Thermoresponsive Copolymer Research Articles

KCl-Modulated Hydration and Subsequent Thermoresponsive Behavior of Poly(sulfobetaine)-Based Diblock Copolymer Thin Films

The KCl-modulated swelling of double thermoresponsive diblock copolymer (DBC) thin films in D2O atmosphere and their subsequent responsive behavior are investigated via spectral reflectance (SR), in situ time-of-flight neutron reflectometry (ToF-NR), and Fourier-transform infrared (FT-IR) spectroscopy. The copolymer consists of a short zwitterionic (poly(4-(N-(3-methacrylamidopropyl)-N,N-dimethylammonio) butane-1-sulfonate)) (PSBP) block and a long non-ionic poly(N-isopropylmethacrylamide) (PNIPMAM) block. DBC thin films are prepared via spin-coating from solutions containing 5 mM or devoid of KCl. The addition of KCl to the DBC thin films leads to a higher swelling ratio and D2O content during vapor treatment with D2O. Upon the subsequent heating of the hydrated DBC films, the films swell further and reach a maximum thickness before contracting. Two separate volume phase transition temperatures (VPTTs) are observed, namely where a further swelling plateau is reached (VPTTfs), and where contraction starts (VPTTc). Based on complementary SR studies of the effect of KCl on the swelling behavior of the respective PSBP and PNIPMAM homopolymer thin films, we conclude that the “further-swelling” period is mainly a consequence of the UCST-type phase transition of PSBP, whereas the “film contraction” period is due to the LCST-type phase transition of PNIPMAM in thin-film geometry. We observe that KCl reduces the VPTTc of the PNIPMAM blocks. Moreover, the salt migrates or aggregates inside the thin film upon heating, thereby forming a KCl enrichment layer in the intermediate section of the film. Furthermore, the observations by FT-IR prove that macroscopic and mesoscopic D2O absorption and desorption are correlated with the effect of KCl on hydration and de-hydration of the hydrophilic groups.

Thermogels based on biocompatible OEGMA-MEGMA diblock copolymers

A series of biocompatible thermoresponsive copolymers were successfully synthesised via group transfer polymerisation (GTP) from methoxy ethylene glycol methacrylate (MEGMA) and methoxy oligo (ethylene glycol) methacrylate (OEGMA, Mn = 300 g mol -1). Statistical and diblock copolymers with molar mass around 8100 g mol−1 and various compositions were investigated. Specifically, the content in OEGMA and MEGMA was varied from 80 to 20, 70–30, 60–40, to 50–50 w/w%. The thermoresponsive and self-assembly behaviour of the copolymers was investigated throughvisual tests, rheology, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Interestingly, the diblock copolymers with higher MEGMA content were able to form gels at relatively low concentrations (as low as 5% w/w) when increasing the temperature, something that is reported for the first time for linear ethylene glycol based copolymers. A transition of spherical micelle to worm-like micelle was observed in these diblock copolymers that promotes gelation. Furthermore, these in-house synthesised polymers were mixed with Pluronic® F127. It was found that the gelation area of Pluronic® F127 was broadened by the addition of the synthesised copolymers with one formulation, specifically a combination of 12.5% w/w Pluronic® F127 and 12.5% w/w of a statistical OEGMA-co-MEGMA, forming a stable gel from 34 °C to 48 °C that is a desirable temperature range for biological applications. Finally, cell viability experiments were performed for the three most promising diblock copolymers and they were confirmed to be non-toxic.

Responsive polymer thin films

Responsive polymer thin films

Betulin‐containing bioactive amphiphilic copolymers: Synthesis, characterization and self‐assembly

AbstractBetulin, a natural triterpene possessing a wide range of biological activities, has been modified via Steglich esterification to produce a methacrylate derivative capable of participating in radical polymerization. The modification is intended to increase the solubility of betulin, which is almost insoluble in water, by incorporating into the composition of an amphiphilic copolymer. The resulting solubility of betulin in water increased from 8·10−5 mg/mL to more than 10 mg/mL per betulin. For this, well‐defined biocompatible thermoresponsive copolymers with high betulin content have been synthesized through the conventional and RAFT copolymerizations of betulin methacrylate (BeMA) with methoxy oligo(ethylene glycol) methacrylate (MOEGMA). BeMA was more reactive in the BeMA‐MOEGMA pair; the resulting copolymers were slightly enriched with BeMA units (r1 = 1.70, r2 = 0.93). The copolymers exhibited LCST‐type behavior. LCST was tuned by balancing the hydrophobic betulin and hydrophilic OEG fragments. The molecular weight characteristics of polymers and their behavior in aqueous and organic solutions have been studied. Copolymers obtained by conventional polymerization had lower cloud points than RAFT copolymers of the same composition. The copolymers are characterized by low critical micelle concentrations that decrease as the BeMA fraction in the copolymers increases. RAFT copolymers were shown to form unimolecular micelles resistant to dissociation, which is promising for their use in targeted drug delivery.

