Multiresponsive Microgels Research Articles

A review on Ag nanoparticles fabricated in microgels.

In recent years, there has been growing interest in the composites of multi-responsive microgels and silver nanoparticles. This innovative hybrid system harnesses the responsive qualities of microgels while capitalizing on the optical and electronic attributes of silver nanoparticles. This combined system demonstrates a rapid response to minor changes in pH, temperature, ionic strength of the medium, and the concentration of specific biological substances. This review article presents an overview of the recent advancements in the synthesis, classification, characterization methods, and properties of microgels loaded with silver nanoparticles. Furthermore, it explores the diverse applications of these responsive microgels containing silver nanoparticles in catalysis, the biomedical field, nanotechnology, and the mitigation of harmful environmental pollutants.

Targeted Therapy of Ischemic Stroke via Crossing the Blood-Brain Barrier Using Edaravone-Loaded Multiresponsive Microgels.

Ischemic stroke, as a prevalent neurological disorder, often results in rapid increases in the production of reactive oxygen species (ROS) and inflammatory factors in the focal ischemic area. Though edaravone is an approved treatment, its effect is limited due to its weak ability to cross the blood-brain barrier (BBB) and short half-life. Other effective pharmacological treatment options are clearly lacking. In this study, PNIVDBrF-3-Eda (also named MG-3-Eda) was prepared using a thermo- and pH dual-responsive PNIVDBrF microgel. These were designed with a positively charged network, as synthesized by simultaneous quaternization cross-linking and surfactant-free emulsion copolymerization, to be loaded with the negatively charged edaravone. We then investigated whether such a targeted delivery of edaravone could provide enhanced neuroprotection. Cytotoxicity assays confirmed that the microgel (<1 mg/mL) exhibited promising cytocompatibility with no remarkable effect on cell viability, cell cycle regulation, or apoptosis levels. In vitro and in vivo experiments demonstrated that the microgels could successfully penetrate the blood-brain barrier where efficient BBB crossing was observed after disruption of the BBB due to ischemic injury. This enabled MG-3-Eda to target the cerebral ischemic area and achieve local release of edaravone. Treatment with MG-3-Eda significantly reduced the cerebral infarct area in transient middle cerebral artery occlusion (tMCAO) mice and significantly improved behavioral scores. MG-3-Eda treatment also prevented the reduction in NF200 expression, a neuronal marker protein, and attenuated microglia activation (as detected by Iba1) in the local ischemic area via local antioxidant and anti-inflammatory effects. A superior neuroprotective effect was noted for MG-3-Eda compared to that for free edaravone. Our results indicate that MG-3-Eda administration represents a clear potential treatment for cerebral ischemia via its targeted delivery of edaravone to ischemic areas where it provides significant local antioxidant and anti-inflammatory effects.

Multiresponsive Microgels: Toward an Independent Tuning of Swelling and Surface Properties.

Dual-responsive poly-(N-isopropylacrylamide) (PNIPAM) microgels surface-functionalized with polyethylene glycol (PEG) or poly-2-dimethylaminoethyl methacrylate (PDMAEMA) were developed to enable the swelling behavior and surface properties of the microgels to be tuned independently. The thermo-triggered swelling and pH-triggered surface properties of the microgels were investigated in aqueous suspensions using dynamic light scattering and on substrates using the surface forces apparatus. Grafting polymer chains on the microgel surface did not impede the thermo-triggered swelling behavior of the microgels in suspensions and immobilized on substrates. An unprecedented decoupling of the swelling behavior and surface properties could be obtained. More particularly, the thermo-triggered swelling behavior of the PNIPAM underlying microstructure could be tuned below and above the phase transition temperature with no change in the surface potential and adhesion provided by the surface non-responsive PEG.

Advanced liposome based PEGylated microgel as a novel release system for 5-fluorouracil against MCF-7 cancer cell

