Studies on thermoresponsive polymers:Phase behaviour,drug delivery and biomedical applications

The present review aims to highlight the applications of thermoresponsive polymers.Thermo-responsive polymers show a sharp change in properties upon a small or modest change in temperature.This behaviour can be utilized for the preparation of so-called‘smart’drug delivery systems,which mimic biological response behaviour to a certain extent.Such materials are used in the development of several applications,such as drug delivery systems,tissue engineering scaffolds and gene delivery.Advances in this field are particularly relevant to applications in the areas of regenerative medicine and drug delivery.This review addresses summary of the main applications of thermoresponsive polymers which are categorized based on their 3-dimensional structure;hydrogels,interpenetrating networks,micelles,films and particles.The physico-chemical behaviour underlying the phase transition is also discussed in brief.

Poly(NIPAM-co-MPS)-grafted multimodal porous silica nanoparticles as reverse thermoresponsive drug delivery system

Hybrid drug delivery systems(DDS) have been prepared by grafting poly(NIPAM-co-MPS) chains on multimodal porous silica nanoparticles having an inner mesoporous structure and an outer thin layer of micropores. The hybrid thermoresponsive DDS were fully characterized and loaded with a model drug. The in vitro drug release tests are carried out at below and above the lower critical solution temperature(LCST) of the copolymer. The results have revealed that due to the presence of small diameter(~1.3 nm) micropores at the periphery of the particles, the collapsed globules of the thermoresponsive copolymer above its LCST hinders the complete release of the drug which resulted in a reverse thermoresponsive drug release profile by the hybrid DDS.

Synthesis of Thermoresponsive Poly( diethyleneglycol methacrylate-co-6-Ovinyladipoyl-D-glucopyranose) Glycopolymer via RAFT Polymerization

The monomer 6-O-vinyladipoyl-D-glucopyranose( VAG)was synthesized by lipase catalyzed trans-esterification of divinyladipate with D-glucopyranose. A novel double hydrophilic glycopolymer poly( diethyleneglycol methacrylate-co-6-Ovinyladipoyl-D-glucopyranose)( P( DEGMA-co-VAG)) with narrow polydispersity( PDI) and thermosensitivity was prepared by reversible addition-fragmentation chain transfer( RAFT)polymerization. P( DEGMA-co-VAG) was characterized by1 H NMR,FTIR and gel permeation chromatography( GPC). The characterization of UV-visible spectroscopy showed that the micelles from glycopolymer P( DEGMA-co-VAG) were thermo-responsive and the low critical solution temperature( LCST) could be controlled by the molar ratio of monomers. When the molar ratio of DEGMA and VAG was 2∶ 1,the LCST of P( DEGMA-co-VAG) was36 ℃ in aqueous solution,which could form nano micelles in the human body environment. It was found that P( DEGMA-co-VAG)was non-toxic at 0. 1-1 mg / m L concentrations when incubated with pig iliac endothelial cells( PIECs) for 24 h. Thus,the synthesized glycopolymers has great potential as drug delivery carriers.

Reversible isomerization of donor-acceptor Stenhouse adduct derivatives in water through dendritic confinement

Modulating reversible isomerization of hydrophobic dyes in aqueous solutions is greatly desired. Here we report on reversible isomerization of solvatochromic donor-acceptor Stenhouse adducts(DASAs) in water through the confinement from dendritic oligoethylene glycols(OEGs). Dendronization of DASAs with dendritic OEGs affords them characteristic thermoresponsiveness. These dendronized DASAs spontaneously isomerize in water from hydrophobic linear state into hydrophilic cyclic state at room temperature due to the strong hydration. However, hydrophobic microenvironment through thermally dehydration and collapse of the dendritic OEGs at elevated temperatures confines hydration of the DASA moieties and mediates their interactions with the collapsed hydrophobic OEG domains, affording their isomerization recovery in water efficiently from the hydrophilic cyclic state into the hydrophobic linear state. The confinement-mediated reversible isomerization of DASA moieties in water can be repeated through alternative photo-irradiation and thermal dehydrations, exhibiting excellent fatigue resistance.