Proteinosomes via Self-Assembly of Thermoresponsive Miktoarm Polymer Protein Bioconjugates.

To fabricate nanoscale proteinosomes, thermoresponsive miktoarm polymer protein bioconjugates were prepared through highly efficient molecular recognition between the β-cyclodextrin modified BSA (CD-BSA) and the adamantyl group anchored at the junction point of the thermoresponsive block copolymer poly(ethylene glycol)-b-poly(di(ethylene glycol) methyl ether methacrylate) (PEG-b-PDEGMA). PEG-b-PDEGMA was synthesized by the Passerini reaction of benzaldehyde-modified PEG, 2-bromo-2-methylpropionic acid, and 1-isocyanoadamantane, followed by the atom transfer radical polymerization of DEGMA. Two block copolymers with different chain lengths of PDEGMA were prepared, and both self-assembled into polymersomes at a temperature above their lower critical solution temperatures (LCST). The two copolymers can undergo molecular recognition with the CD-BSA and form miktoarm star-like bioconjugates. The bioconjugates self-assembled into ∼160 nm proteinosomes at a temperature above their LCSTs, and the miktoarm star-like structure has a great effect on the formation of the proteinosomes. Most of the secondary structure and esterase activity of BSA in the proteinosomes were maintained. The proteinosomes exhibited low toxicity to the 4T1 cells and could deliver model drug doxorubicin into the 4T1 cells.

Smart Anisotropic Colloidal Composites: A Suitable Platform for Modifying the Phase Transition of Diblock Copolymers by Gold Nanoparticles

Surface modification of metallic nanoparticles (NPs) by stimuli-responsive polymers is a benign method to prepare smart colloidal composites which tune the characteristic properties of individual systems. The temperature-dependent transition of diblock copolymer poly(N-isopropylacrylamide)-block-poly(N-vinylcaprolactam) (PNIPMA-b-PVCL) synthesized using reversible addition-fragmentation chain transfer polymerization was studied by incorporating anisotropic gold NPs (AGPs) such as spheres (AuNSs), rods (AuNRs), cubes (AuNCs), and rhombic dodecahedrals (AuRDs). Shape-dependent physiochemical properties of nanostructures alter the lower critical solution temperature (LCST) of the chemical inhomogeneous diblock copolymer. Heterogeneous nucleation of AuNPs was facilitated by seed-mediated synthesis for incorporating uniformity. In the mixed system, the presence of PNIPAM-b-PVCL modifies the surface of AGPs through physisorption which is supported by transmission electron microscopy and field emission scanning electron microscopy showing the NPs embedding in the polymeric matrix. Furthermore, steady state fluorescence spectroscopy and Fourier transform infrared spectroscopy were performed to examine the phase transition behavior of PNIPAM-b-PVCL in AGPs. The formation of a smart polymer nanocomposite alters the physiochemical properties of the diblock copolymer as demonstrated from the variation of LCST in the dynamic light scattering measurement. Henceforth, functionalizing the surfaces of AGPs with a thermoresponsive diblock copolymer provides combinatorial benefits in the properties of smart polymeric colloidal systems with potential applications in bioimaging and drug delivery.

Radio Wave-Activated Chemotherapy-A Novel Nanoparticle Thermoresponsive Copolymer Drug Delivery Platform.

Radio waves are highly penetrating, non-ionizing, and cause minimal damage to surrounding tissues. Radio wave control of drug release has been achieved using a novel thermoresponsive copolymer bound to a superparamagnetic iron oxide nanoparticle (SPION) core. A NIPAM-acrylamide-methacrolein copolymer underwent a coil-to-globular structure phase change upon reaching a critical temperature above the human body temperature but below hyperthermic temperatures. The copolymer was covalently bound to SPIONs which increase in temperature upon exposure to radio waves. This effect could be controlled by varying input energies and frequencies. For controlled drug release, proteins were bound via aldehyde groups on the copolymer and amine groups on the protein. The radio wave-induced heating of the complex thereby released the drug-bearing proteins. The fine-tuning of the radio wave exposure allowed multiple cycles of protein-drug release. The fluorescent tagging of the complex by FITC was also achieved in situ, allowing the tagging of the complex. The localization of the complex could also be achieved in vitro under a permanent magnetic field.

