Thermoresponsive System Research Articles

Thermoresponsive and Substrate Self-Cycling Nanoenzyme System for Efficient Tumor Therapy.

Cerium oxide (CeO2-x) performs well in photothermal and catalytic properties due to its abundance of oxygen vacancies. Based on this, we designed a thermosensitive therapeutic nanoplatform to achieve continuous circular drug release in tumor. It can solve the limitation caused by insufficient substrate in the process of tumor treatment. Briefly, CeO2-x and camptothecin (CPT) were wrapped in an agarose hydrogel, which could be melted by the photothermal effect of CeO2-x. At the same time, the local temperature increase provided photothermal treatment, which could induce the apoptosis of tumor cell. After that, CPT was released to damage the DNA in tumor cells to realize chemical treatment. In addition, CPT could active nicotinamide adenine dinucleotide oxidase to react with O2 to increase the intracellular H2O2. After that, the exposed CeO2-x could catalyze H2O2 to generate cytotoxic reactive oxygen species for chemodynamic therapy. More importantly, CeO2-x could catalyze H2O2 to produce O2, which could combine with the catalytic action of CPT to construct a substrate self-cycling nanoenzyme system. Overall, this self-cycling nanoplatform released hypoxia in the tumor microenvironment and built a multimode tumor treatment, which achieved an ideal antitumor affect.

Thermo-responsive aqueous two-phase system for two-level compartmentalization

Hierarchical compartmentalization responding to changes in intracellular and extracellular environments is ubiquitous in living eukaryotic cells but remains a formidable task in synthetic systems. Here we report a two-level compartmentalization approach based on a thermo-responsive aqueous two-phase system (TR-ATPS) comprising poly(N-isopropylacrylamide) (PNIPAM) and dextran (DEX). Liquid membraneless compartments enriched in PNIPAM are phase-separated from the continuous DEX solution via liquid-liquid phase separation at 25 °C and shrink dramatically with small second-level compartments generated at the interface, resembling the structure of colloidosome, by increasing the temperature to 35 °C. The TR-ATPS can store biomolecules, program the spatial distribution of enzymes, and accelerate the overall biochemical reaction efficiency by nearly 7-fold. The TR-ATPS inspires on-demand, stimulus-triggered spatiotemporal enrichment of biomolecules via two-level compartmentalization, creating opportunities in synthetic biology and biochemical engineering.

Fabrication of thermo-responsive microcapsule pesticide delivery system from maleic anhydride-functionalized cellulose nanocrystals-stabilized pickering emulsion template

The overuse of pesticides has shown their malpractices. Novel and sustainable formulations have consequently attracted abundant attention but still appear to have drawbacks. Here, we use a maleic anhydride-functionalized cellulose nanocrystals-stabilized Pickering emulsions template to prepare thermo-responsive microcapsules for a pesticide delivery system via radical polymerization with N-isopropyl acrylamide. The microcapsules (MACNCs-g-NIPAM) are characterized by the microscope, SEM, FTIR, XRD, TG-DTG, and DSC techniques. Imidacloprid (IMI) is loaded on MACNCs-g-NIPAM to form smart release systems (IMI@MACNCs-g-NIPAM) with high encapsulation efficiency (~88.49%) and loading capability (~55.02%). The IMI@MACNCs-g-NIPAM present a significant thermo-responsiveness by comparing the release ratios at 35°C and 25°C (76.22% vs 50.78%). It also exhibits advantages in spreadability, retention and flush resistance on the leaf surface compared with the commercial IMI water-dispersible granules (CG). IMI@MACNCs-g-NIPAM also manifest a significant advantage over CG (11.12 mg/L vs 38.90 mg/L for LC50) regarding activity tests of targeted organisms. In addition, IMI@MACNCs-g-NIPAM has shown excellent biocompatibility and low toxicity. All the benefits mentioned above prove the excellent potential of IMI@MACNCs-g-NIPAM as a smart pesticide formulation.

Tuning Structural Organization via Molecular Design and Hierarchical Assembly to Develop Supramolecular Thermoresponsive Hydrogels.