In situ thermoresponsive supramolecular assembly for switchable circularly polarized luminescence

The dynamic regulation of circularly polarized luminescence(CPL)holds profound significance in various fields,such as highlevel information storage and encryption.Here we developed a chiral amphiphilic molecule,CPSB-GLU-PEG350(CGP),composed of aggregation-induced emission(AIE)chromophores(Z)-4-(1-cyano-2-phenylvinyl)benzoic acid(CPSB),a chiral linker Glutamic acid and polyethylene glycol(PEG)thermoresponsive segments.Within the self-assembled supramolecular system formed by CGP,we have achieved in-situ temperature-responsive chiral structures,facilitating the thermal control switch of the CPL signal.Molecular dynamics simulations demonstrate the distinct behaviors of AIE and PEG units during the temperature-variable assembly process.Furthermore,by co-assembling achiral dye molecules with CGP,we have expanded the color range of the temperature-responsive CPL assembly system in situ and confirmed the occurrence of circularly polarizedF?rster resonance energy transfer(C-FRET)phenomenon in this process,which successfully enriched the strategies for in-situ CPL control in aqueous phases.In addition,the contactless radiative energy transfer of CPL can also be realized in this system,exhibiting more flexible temperature regulation of the CPL signal.This study provides a convenient and universal strategy for the construction of dynamically smart chiroptical materials.

Fluorescent Nile blue-functionalized poly(N-isopropylacrylamide)microgels responsive to temperature and polyamines

Fluorescent poly(N-isopropylacrylamide-co-Nile blue)(pNIPAm-co-NB)microgels were synthesized that exhibited fluorescence intensity changes in a water temperature-dependent fashion.NB is well known to exhibit fluorescence intensity that depends on the hydrophobicity of the environment,while pNIPAm-based microgels are well known to transition from swollen(hydrophilic)to collapsed(relatively hydrophobic)at temperatures greater than 32℃;hence,we attribute the above behavior to the hydrophobicity changes of the microgels with increasing temperature.This phenomenon is ultimately due to NB dimers(relatively quenched fluorescence)being broken in the hydrophobic environment of the microgels leading to relatively enhanced fluorescence.We went on to show that the introduction of cucurbit[7]uril(CB[7])into the pNIPAm-co-NB microgels enhanced their fluorescence allowing them to be used for polyamine(e.g.,spermine[SPM])detection.Specifically,CB[7]forms a host–guest interaction with NB in the microgels,which prevents NB dimerization and enhances their fluorescence.When SPM is present,it forms a host–guest complex that is favored over the CB[7]-NB host–guest interaction,which frees the NB for dimerization and leads to fluorescence quenching.As a result,we could generate an SPM sensor capable of SPM detection down to~0.5µmol/L in complicated matrixes such as serum and urine.

Visualized thermoresponsive helix-helix switch of polyphenylacetylene with a wide-range tunable transition temperature

Polymers with tunable helicity and naked-eye structural change under external stimuli are valuable for fabricating smart materials. Herein, we report a novel thermoresponsive color and fluorescent polyphenylacetylene switch with a tunable critical temperature. It relies on the temperature and solvent sensitivity of intramolecular n→π* interactions between the vicinal carbonyl groups of ester substituents located at 3,5-positions, which are indispensable for forming the cis-cisoid helical conformation of polyene backbones. In a properly chosen solvent, a compressed cis-cisoid helix is stabilized by n→π* interactions at low temperatures and yields a colorless solution. Increasing temperature causes the conformational transition toward an extended cis-transoid helix due to the disruption of n→π* interactions and produces a yellow solution. Reducing the hydrogen bond donating ability or polarity of solvents increases the switching temperature. By introducing a fluorogenic pendant, this conformational transition can also be read out by fluorescence quenching. This work may open a new window for developing intelligent materials through precisely tuning conformational transitions.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer

Reversal of cancer drug resistance remains a critical challenge in chemotherapy.Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer.To overcome the intrinsic limitations in conventional mitochondrial targeting strategies,we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin(DOX)resistance in lung cancer.Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors.As a consequence,thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice.This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

Spectral Insights into Microdynamics of Thermoresponsive Polymers from the Perspective of Two-dimensional Correlation Spectroscopy

Generalized two-dimensional correlation spectroscopy （2DCOS） and its derivate technique, perturbation correlation moving window （PCMW）, have found great potential in studying a series of physico-chemical phenomena in stimuli-responsive polymeric systems. By spreading peaks along a second dimension, 2DCOS can significantly enhance spectral resolution and discern the sequence of group dynamics applicable to various external perturbation-induced spectroscopic changes, especially in infrared （IR）, near-infrared （NIR） and Raman spectroscopy. On the basis of 2DCOS synchronous power spectra changing, PCMW proves to be a powerful tool to monitor complicated spectral variations and to find transition points and ranges. This article reviews the recent work of our research group in the application of 2DCOS and PCMW in thermoresponsive polymers, mainly focused on liquid crystalline polymers and lower critical solution temperature （LCST）-type polymers. Details of group motions and chain conformational changes upon temperature perturbation can thus be elucidated at the molecular level, which contribute to the understanding of their phase transition nature.