Synthesis of an original oxazoline based monomer containing a photosensitive azobenzene moiety and investigation of the behavior in solid state, in aqueous and vapor media of a photo and thermo-responsive polyoxazoline copolymer

In this paper, the synthesis of original thermo-sensitive polyoxazoline copolymers, also containing photo-sensitive azobenzene moieties is reported. An original oxazoline monomer containing an azobenzene moiety is first synthesized and then engaged in CROP copolymerization with 2-isopropyl-2-oxazoline. Copolymers with different ratio of azobenzene moieties are then fully characterized. The presence of azobenzene moieties clearly increases the glass transition temperature and decreases the cloud point temperature of the resulting copolymers due to their hydrophobicity. The presence of azobenzene moieties also influences the water uptake capacity of the copolymers. It is also demonstrated that the presence of a few azobenzene moieties increases the water sorption of the copolymer compared to a comparable polyoxazoline homopolymer. Finally, the trans-cis isomerization of the azobenzene moieties under UV radiation is used to tune different properties of the final copolymers such as the glass transition temperature in solid state, the cloud point temperature in aqueous media and the water uptake capacity in vapor state. Thus, thanks to this new photo-sensitive copolymer, it is possible to easily tune various properties with a simple light radiation which can be useful for various applications.

Modifying the Properties of Microemulsion Droplets by Addition of Thermoresponsive BAB* Copolymers.

Oil-in-water (O/W) microemulsions (ME) typically feature a low viscosity and exhibit ordinary viscosity reduction as a function of temperature. However, for certain applications, avoiding or even reverting the temperature trend might be required. This can be conceived by adding thermoresponsive (TR) block copolymers that induce network formation as the temperature increases. Accordingly, various ME-polymer mixtures were studied for which three different block copolymer architectures of BAB*-, B2AB*-, and B(AB*)2-types were employed. Here, "B" represents a permanently hydrophobic, "A" a permanently hydrophilic, and "B*" a TR block. For the TR-block, three different poly(acrylamide)s, namely poly(N-n-propylacrylamide) (pNPAm), poly(N,N-diethylacrylamide) (pDEAm), and poly(N-isopropylacrylamide) (pNiPAm), were used, which all exhibit a lower critical solution temperature. For a well-selected ME concentration, these block copolymers lead to a viscosity enhancement with increasing temperature. At a polymer concentration of about 22 g L-1, the most pronounced enhancement was observed for the pNPAm-based systems with factors up to 3, 5, and 8 for BAB*, B2AB*, and B(AB*)2, respectively. This phenomenon is caused by the formation of a transitory network mediated by TR-blocks, as evidenced by the direct correlation between the attraction strength and the viscosity enhancement. For applications requiring a high hydrophobic payload, which is attained via ME droplets, this kind of tailored temperature-dependent viscosity control of surfactant systems should therefore be advantageous.

Thermo-responsive block copolymers: assembly and application

The review focuses on the assembly and application of five thermo-responsive block copolymers containing one or two thermo-responsive blocks, and aims to provide an overview to guide the design of these copolymers and stimulate more applications.

One-pot catalyst-switching synthesis of thermoresponsive amphiphilic diblock copolymers consisting of poly(N,N-diethylacrylamide) and biodegradable polyesters

A method for the syntheses of thermoresponsive amphiphilic diblock copolymers through sequential organocatalyzed polymerizations using group transfer polymerization (GTP) and ring-opening polymerization (ROP), respectively, is described.

Self-assembly behavior of thermoresponsive difunctionalized γ-amide polycaprolactone amphiphilic diblock copolymers

Thermoresponsive difunctionalized γ-amide polycaprolactone amphiphilic diblock copolymers readily self-assembled to form spherical micelles in phosphate buffered saline.

Bilayer-domain formation of thermoresponsive amphiphilic block copolymers in hybrid liposomes for synthetic molecular channels

Maltopentaose-b-PPO copolymer can be incorporated into phospholipid membranes and form bilayer-domains, where they act as synthetic molecular channels.

