by nuclear magnetic resonance (NMR) and size exclusion chromatography (SEC) analyses before comparing both pathways is demonstrated. After deprotection, a novel double hydrophilic block copolymer, poly(ethylene oxide)‐block‐poly(dehydroalanine), is obtained, which is investigated using SEC (aqueous and DMSO) and ¹H‐NMR spectroscopy. Containing a potentially zwitterionic PDha segment and a high density of both amino and carboxylic groups, pH‐dependent aggregation of the block copolymer is expected and is studied using dynamic light scattering, revealing interesting solution properties. The corresponding polymers are applied in various areas including drug delivery systems or in biomineralization.     

Competition Between Motion Constraint and Aggregation of Macromolecular Chains in Poly(vinyl methyl ether)/Poly(ethylene oxide) Aqueous Solution During Phase Transition

Resonance light scattering (RLS) technique was applied to study macromolecular entanglements in highly dilute poly(vinyl methyl ether) (PVME)/poly(ethylene oxide) (PEO) solution during phase transition process. Temperature dependences of RLS intensities of PVME, PEO and PVME/PEO solutions were recorded. In addition, simulated temperature dependence of RLS intensity of PVME/PEO solution was drawn supposing there was no interaction between PEO and PVME. Comparison between the measured with the simulated results indicated that there were obvious differences in RLS intensities and transition temperatures. The present work proved the existence of entanglements during phase separation in highly dilute solution. Moreover, a model was proposed to describe the entanglement behavior.     

Tunable Arrangement of Gold Nanoparticles in Epoxidated Poly(styrene‐block‐butadiene) Diblock Copolymer Matrices

A new approach to synthesize block‐copolymer‐mediated/gold nanoparticle (Au NP) composites is developed. Stable and narrowly distributed Au NPs modified with a 2‐phenylethanethiol ligand are prepared by a two‐phase liquid–liquid method. A new epoxidation of a poly(styrene‐block‐butadiene) diblock copolymer, to form poly(styrene‐block‐vinyl oxirane) (PS‐b‐PBO), is achieved through chemical modification. It is found that the Au NPs disperse well in the PS block segment by partially crosslinking the PBO block segment with poly(ethylene oxide bisamine) (D230), a curing agent. The aggregation of Au NPs leads to a red‐shift of the plasmon absorption with the increase in the D230 content. However, without crosslinking the PBO block segment with D230, Au NPs distributes in both the PS and PBO segments.     

Disassembly of Crystalline Platelets of an Amphiphilic Triblock Copolymer Mediated by Varying pH and Organic Diacids

Regulation of crystalline micelles is difficult to achieve because of the strong solidification of crystallization. In this present work, an amphiphilic triblock copolymer poly(ethylene oxide)‐b‐poly(ε‐caprolactone)‐b‐poly(4‐vinylpyridine) (PEO‐b‐PCL‐b‐P4VP) is prepared, in which the P4VP block serves as an H‐bonding acceptor. It is originally self‐assembled into crystalline lamellar micelles in aqueous solution. Subsequently, the effect of varying pH and organic diacids on morphological transition is investigated in detail. Lamellae‐to‐cylinder‐to‐sphere transitions are observed after decreasing the pH or with the addition of organic diacids with different chain spacers. The decreasing pH causes increasing hydrophilicity of the P4VP block, while adding organic diacids results in an increasing corona swelling of the P4VP segment, both of which lead to a decreasing crystallinity of the poly(ε‐caprolactone) core. Consequently, morphological variety changing from lamellar to worm‐like to spherical micelles can be achieved.     

Unexpected Large Depression of VPTT of a PNIPAM Microgel by Low Concentration of PVA

Many low molecular weight and polymeric additives are found to be able to shift the phase transition temperature of poly(N‐isopropylacrylamide) (PNIPAM), however, a large change can only be observed at a high concentration of the additive. Particularly, poly(vinyl alcohol) (PVA), a polymeric additive, can only induce a very small change in the phase transition temperature of PNIPAM, even at a high concentration. Unexpectedly, it is found that a low concentration of PVA can dramatically reduce the volume phase transition temperature (VPTT) of the surface layer of poly(N‐isopropylacrylamide‐co‐2‐acrylamido‐phenylboronic acid) (P(NIPAM‐2‐AAPBA)) microgel. The concentration of PVA is about three orders of magnitude lower than the required concentration for other additives to achieve a comparable decrease in phase transition temperature of PNIPAM. The lowered VPTT cannot be explained by a change in the ionization degree of the PBA groups, or cross‐link density, or hydrophilicity–hydrophobicity balance of the gel. Instead, it is proposed that the adsorption of PVA chains onto the P(NIPAM‐2‐AAPBA) microgel spheres shortens the distance between the PVA and PNIPAM chains, allowing they influence the thermal behavior of PNIPAM more effectively and hence dramatically reducing the phase transition temperature of the latter.     