Thermoresponsive Fluorescent Semicrystalline Polymers Decorated with Aggregation Induced Emission Luminogens

Thermoresponsive fluorescent polymers(TFPs) with unique temperature-dependent luminescent properties are of great importance for the development of new functional devices in recent years. Herein, we facilely synthesized an efficient blue-emissive polymer, abbreviated as PCB-TPE, using tetraphenylethene(TPE) as the main building block. PCB-TPE is thermally stable with a novel property of aggregation induced emission(AIE). The thermoresponsive property and mechanism of PCB-TPE were investigated. Its emission shows temperature-dependent features and reveals fine details in the thermal transitions from-10 °C to 60 °C. The polymer offers a platform for the development of efficient luminescent materials for further biological and optoelectronic applications.

The E3 ligase XBAT35 mediates thermoresponsive hypocotyl growth by targeting ELF3 for degradation in Arabidopsis

Plants are capable of coordination of their growth and development with ambient temperatures.EARLY FLOWERING3(ELF3), an essential component of the plant circadian clock, is also involved in ambient temperature sensing, as well as in inhibiting the expression and protein activity of the thermoresponsive regulator phytochrome interacting factor4(PIF4). The ELF3 activity is subjected to attenuation in response to warm temperature;however,how the protein level of ELF3 is regulated at warm temperature remains less understood. Here, we report that the E3 ligase XB3 ORTHOLOG 5 IN ARABIDOPSIS THALIANA, XBAT35, mediates ELF3 degradation. XBAT35 interacts with ELF3 and ubiquitinates ELF3. Loss-of-function mutation of XBAT35 increases the protein level of ELF3 and confers a short-hypocotyl phenotype under warm temperature conditions. Thus, our findings establish that XBAT35 mediates ELF3 degradation to lift the inhibition of ELF3 on PIF4 for promoting thermoresponsive hypocotyl growth in plants.

Preparation and Characterization of Thermoresponsive Hyperbranched Polyethylenimine with Plenty of Reactive Primary Amine Groups

Certain amount of primary amine （NH2） groups of hyperbranched polyethylenimine （HPEI） was first protected by Boc groups. Subsequently, the residual reactive amine groups were reacted with isobutyric anhydride to introduce isobutyramide （IBAm） groups to HPEI. Finally, Boc groups were deprotected to result in HPEI-IBAm-NH2 with 18% of primary amine terminals on the periphery and 80% of IBAm terminal groups （abbreviated as HPEI-IBAm0.80-NH2）. 1H-NMR characterization proved the successful preparation of the product in each step. Compared with its spatial isomer HPEI- IBAm0.8o without primary amine groups, IH-NMR spectra verified that more IBAm groups were located in the interior of HPEI-IBAm0.80-NH2. The further modification of HPEI-IBAmo.so-NH2 and HPEI-IBAmo.8o with p-nitrobenzaldehyde demonstrated that HPEI-IBAm0.so-NH2 was more reactive than HPEI-IBAm0.80 due to its possession of primary amines. Turbidimetry measurements showed that HPEI-IBAm0.80-NH2 was thermoresponsive in water. In the pH range of 9.5-10 its cloud point temperature （Top） was constant, and it increased obviously upon decreasing the pH below 9.5. The thermoresponsive HPEI-IBAmo.8 exhibited the similar trend, but the pH threshold to achieve the constant Top was around 8.5. Moreover, HPEI-IBAm0.8-NH2 showed higher Top and broader phase transition than HPEI-IBAm0.8. The mechanism leading to the different thermoresponsive properties between HPEI-IBAm0.8-NH2 and its spatial isomer HPEI-IBAm0.8 was discussed.