The cellular microenvironment is composed of a dynamic hierarchical fibrillar architecture providing a variety of physical and bioactive signals to the surrounding cells. This dynamicity, although common in biology, is a challenge to control in synthetic matrices. Here, responsive synthetic supramolecular monomers were designed that are able to assemble into hierarchical fibrous structures, combining supramolecular fiber formation via hydrogen bonding interactions, with a temperature-responsive hydrophobic collapse, resulting in cross-linking and hydrogel formation. Therefore, amphiphilic molecules were synthesized, composed of a hydrogen bonding ureido-pyrimidinone (UPy) unit, a hydrophobic alkyl spacer, and a hydrophilic oligo(ethylene glycol) tail. The temperature responsive behavior was introduced by functionalizing these supramolecular amphiphiles with a relatively short poly(N-isopropylacrylamide) (PNIPAM) chain (M n ∼ 2.5 or 5.5 kg/mol). To precisely control the assembly of these monomers, the length of the alkyl spacer between the UPy moiety and PNIPAM was varied in length. A robust sol-gel transition, with the dodecyl UPy-PNIPAM molecule, was obtained, with a network elasticity enhancing over 2000 times upon heating above room temperature. The UPy-PNIPAM compounds with shorter alkyl spacers were already hydrogels at room temperature. The sol-gel transition of the dodecyl UPy-PNIPAM hydrogelator could be tuned by the incorporation of different UPy-functionalized monomers. Furthermore, we demonstrated the suitability of this system for microfluidic cell encapsulation through a convenient temperature sol-gel transition. Our results indicate that this novel thermoresponsive supramolecular system offers a modular platform to study and guide single-cell behavior.

Environmentally responsive systems for topical administration of copaiba oil-resin: The effect of carbomer 974P on the mechanical, rheological, drug release and skin permeation

Topical wound therapy using copaiba oil-resin (CO) can be improved by combining it with a thermoresponsive bioadhesive release system. Emulgel systems composed of the bioadhesive carbomer 974P (C974P) and the thermoresponsive poloxamer 407 (P407) can prolong the CO contact time with the skin and facilitate the drug permeation through the skin layers. The aim of this work was to develop and investigate the C974P's effect on rheological, mechanical, bioadhesive, in vitro drug release and ex vivo skin permeation properties of this system. The system development was based on a 23 (plus two central points) factorial design and the influence of different amounts of C974P on formulations was investigated. C974P enabled the formation of viscous and stable emulgels, and could structure with P407 and CO, resulting on physicochemical stable formulations. Formulation composed of 0.5 % (w/w) C974P, 20 % (w/w) P407 and 8 % (w/w) CO (F8) displayed improved properties. F8 exhibited extended release, enhanced bioadhesive strength, improved hardness, compressibility, elasticity, adhesiveness, cohesiveness, pseudoplasticity with yield value, thixotropy, and high viscoelasticity. It also displayed skin permeation and retention. The P407's high capacity to form micelles with CO enabled their integration into the polymeric matrix formed by C974P, resulting in viscous and stable gel.

Photothermally modulated drug release kinetics for pH and thermo-responsive hydrogel system

Photothermally modulated drug release kinetics for pH and thermo-responsive hydrogel system

Near-Infrared Light-Triggered Thermoresponsive Pyroptosis System for Synergistic Tumor Immunotherapy.

Pyroptosis, as an inflammatory cell death, has been widely applied in tumor therapy, but its systemic adverse reactions caused by nonspecific activation still seriously hinder its application. Herein, a near-infrared (NIR) light-triggered thermoresponsive pyroptosis strategy is designed for on-demand initiation of pyroptosis and synergistic tumor immunotherapy. Specifically, glucose oxidase (GOx) loaded and heat-sensitive material p(OEOMA-co-MEMA) (PCM) modified mesoporous Pt nanoparticles (abbreviated as PCM Pt/GOx) are prepared as the mild-temperature triggered pyroptosis inducer. Pt nanoparticles can not only serve as nanozyme with catalase-like activity to promote GOx catalytic reaction, but also act as photothermal agent to achieve mild-temperature photothermal therapy (PTT) and thermoresponsive GOx release on-demand under the irradiation of NIR light, thereby activating and promoting pyroptosis. In vitro and in vivo experiments prove that NIR light-triggered thermoresponsive pyroptosis system exhibits excellent antitumor immunity activity as well as significantly inhibits tumor growth. The precise control of pyroptosis by NIR light as well as pyroptosis cooperated with mild-temperature PTT for synergistically attenuated tumor immunotherapy are reported for the first time. This work provides a new method to initiate pyroptosis on demand, which is of great significance for spatiotemporally controllable pyroptosis and immunotherapy.

Temperature-Modulated Reversible Clustering of Gold Nanorods Driven by Small Surface Ligands.

