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.

Rheological property and drying mechanism of thermoresponsive gelcasting of ZnO

To solve the problem of drying gelcast green body, the thermoresponsive gel system which contains macromonomer graft chains was used in gelcasting of ZnO. The effects of the amount and length of graft chains macromonomer PIPAAm, the total amount of organic matters, and the solid loading on the rheological properties of suspensions were investigated, and the drying mechanism of gelcast green body was analyzed. The results show that ZnO suspensions with the gel system still display shear- thinning rheological behavior, but its viscosity increases with increasing the addition amount and relative molecular mass of PIPAAm graft chain, and the total organic matter content. The PIPAAm graft chains inhibit or even eliminate the formation of the ＂dense layer” on the surface of gelcast ZnO green bodies, and accelerate the drying of green bodies. The introduction of PIPAAm graft chains facilitates the shrinkage of the gelcast ZnO green bodies, which is a feasible method to increase the relative density of green bodies.

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.

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.

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.

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.

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.

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.

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.

Surface-modulated and thermoresponsive polyphosphoester nanoparticles for enhanced intracellular drug delivery

The chemical structure of end groups influenced the phase transition temperature of thermoresponsive polymers. We demonstrated a strategy for the preparation of the pH/thermo-responsive polymeric nanoparticles via subtle modification of end groups of thermoresponsive polymer segments with a carboxyl group and revealed its potential application for enhanced intracellular drug delivery. By developing a polymeric nanoparticle composed of poly(aliphatic ester) as the inner core and thermoresponsive polyphosphoester as the outer shell, we showed that end groups of thermoresponsive polyphosphoester segments modified by carboxyl groups exhibited a pH/thermo-responsive behavior due to the hydrophilic to hydrophobic transitions of the end groups in response to the pH. Moreover, by encapsulating doxorubicin into the hydrophobic core of such pH/thermo-responsive polymer nanoparticles, their intracellular delivery and cytotoxicity to wild-type and drug-resistant tumor cells were significantly enhanced through the phase-transition-dependent drug release that was triggered by endosomal/lysosomal pH. This novel strategy and the multi-responsive polymer nanoparticles achieved by the subtle chain-terminal modification of thermoresponsive polymers provide a smart platform for biomedical applications.

“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.

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.

Thermoresponsive dendronized copolymers for protein recognitions based on biotin-avidin interaction

Thermoresponsive biotinylated dendronized copolymers carrying dendritic oligoethylene glycol（OEG）pendants were prepared via free radical polymerization,and their protein recognitions based on biotin-avidin interaction investigated.Both first（PG1） and second generation（PG2） dendronized copolymers were designed to examine possible thickness effects on the interaction between biotin and avidin.Inherited from the outstanding thermoresponsive properties from OEG dendrons,these biotinylated cylindrical copolymers show characteristic thermoresponsive behavior which provides an envelope to capture avidin through switching temperatures above or below their phase transition temperatures（T_（cp）s）.Thus,the recognition of polymer-supported biotin with avidin was investigated with UV/vis spectroscopy and dynamic laser light scattering.In contrast to the case for PG1,the increased thickness for copolymer PG2 hinders partially and inhibits the recognition of biotin moieties with avidin either below or above its T_（cp）.This demonstrates the significant architecture effects from dendronized polymers on the biotin moieties to shift onto periphery of the collapsed aggregates,which should be a prerequisite for protein recognition.These kinds of novel thermoresponsive copolymers may pave a way for the interesting biological applications in areas such as reversible activity control of enzyme or proteins,and for controlled delivery of drugs or genes.

Influence of Aliphatic Amide Terminals on the Thermoresponsive Properties of Hyperbranched Polyethylenimines

Acetamide （C2）, propionamide （C3）, butyramide （C4）, isobutyramide （i-C4）, isovaleramide （i-C5） and trimethylacetamide （t-C5） groups each were introduced to the terminals of hyperbranched polyethylenimine （HPEI） through the amidation reaction between HPEI and the corresponding anhydride. Moreover, HPEIs terminated with two kinds of amides were also prepared. The first amide was fixed to be i-C4 with 52% degree of amidation （DA）, and the second amide varied from C2, C3, C4, i-C5 to t-C5. All the polymers were characterized by 1H-NMR. Turbidimetry measurements were performed for these polymers in water at different temperatures. With respect to the polymers bearing only one kind of amide group, except C2, all the other amide groups could render thermoresponsive properties to HPEI. The specific ordering of these amide groups to reduce the cloud point temperature （Top） was as follows： i-C5 〉 t-C5 〉 C4 〉 i-C4 〉 C3. Moreover, the more branched i-C4 and t-C5 were better groups than their less branched isomers C4 and i-C5 in the Tcp range of 12-51 ~C to render the sharper phase transition to the thermoresponsive polymers. As for the polymers bearing two kinds of amide groups, the further introduction of C2, C3, C4, i-C5 or t-C5 could effectively endow HPEI bearing 52% of i-C4 with thermoresponsive properties. The specific ordering of these second amide groups to reduce the Top was as follows： i-C5 〉 C4 〉 i-C4 〉 C3 〉 C2. C4, i-C5 and t-C5 were all effective second amide groups to prepare the thermoresponsive polymers with sharper phase transition.

Thermoresponsive Nanogels from Dendronized Copolymers for Complexation,Protection and Release of Nucleic Acids

A series of thermoresponsive cationic dendronized copolymers and their corresponding nano gels containing den dritic oligoethylene glycol(OEG)units and guanidine groups were prepared,and their complexation,protect!on,and release of nucleic acids were investigated.The dendritic OEGs endow these copolymer materials with good biocompatibility and characteristic thermoresponsiveness,while cationic guanidine groups can efficiently bind with the nucleic acids.The dendritic topology also affords the copolymers specific shielding effect which plays an essential role in protecting the activity of nucleic acids.At room temperature,dendronized copolymers and the corresponding nanogels could efficiently capture and condense the nucleic acids,while above their cloud points(Tcps),more than 75%of siRNA could be released in 1 h triggered by ATP.More importantly,the copolymer showed protective capability to siRNA,while nano gels exhibit even better protection when compared to the copolymers due to the synergetic effect from the three-dimensional cross-linked network and high density of dendritic units in vicinity.This kind of smart dendr on ized copolymer nano gels form a no vel class of scaffolds as promisi ng materials for biomedical applicatio ns.

Controlling the Chain Folding for the Synthesis of Single-Chain Polymer Nanoparticles Using Thermoresponsive Polymers

Synthetic polymer single-chain nanoparticles(SCNPs)are an emerging new class of nanomaterials that possess similar folded structures as natural proteins.However,most SCNPs reported so far are packed loosely in their interior,resembling those of intrinsically disordered proteins(IDPs).Here,we report a facile strategy to synthesize SCNPs with controllable folding in aqueous solution.