Rechargeable quasi-solid-state aqueous hybrid Al^(3+)/H^(+) battery with 10,000 ultralong cycle stability and smart switching capability

Safe and long lifespan batteries facilitate the development of portable electronics and electric vehicles.Owing to the low-cost,naturally abundance,and trivalent charge carrier of aluminum with the highest theoretical volumetric capacity,rechargeable aqueous aluminum-ion-based batteries are considered as promising next-generation secondary batteries.However,traditional electrolytes and frequent collapse of the host structure of electrode materials greatly jeopardize the cycle stability of the batteries.Here,we develop a novel hydrogel-based electrolyte coupled with stable layered intercalation electrodes for the first time to fabricate a highly safe and flexible rechargeable hybrid Al^(3^(+))/H^(+)battery.The as-fabricated hybrid-ion battery(HIB)delivers a high specific capacity of 125 mAh·g^(−1) at 0.1 A·g^(−1) and exhibits an unprecedented super long-term cycling stability with no capacity fading over 10,000 cycles at 2 A·g^(−1).In addition,the hydrogel-based electrolyte possesses smart function of thermoresponsive switching,which can effectively prevent thermal runaway for the batteries.The unprecedented long cycle stability,highly intrinsic safety as well as low-cost indicate that the flexible aqueous HIBs are promising for applications.

Dynamic materials fabricated from water soluble pillar[n]arenes bearing triethylene oxide groups

Pillar[n]arenes are a new kind of supramolecular macrocyclic hosts which have developed rapidly due to their unique topology and high functionality, giving rise to many applications in the construction of interesting and functional materials. Among them, water-soluble pillar[n]arenes bearing triethylene oxide (TEO) chains have drawn increasing research interest due to their advantageous properties. In this review, we summarized the recent progress of dynamic materials fabricated from water soluble pillar[n]arenes bearing TEO groups, including thermo responsive materials with lower critical solution temperature (LCST) behavior, cyclic host liquids, and smart windows. It is anticipated that more and more ‘smart' supramolecular materials based on modified pillar[n]arenes will be developed in this burgeoning area of research.

“Several birds with one stone”strategy of pH/thermoresponsive flame-retardant/photothermal bactericidal oil-absorbing material for recovering complex spilled oil

Although many material designs or strategic methods have been proposed for treating oil spills and oily wastewater,the complex oily state,dealing with the harsh operating conditions of oil–water separation(such as the recovery of viscous spilled crude oil,bacteria-containing oily wastewater,and removal of spilled oil under fire),and the autorecycling of oil and absorption materials remain a great challenge.This work proposed an ingenious design strategy of“several birds with one stone”to prepare p H/thermoresponsive flame-retardant/photothermal bactericidal P-Fe_(3)O_(4)-polydopamine(PDA)@melamine–formaldehyde(MF)foams.This design makes the foams remarkably effective in the recovery of spilled viscous crude oil as well as in the separation of bacteria-containing oily emulsions,particularly for instant fire extinguishing by magnetically controlled oil absorption as well as for fire alarms.The photothermal effect and p H response induce a change in the surface wettability of the foams,facilitating excellent autoadsorption/desorption of the spilled oil.The photothermal bactericidal activity and fouling resistance of the foam are beneficial to the separation of bacteria-containing oily wastewater.Outstanding flame-retardant properties and maneuverable magnetic control enable the foam to rapidly recover the spilled oil in a large range of fires,extinguish fires instantly,and facilitate early fire warning.The proposed strategy is expected to inspire further research on treating oil spills under complex conditions.

In-situ polymerization for mechanical strong composite actuators based on anisotropic wood and thermoresponsive polymer

Stimuli-responsive hydrogels hold an irreplaceable statue in intelligent actuation materials because of their reversible stretchability and excellent biocompatibility.However,the poor mechanical performance and complicated fabrication process of anisotropic structures severely limit their further applications.Herein,we report a high-strength thermoresponsive wood-PNIPAM composite hydrogel actuator with complex deformations,through a simple in-situ polymerization.In this composite hydrogel actuator,the anisotropic wood and the thermoresponsive PNIPAM hydrogel hydroel can work together to pro-vide bending and even other complex deformations.Owing to strong interfacial interaction,this actuator perfectly realized the combination of good mechanical properties(∼1.1 MPa)and fast actuation speed(∼0.9 s).In addition,by adjusting the orientation direction of wood,this actuator can achieve various complex deformations.Such composite hydrogel actuator could be a good candidate for intelligent appli-cations,such as intelligent actuators,smart valves,manipulators and even soft robots.