Synthesis and Characterization of Thermosensitive Poly(N‐Vinyl Caprolactam)‐Grafted‐Aminated Alginate Hydrogels

Thermosensitive hydrogels are characterized by the drastic and reversible change of their physical properties with temperature. Herein is presented the development of a thermosensitive poly(N‐vinylcaprolactam)‐grafted‐aminated alginate (PNVCL‐g‐Alg‐NH₂) having a temperature‐dependent phase transition close to physiological temperature. The hybrid copolymer is formed through the combinational use of chemical and physical methods, that is, carbodiimide chemistry, and ionotrophic gelation by calcium cations. PNVCL‐g‐Alg‐NH₂ exhibits a phase transition at ≈35 °C, and temperature‐dependent water uptake. Copolymerization with PNVCL leads to a decrease in the water uptake of aminated alginate, while improving its thermal stability. Model protein (bovine serum albumin) release from PNVCL‐g‐Alg‐NH₂ scaffolds indicates a higher rate of release below the lower critical solution temperature (LCST) than that of the above, owing to the fact that PNVCL chains collapse at above the LCST and forms a more compact network. In vitro cytotoxicity and hemocompatibility analyses confirm that PNVCL‐g‐Alg‐NH₂ scaffolds are basically non‐cytotoxic and non‐hemolytic.     

Complexation of Amino‐Acid‐Based Block Copolymers With Dual Thermoresponsive Properties and Water‐Soluble Silsesquioxane Nanoparticles

Smart organic–inorganic hybrids are prepared using non‐covalent interactions between water‐soluble silsesquioxane nanoparticles and two amino acid‐based block copolymers prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization. A block copolymer displaying lower critical solution temperature (LCST) and upper critical solution temperature (UCST) is employed, in which only poly(N‐acryloyl‐4‐trans‐hydroxy‐L ‐proline) segment could interact with the nanoparticles, whereas another poly(N‐acryloyl‐L ‐proline methyl ester) segment shows a thermoresponsive property without any interaction. The complexation of another type of dual thermosensitive block copolymer with two different LCSTs and the silsesquioxane nanoparticles is also investigated.     

Counterion‐Mediated Self‐Assembly of Ion‐Containing Block Copolymers on the Basis of the Hofmeister Series

A Cl^? and I^? ion‐containing amphiphilic diblock copolymer [PEO‐b‐P(qVBC‐co‐St)], IBCP , which comprises the poly(ethylene oxide) block and poly(quaternized 4‐vinylbenzyl chloride‐co‐styrene) is prepared by sequence reactions. Then the counterion‐mediated self‐assembly behavior in aqueous solution is investigated in detail. The hydrophilicity of anion containing units (qVBC) is controlled by the nature of the different counterions after ion exchange, which is crucial in regulating the self‐assembly process. The addition of Br^?, I^?, and SCN^? counterions (based on the Hofmeister series) results in the formation of tighter ion‐pairs with cations (i.e., more hydrophobic as the qVBC units), which triggers spheres to vesicles, micro‐meter long cylinders and “branched wormlike” aggregates, respectively. Moreover, addition of different amounts of Cl^? also causes morphological transition from spheres to long cylinders. And this morphological transition is totally reversible after removing additional Cl^?. The adhesive collisions of spherical particles may contribute to the observed sphere‐to‐cylinder morphological transition.     

Supramolecularly Designed Thermoresponsive Polymers in Different Polymer Backbones

Thermoresponsive polymers in water, for example, poly(N‐isopropylacrylamide) (PNIPAM) are investigated extensively, due to a wide range of biomedical applications. However, the attempts to control thermoresponsiveness are still rare in less or nonpolar media. Herein, the three thermoresponsive homopolymers tethering an N‐butylurea group in the side chain with a different polymer backbone are reported. They exhibit lower critical solution temperature (LCST)‐type and upper critical solution temperature (UCST)‐type thermoresponsiveness depending on association of the urea group in the polymer chain and hydrogen bonding small molecules (effectors) in ternary systems (polymer/effector/organic solvent). The difference of polymer backbone appears as their change of solvophobicity in organic solvents. Poly(methacrylate) backbone needs more amount of the effector in nonpolar organic solvents, and poly(vinyl ether) backbone needs more amount in polar organic solvents. However, the influence of polymer backbone is too little to change the phase transition behavior, and the thermoresponsiveness is dominated by association and dissociation of hydrogen bondings between polymers and effectors. The supramolecular design of the thermoresponsive polymers is strong and extensible for the design of their phase transitions.     

Synthesis and Characterization of Amphiphilic Poly(ethylene oxide)‐block‐poly(hexyl methacrylate) Copolymers

We describe the preparation of amphiphilic diblock copolymers made of poly(ethylene oxide) (PEO) and poly(hexyl methacrylate) (PHMA) synthesized by anionic polymerization of ethylene oxide and subsequent atom transfer radical polymerization (ATRP) of hexyl methacrylate (HMA). The first block, PEO, is prepared by anionic polymerization of ethylene oxide in tetrahydrofuran. End capping is achieved by treatment of living PEO chain ends with 2‐bromoisobutyryl bromide to yield a macroinitiator for ATRP. The second block is added by polymerization of HMA, using the PEO macroinitiator in the presence of dibromobis(triphenylphosphine) nickel(II), NiBr₂(PPh₃)₂, as the catalyst. Kinetics studies reveal absence of termination consistent with controlled polymerization of HMA. GPC data show low polydispersities of the corresponding diblock copolymers. The microdomain structure of selected PEO‐block‐PHMA block copolymers is investigated by small angle X‐ray scattering experiments, revealing behavior expected from known diblock copolymer phase diagrams.

SAXS diffractograms of PEO‐block‐PHMA diblock copolymers with 16, 44, 68 wt.‐% PEO showing spherical (A), cylindrical (B), and lamellae (C) morphologies, respectively.