Thermoresponsive block copolymers of increasing architecture complexity: a review on structure–property relationships

The position of the monomers within the polymer chain and the 3D structure of the polymer affect the thermoresponsive properties.

Solvent-free, photoinduced block copolymer synthesis from polymerizable eutectics by simultaneous PET-RAFT and ring-opening polymerization in air

We report the preparation of thermoresponsive block copolymers via the simultaneous RAFT polymerization and anionic ring-opening polymerization (ROP) of N-isopropylacylamide and ε-caprolactone respectively, in the absence of traditional solvents.

Stable and Thermo-Responsive Dextran Sulfate-Graft-PNIPAm Amphiphilic Nanoparticles for Potential Target Methotrexate Delivery

Thermo-responsive copolymers grafted with N-isopropylacrylamide (NIPAm) are excellent candidates for drug release. Dextran sulfate (DS) acts as a specific ligand in inflamed regions, turning it highly useful as a target for drug delivery. DS was associated with NIPAm to produce amphiphilic graft copolymers prepared via free radicals. The molar ratio of feed reagents NIPAm/DS varied from 1 (DS-g-PNIPAm) to 4 (DS-g-4PNIPAm). The synthesis was confirmed by spectroscopic techniques (Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR)). All copolymers showed self-organization capacity in an aqueous medium in temperatures higher than 34 °C, and sizes less than 300 nm. DS-g-3PNIPAm exhibited stability in water and in phosphate buffer at pH 7.4. Scanning electron microscopy confirmed their spherical shape. This copolymer showed specificity to leukemic cells, and normal cells’ proliferation. Methotrexate (MTX) is a very low water-soluble drug used for rheumatoid arthritis and cancer. Unfortunately, MTX have severe collateral effects. MTX-loaded nanoparticles can overcome such issues as well as enhance bioactivity and stability. The MTX was encapsulated and delivered from the DS-g-3PNIPAm with potential target delivery due to the presence of DS. Comparison with MTX encapsulated in other nanoparticles reveals that the DS-g-PNIPam presents the best performance among the thermoresponsive and the second among the target MTX nanocarriers.

Linear and nonlinear rheology of liberase-treated breast cancer tumors.

Extracellular matrix (ECM) rigidity has been shown to increase the invasive properties of breast cancer cells, promoting transformation and metastasis through mechanotransduction. Reducing ECM stiffness via enzymatic digestion could be a promising approach to slowing breast cancer development by de-differentiation of breast cancer cells to less aggressive phenotypes and enhancing the effectiveness of existing chemotherapeutics via improved drug penetrance throughout the tumor. In this study, we examine the effects of injectable liberase (a blend of collagenase and thermolysin enzymes) treatments on the linear and nonlinear rheology of allograft 4T1 mouse mammary tumors. We perform two sets of in vivo mouse studies, in which either one or multiple treatment injections occur before the tumors are harvested for rheological analysis. The treatment groups in each study consist of a buffer control, free liberase enzyme in buffer, a thermoresponsive copolymer called LiquoGel (LQG) in buffer, and a combined, localized injection of LQG and liberase. All tumor samples exhibit gel-like linear rheological behavior with the elastic modulus significantly larger than the viscous modulus and both independent of frequency. Tumors that receive a single injection of localized liberase have significantly lower tumor volumes and lower tissue moduli at both the center and edge compared to buffer- and free liberase-injected control tumors, while tissue viscoelasticity remains relatively unaffected. Tumors injected multiple times with LQG and liberase also have lower tissue volumes but possess higher tissue moduli and lower viscoelasticities compared to the other treatment groups. We propose that a mechanotransductive mechanism could cause the formation of smaller but stiffer tumors after repeated, localized liberase injections. Large amplitude oscillatory shear (LAOS) experiments are also performed on tissues from the multiple injection study and the results are analyzed using MITlaos. LAOS analysis reveals that all 4T1 tumors from the multiple injection study exhibit nonlinear rheological behavior at high strains and strain rates. Examination of the Lissajous-Bowditch curves, Chebyshev coefficient ratios, elastic moduli, and dynamic viscosities demonstrate that the onset and type of nonlinear behavior is independent of treatment type and elastic modulus, suggesting that multiple liberase injections do not affect the nonlinear viscoelasticity of 4T1 tumors.