Micellization and Gelation of the Double Thermoresponsive ABC-type Triblock Copolymer Synthesized by RAFT

A double thermoresponsive ABC-type triblock copolymer （poly（ethyleneglycol）-block-poly （2-（2-methoxyethoxy）ethyl methacrylate）-block-poly（2-（2-methoxy ethoxy） ethyl methacrylate-co-oligo（ethylene glycol） methyl ether methacrylate, PEG-b-PMEO2MA-b-P（MEO2MA-co-OEGMA）） was designed and synthesized by reversible addition- fragmentation chain transfer polymerization （RAFT）. The ABC-type triblock copolymer endowed a thermal-induced two- step phase transition at 29 and 39 ℃corresponding to the thermosensitive properties of PMEOzMA and P（MEO2MA-co- OEGMA） segments, respectively. The two-step self-assembly of copolymer solutions was studied by UV transmittance measurement, dynamic light scattering （DLS）, transmission electron microscopy （TEM） and so on. The triblock copolymers showed the distinct thermosensitive behavior with respect to transition temperatures, aggregate type and size, which was correlated to the degree of polymerization of thermosensitive blocks and the molar fraction of OEGMA in the P（MEO2MA- co-OEGMA） segments. In addition, micelles could further aggregate to form the hydrogel by the self-associate of PEG chains under the abduction of the concentration and temperature. The transition from sol to gel was investigated by a test tube inverting method and dynamic rheological measurement.

Construction of Self-Reporting Biodegradable CO_(2)-Based Polycarbonates for the Visualization of Thermoresponsive Behavior with Aggregation-Induced Emission Technology

Thermoresponsive polymers with simultaneous biodegradability and signal“self-reporting”outputs that meet for advanced applications are hard to obtain.To address this issue,we developed fluorescence signal“self-reporting”biodegradable thermoresponsive polycarbonates through the immortal copolymerization of CO_(2)and oligoethylene glycol monomethyl ether-functionalized epoxides in the presence of hydroxyl-modified tetraphenylethylene(TPE-OH).TPE-OH was used as chain transfer agent to afford well-defined polycarbonates with controlled molecular weight(6000—17000 g·mol^(–1))and aggregation-induced emission characteristics.Through temperature-dependent fluorescence intensity study,low critical solution transition of TPE-labeled polycarbonates were determined and the fine details of thermal-induced phase transition process were monitored.Further research indicated that temperature-controlled aggregation and dissociation of TPE moieties are the main reason for fluorescence intensity variations.We anticipate that this work could offer a method to visualize the thermal transition process of thermoresponsive polycarbonates and broaden their application fields as smart materials.

Thermoresponsive block copolymer supported Pt nanocatalysts for base-free aerobic oxidation of 5-hydroxymethyl-2-furfural

A base-free catalytic system for the aerobic oxidation of 5-hydroxymethyl-2-furfural was exploited by using Pt nanoparticles immobilized onto a thermoresponsive poly(acrylamide-co-acrylonitrile)-b-poly(N-vinylimidazole)block copolymer,with an upper critical solution temperature of about 45°C.The Pt nanocatalysts were well-dispersed and highly active for the base-free oxidation of 5-hydroxymethyl-2-furfural by molecular oxygen in water,affording high yields of 2,5-furandicarboxylic acid(up to>99.9%).The imidazole groups in the block copolymer were conducive to the improvement of catalytic performance.Moreover,the catalysts could be easily separated and recovered based on their thermosensitivity by cooling the reaction system below the upper critical solution temperature.Good stability and reusability were observed over these copolymer-immobilized catalysts with no obvious decrease in catalytic activity in the five consecutive cycles.

Finely Tuning the Lower Critical Solution Temperature of Ionogels by Regulating the Polarity of Polymer Networks and Ionic Liquids

Nonvolatile ionogels have recently emerged as promising soft electrolyte materials due to their high ionic conductivity and good durability.However,the compatibility between polymer networks and ionic liquids(ILs),which show significant influence on the physicochemical properties of the ionogels,has been rarely studied.Herein,we elucidate a lower critical solution temperature(LCST)-type phase behavior of ionogels composed of polyacrylates and hydrophobic 1-alkyl-3-methylimidazolium bis{(trifluoromethyl)sulfonyl}amide ILs.We systematically study the structural effects of ILs and monomers on the LCST of ionogels.Our work illustrates that the LCST of ionogels is primarily determined by the polarity of polymer side chains and the alkyl chain on cations of ILs.The oriented solvation between polymers and ILs caused by hydrogen-bonding effects and van der Waals interactions may serve as the driving force for the LCST phase behavior in our system.Furthermore,by varying the mixing ratio of two structurally similar ILs in their blends,the LCST of ionogels can be tuned to exhibit a linear variation within a wide temperature range(from subzero to over 200℃).Finally,thermoresponsive ionogels with desired patterns are prepared using photomasks.These nonvolatile ionogels with tunable LCST enriched the functionality of state-of-the-art ionogels,which provides insight into the design and fabrication of smart and flexible electronic/optical devices.