Temperature-modulated colloidal phase of plasmonic nanoparticles is a convenient playground for resettable soft-actuators or colorimetric sensors. To render reversible clustering under temperature change, bulky ligands are required, especially if anisotropic morphologies are of interest. This study showcases thermoresponsive gold nanorods by employing small surface ligands, bis (p-sulfonatophenyl) phenyl-phosphine dihydrate dipotassium salt (BSPP) and native cationic surfactant. Temperature-dependent analysis in real-time allowed to describe the structural features (interparticle distance and cluster size) as well as thermal parameters, melting and freezing temperatures. These findings suggest that neither covalent Au-S bonds nor bulky ligands are required to obtain a robust thermoresponsive system based on anisotropic gold nanoparticles, paving the way to stimuli-responsive nanoparticles with a wide range of sizes and geometries.

Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS.

Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.

Regulating Electrostatic Interactions toward Thermoresponsive Hydrogels with Low Critical Solution Temperature.

Low critical solution temperature (LCST) of commonly used thermoresponsive polymers in water is basically dominated by hydrophobic interactions. Herein, a novel thermoresponsive system based on electrostatic interactions is reported. By simply loading aluminum chloride (AlCl3 ) into non-responsive poly(2-hydroxyethyl acrylate) (PHEA) hydrogels, PHEA-Al gels turn to have reversible thermoresponsive behavior between transparent and opaque without any volume change. Further investigations by changing metal ion-polymer compositions unravel the necessity of specific electrostatic interactions, namely, cation-dipole bonding interactions between hydroxy groups and trivalent metal ions. The thermoresponsive hydrogel demonstrates high transparency (≈95%), excellent luminous modulation capability (>98%), and cyclic reliability, suggesting great potential as an energy-saving material. Although LCST control by salt addition is widely known, salt-induced expression of thermoresponsiveness has barely been discussed before. This design provides a new approach of easy fabrication, low cost, and scalability to develop stimuli-responsive materials.

Cellulose nanocrystal and Pluronic L121-based thermo-responsive composite hydrogels

Cellulose nanocrystal (CNC) is a promising sustainable material with its biocompatibility, high aspect ratio, and mechanical strength. CNC-based systems have potential applications in various fields including biosensors, packaging, coating, energy storage, and pharmaceuticals. However, turning CNC into smart systems remains a challenge due to the lack of stimuli-responsiveness, limitation in compatibility with hydrophobic matrices, and their agglomeration tendency. In this work, a thermo-responsive nanocomposite system is constructed with CNCs and polymersome forming Pluronic L121 (L121), and its phase behavior and mechanical properties are investigated in detail. Two different CNC concentration (4 % and 5 %) is studied by changing the L121 concentration (1–20 %) to understand the effect of unimers and polymersomes on the CNC network. At dilute L121 concentrations (1–5 %), the composite system becomes softer but more fragile below the transition temperature. However, it becomes much stronger at higher L121 concentrations (10–20 %), and a gel network is obtained above the transition temperature. Interestingly, the elastically reinforced CNC gels exhibit greater resistance to microstructural breakdown at large strains due to the soft and deformable nature of the large polymersomes. It is also found that the gelation temperature for hydrogels is tunable with increasing L121 concentration, and the nanocomposite hydrogels displayed thermo-reversible rheological behavior.

Ultrasound-controlled release of growth factors from lyophilized platelet-loaded thermoresponsive hydrogel

Platelet-rich plasma (PRP) and hyaluronic acid (HA) injection is commonly used for the treatment of osteoarthritis. However, the immediate bolus release of growth factors from PRP and inability of HA to stay in situ limit their beneficial therapeutic effects. An injectable, biocompatible, and thermoresponsive hydrogel (mPEG-PLGA-BOX block copolymer) is applicable for a long-term ultrasound-triggered lyophilized platelet (LP) release. In this study, an US-controlled release thermoresponsive hydrogel system loaded with LPs was evaluated for its long-term pharmacokinetics in a dry culture chamber at 37 °C. At 0.5 wt% constituent ratio of the LP-loaded hydrogels (0.2 ± 0.6 mV positively charged, which would be suitable for the treatments of negatively charged cartilages), the release amount of growth factors (PDGF-B and TGFβ-1) from the hydrogel could be increased to ∼300-folds in the presence of US (1 MHz, 0.4 W/cm2, 5% duty cycle, 5 min) compared to the amount in the absence of US during the 2 weeks of evaluation period. In comparison to 0.5 wt% of the LP-loaded HA (−2.4 ± 1.1 mV negatively charged), which had only a 5-day release ability, the US-controlled release thermoresponsive hydrogel system may be a more suitable platform for diseases that needed long-term treatments.