Shape-Shifting Thermoresponsive Block Copolymer Nano-Objects

In this Feature Article, we review our recent progress in the design of shape-shifting thermoresponsive diblock copolymer nano-objects, which are prepared using various hydroxyl-functional (meth)acrylic monomers (e.g. 2‑hydroxypropyl methacrylate, 4‑hydroxybutyl acrylate or hydroxybutyl methacrylate) to generate the thermoresponsive block. Unlike traditional thermoresponsive polymers such as poly(N-isopropylacrylamide), there is no transition between soluble and insoluble polymer chains in aqueous solution. Instead, thermally driven transitions between a series of copolymer morphologies (e.g. spheres, worms, vesicles or lamellae) occur on adjusting the aqueous solution temperature owing to a subtle change in the partial degree of hydration of the permanently insoluble thermoresponsive block. Such remarkable self-assembly behavior is unprecedented in colloid science: no other amphiphilic diblock copolymer or surfactant system undergoes such behavior at a fixed chemical composition and concentration. Such shape-shifting nano-objects are characterized by transmission electron microscopy, dynamic light scattering, small-angle X-ray scattering, rheology and variable temperature 1H NMR spectroscopy. Potential applications for this fascinating new class of amphiphiles are briefly considered.

Novel thermo and ion-responsive copolymers based on metallo-base pair directed host-guest complexation for highly selective recognition of Hg2+ in aqueous solution

The development of materials with highly selective recognition towards Hg2+ is of great significance in environmental monitoring. Herein, a novel thermo-responsive copolymer with Hg2+ recognition property is prepared via thermally-initiated copolymerization of 5′-O-Acryloyl 5-methyl-uridine (APU) and N-isopropylacrylamide (NIPAM). The chemical structure and stimuli-sensitive properties of poly(N-isopropylacrylamide-co-5-methyl-uridine) (P(NIPAM-co-APU)) linear polymers and hydrogel are thoroughly investigated. At the supramolecular level, P(NIPAM-co-APU) linear polymers could respond to both temperature and Hg2+ stimuli with highly selective recognition towards Hg2+ over other 18 metal ion species (at least 5 fold difference) and common anions. Upon capturing Hg2+ by APU units as host metal receptors, the lower critical solution temperature (LCST) of P(NIPAM-co-APU, PNU-7 and PNU-11) linear polymers are significantly shifted more than 10 °C due to the formation of stable APU-Hg2+-APU directed host-guest complexes. Accordingly, at the macroscopic level, P(NIPAM-co-APU) hydrogel display selective and robust recognition of Hg2+ under optimum conditions, and its maximum Hg2+ uptake capacity was 33.1 mg g−1. This work provides a new option for Hg2+ recognition with high selectivity, which could be facilely integrated with other smart systems to achieve satisfactory detection of environmental Hg2+.

Thermoresponsive Self-Healing Zwitterionic Hydrogel as an In Situ Gelling Wound Dressing for Rapid Wound Healing.

It is highly desired yet challenging to fabricate biocompatible injectable self-healing hydrogels with anti-bacterial adhesion properties for complex wounds that can autonomously adapt to different shapes and depths and can promote angiogenesis and dermal collagen synthesis for rapid wound healing. Herein, an injectable zwitterionic hydrogel with excellent self-healing property, good cytocompatibility, and antibacterial adhesion was developed from a thermoresponsive ABA triblock copolymer poly[(N-isopropyl acrylamide)-co-(butyl acrylate)-co-(sulfobetaine methacrylate)]-b-poly(ethylene glycol)-b-poly[(N-isopropyl acrylamide)-co-(butyl acrylate)-co-(sulfobetaine methacrylate)] (PZOPZ). The prepared PZOPZ hydrogel exhibits a distinct thermal-induced sol-gel transition around physiological temperature and could be easily applied in a sol state and in situ gelled to adapt complex wounds of different shapes and depths for complete coverage. Meanwhile, the hydrogel possesses a rapid self-healing ability and can recover autonomously from damage to maintain structural and functional integrity. In addition, the CCK-8 and 2D/3D cell culture experiments revealed that the PZOPZ hydrogel dressing shows low cytotoxicity to L929 cells and can effectively prevent the adhesion of Staphylococcus aureus and Escherichia coli. In vivo investigations verified that the PZOPZ hydrogel could increase angiogenesis and dermal collagen synthesis and shorten the transition from the inflammatory to the proliferative stage, thereby providing more favorable conditions for faster wound healing. Overall, this work provides a promising strategy to develop injectable zwitterionic hydrogel dressings with multiple functions for clinic wound management.