A novel Thermo-responsive hydrogel system (THS) loaded with the active ingredient of Gardenia jasminoides J. Ellis exhibits anti-depressant effects in vivo via intranasal administration

A novel Thermo-responsive hydrogel system (THS) loaded with the active ingredient of Gardenia jasminoides J. Ellis exhibits anti-depressant effects in vivo via intranasal administration

Fe3O4 magnetic nanoparticles-loaded thermoresponsive poly(N-vinylcaprolactam)-g-galactosylated chitosan microparticles: investigation of physicochemical, morphological and magnetic properties

A novel thermoresponsive magnetic hydrogel microparticle system was obtained by magnetic nanoparticles (MNPs) combined with poly(N-vinylcaprolactam)-g-galactosylated chitosan (GC) (PNVCL-g-GC) hybrid hydrogel. Fe3O4@PNVCL-g-GC microparticles (MPs) were synthesized by the suspension crosslinking method and the Fe3O4 MNPs were successfully encapsulated in the hybrid hydrogel with good magnetism. Fe3O4@PNVCL-g-GC MPs were characterized by ATR-FTIR, LCST, SEM-EDAX, particle size, zeta potential, TGA and VSM analyses. The size distribution of the spherical Fe3O4@PNVCL-g-GC MPs at room temperature was in the range of 390-530 nm, while it was measured as ∼220–340 nm above the LCST. The cytocompatibility and hemocompatibility of the Fe3O4@PNVCL-g-GC MPs were confirmed by in vitro ISO analyses. In conclusion, biocompatible, temperature- and magnetic-responsive small-size Fe3O4@PNVCL-g-GC MPs with enhanced mechanical stability were developed which could have the potential for a variety of biomedical applications such as controlled release systems, in situ bioactive agents carrier, and anti-cancer therapy in the future.

Thermoresponsive Hydrogel-Enabled Thermostatic Photothermal Therapy for Enhanced Healing of Bacteria-Infected Wounds.

Photothermal therapy (PTT) has emerged as an attractive technique for the treatment of bacterial infections. However, the uncontrolled heat generation in conventional PTT inevitably causes thermal damages to healthy tissues and/or organs. It is thus essential to develop a smart and universal strategy to regulate the photothermal equilibrium temperature to a preset safe threshold. Herein, a thermoresponsive hydrogel-enabled thermostatic PTT system for enhanced healing of bacteria-infected wounds is reported. In this system, the near-infrared (NIR)-triggered heat generation by photothermal nanomaterials is spontaneously transferred to a thermoresponsive hydrogel with a lower critical solution temperature (LCST), leading to its rapid phase transition by forming considerable light-scattering centers to block NIR penetration. Such a dynamic and reversible process automatically regulates the photothermal equilibrium temperature to the phase-transition point of the LCST-type hydrogel. In contrast to temperature-uncontrolled conventional PTT with severe thermal damages, the thermoresponsive hydrogel-enabled thermostatic PTT provides effective protection on healthy tissues and/or organs, which remarkably accelerates wound healing by efficient bacterial eradication. This study establishes a smart, simple and universal PTT platform, holding great promise in the safe and efficient treatment of bacterial skin infections.

Gel-sol transition of thermoresponsive poly(vinyl alcohol) solution: Validation of the universal critical scaling relations

While undergoing gelation transition, a material passes through a distinctive state called the critical gel state. In the neighborhood of this critical gel state, how viscosity, equilibrium modulus, and relaxation times evolve are correlated by scaling relations, and their universality has been validated for materials undergoing the sol-gel transition. In this work, we extend this approach for the gel-sol transition of a thermoresponsive polymeric system of aqueous poly(vinyl alcohol) (PVOH) gel that passes through the critical state upon increasing temperature. We observe that, in the neighborhood of the critical gel state, the equilibrium modulus and viscosity demonstrate a power law dependence on the relative distance from the critical state in terms of normalized temperature. Furthermore, the relaxation times in the gel and the sol state shows symmetric power law divergence near the critical state. The corresponding critical power law exponents and the dynamic critical exponents computed at the critical gel-sol transition state validate the scaling and hyperscaling relations originally proposed for the critical sol-gel transition very well. Remarkably, the dependence of complex viscosity on frequency at different temperatures shows a comprehensive master curve irrespective of the temperature ramp rate independently in the gel and the sol state. This observation demonstrates how the shape of relaxation time spectrum is independent of both the temperature as well as the ramp rate. Since sol-gel and the gel-sol transitions are opposite to each other, the applicability of the scaling relations validated in this work suggests broader symmetry associated with how the structure evolves around the critical state irrespective of the direction.

A temperature-responsive artificial light-harvesting system in water with tunable white-light emission

A tadpole-type amphiphilic monomer containing cyanostilbene and oligo(ethylene glycol) chains has been designed and synthesized, which can be used to construct a thermo-responsive light-harvesting system in water with tunable white-light emission.

From Hofmeister to hydrotrope: Effect of anion hydrocarbon chain length on a polymer brush

HypothesisSpecific ion effects govern myriad biological phenomena, including protein–ligand interactions and enzyme activity. Despite recent advances, detailed understanding of the role of ion hydrophobicity in specific ion effects, and the intersection with hydrotropic effects, remains elusive. Short chain fatty acid sodium salts are simple amphiphiles which play an integral role in our gastrointestinal health. We hypothesise that increasing a fatty acid’s hydrophobicity will manifest stronger salting-out behaviour. ExperimentsHere we study the effect of these amphiphiles on an exemplar thermoresponsive polymer brush system, conserving the carboxylate anion identity while varying anion hydrophobicity via the carbon chain length. Ellipsometry and quartz crystal microbalance with dissipation monitoring were used to characterise the thermoresponse and viscoelasticity of the brush, respectively, whilst neutron reflectometry was used to reveal the internal structure of the brush. Diffusion-ordered nuclear magnetic resonance spectroscopy and computational investigations provide insight into polymer-ion interactions. FindingsSurface sensitive techniques unveiled a non-monotonic trend in salting-out ability with increasing anion hydrophobicity, revealing the bundle-like morphology of the ion-collapsed system. An intersection between ion-specific and hydrotropic effects was observed both experimentally and computationally; trending from good anti-hydrotrope towards hydrotropic behaviour with increasing anion hydrophobicity, accompanying a change in hydrophobic hydration.

Injectable Composite Systems of Gellan Gum:Alginate Microparticles in Pluronic Hydrogels for Bioactive Cargo Controlled Delivery: Optimization of Hydrogel Composition based on Rheological Behavior

Due to the high complexity of some treatments, there is a need to develop drug-delivery systems that can release multiple drugs/bioactive agents at different stages of treatment. In this study, a thermoresponsive injectable dual-release system was developed with gellan gum/alginate microparticles (GG:Alg) within a thermoresponsive Pluronic hydrogel composed of a mixture of Pluronic F127 and F68. The increase in F68 ratio and decrease in F127 lead to higher transition temperatures. The addition of the GG:Alg microparticles decreased the transition temperatures with a linear tendency. In Pluronic aqueous solutions (20 wt.%), the F127:F68 ratios of 16:4 and 17:3 (wt.%:wt.%) and the addition of microparticles (up to 15 wt.%) maintained the sol–gel transition temperatures within a suitable range (between 25 °C and 37 °C). Microparticles did not hinder the injectability of the system in the sol phase. Methylene blue was used as a model drug to evaluate the release mechanisms from microparticles, hydrogel, and composite system. The hydrogel delayed the release of methylene blue from the microparticles. The hydrogel loaded with methylene blue released at a faster rate than the microparticles within the hydrogel, thus demonstrating a dual-release profile.

Development of Thermoresponsive-Gel-Matrix-Embedded Amoxicillin Trihydrate-Loaded Bovine Serum Albumin Nanoparticles for Local Intranasal Therapy.

A high dose of amoxicillin is recommended as the first-line therapy for acute bacterial rhinosinusitis (ABR). However, oral administration of amoxicillin is connected to many adverse reactions coupled with moderate bioavailability (~60%). Therefore, this study aimed to develop a topical nasal preparation of amoxicillin, employing a thermoresponsive nanogel system to increase nasal residence time and prolong drug release. Rheological investigations revealed that formulations containing 21-23% w/w Poloxamer 407 (P407) were in accordance with the requirement of nasal administration (gelling temperature ~35 °C). The average hydrodynamic diameter (<200 nm), pH (6.7-6.9), and hypertonic osmolality (611-663 mOsmol/L) of the in situ gelling nasal nanogel appeared as suitable characteristics for local rhinosinusitis treatment. Moreover, taking into account the mucoadhesive strength and drug release studies, the 21% w/w P407 could be considered as an optimized concentration for effective nasal delivery. Antibacterial activity studies showed that the ability of amoxicillin-loaded in situ gelling nasal nanogel to inhibit bacterial growth (five common ABR pathogens) preserved its effectiveness in comparison to 1 mg/mL amoxicillin aqueous solution as a positive control. Altogether, the developed amoxicillin-loaded in situ gelling thermoresponsive nasal nanogel can be a potential candidate for local antibiotic therapy in the nasal cavity.