Micro/nano-sized particles provide a control on optimization of the therapeutic index of cancer drugs. This study reports successful modification of the multi-responsive microgels based on a water-soluble 2-(N-morpholino)ethyl methacrylate (MEMA) monomer for sustained drug delivery of 5-fluorouracil (5-FU). PMEMA microgel hosting 5-FU loaded 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposome system was successfully prepared. DPPC liposome-based PMEMA microgel system was also studied in in-vitro studies as a drug carrier and controlled drug release system in phosphate buffer solution and normal saline solution. The release of 5-FU from both PMEMA microgel and liposome-based PMEMA microgel systems was analyzed using HPLC with ultraviolet spectrophotometer detector (λ 266 nm). The cytotoxic assays of liposome-based microgel and 5-FU loaded liposome-based microgel systems were investigated using L929 and MCF-7 which are mouse fibroblast cell line and breast cancer cell line, respectively. In conclusion, PEGylated PMEMA microgel and liposome-based PEGylated PMEMA microgel system provided long-time sustained drug release of 5-FU. It has been observed that the 5-FU release from PEGylated PMEMA system was faster than that of DPPC liposome-based microgel system. Additionally, 5-FU release from DPPC liposome-based microgel system was determined to be very effective on MCF-7 breast cancer cell line, which indicates great potential for further in-vivo studies.

Microstructure-driven self-assembly and rheological properties of multi-responsive soft microgel suspensions

HypothesesThe deformation and swelling ability of microgels is influenced by the crosslinking distribution. Varying microgels microstructure is expected to obtain suspensions with different flow behavior and thereby, different rheological properties. ExperimentsDifferent multi-responsive microgels were synthesized using two different crosslinkers and varying their amounts: N,N-methylene bis-acrylamide (MBA) and oligo(ethylene glycol) diacrylate (OEGDA). The rheological results were obtained by zero-shear viscosity and long-time creep measurements on concentrated microgel suspensions Microgel microstructure was analyzed by 1H nuclear magnetic resonance transverse relaxation measurements. FindingsAt a constant crosslinking rate, we show that the viscosity of OEGDA-crosslinked microgels diverges at a higher concentration than MBA ones, suggesting a looser shell and less restricted dangling chains at the periphery for the later. By scaling with the effective volume fraction, the viscosity curves of the different microgel suspensions reduce into a single curve and closely follow hard sphere models up to ϕeff < 0.45. The results from creep tests revealed a much higher yield stress for MBA-crosslinked microgels, strengthening the hypothesis of a looser shell for the later. Finally, transverse relaxation (T2) NMR measurements demonstrated that, although all microgels exhibit a core–shell microstructure, MBA samples present a less crosslinked shell corroborating with the rheological results.

Double security drug delivery system DDS constructed by multi-responsive (pH/redox/US) microgel

In this paper, the multi-responsive core-shell microgels were prepared for constructing a double-locked drug delivery system. The pH- sensitive poly(2-(diisopropylamino ethylmethacry-late)-block-poly(ethyleneimine) diblock copolymers (PDPA-b-PEI) were synthesized and used to prepare micelles through their self-assembly in neutral solution. Redox-responsive gel shells were formed by Michael addition of primary amine group of branched PEI using disulfide as a cross-linker, which was specifically cleaved by glutathione (GSH). Anticancer drug doxorubicin DOX and perfluorohexane (PFH) could be encapsulated in the core of microgel. The DOX was released sustainably only under the condition of pH and GSH were both right. For example, under neutral condition with GSH, DOX could not release swimmingly due to the core of microgels was in hydrophobic state and wrapped the DOX firmly, although the gel shells were collapsed by GSH. When exposed to ultrasound, the drug released abruptly and achieved a complete release instantly. Moreover, it was found that the structure of the microgels was not destroyed after the ultrasound stimulus but had undergone an expansion-recovery process. Finally, it was demonstrated that the microgel had a “double security” effect, ensuring the low drug leakage during the normal blood circulation and efficient drug release under the pH/redox/ultrasound stimulus. The multi-responsive microgels designed here, which combines the usage of both endogenous and exogenous stimuli, has the advantages of low side-effect, high spatiotemporal controllability and complete release.

Multiresponsive Microgels with Phase-Separated Nanodomains and Self-Regulating Properties via Incorporation of Anthraquinone Moieties.

Of the multitude of stimuli-responsive microgels, it is still a challenge to achieve multiple responsivenesses to one single stimulus, which can even revert to the corresponding original state autonomously after stimulus. In this work, we reported a series of anthraquinone functionalized microgels (PNI-xVAQ) with thermosensitivity and redox-actuated self-regulating color, size, and fluorescent properties, which were easily synthesized via surfactant-free emulsion copolymerization (SFEP) with N-isopropylacrylamide (NIPAm) as the monomer, 2-vinylanthraquinone (VAQ) as the comonomer, and N,N'-methylenebis(acrylamide) (BIS) as the cross-linker in an aqueous solution at 70 °C. The hydrophobic interactions of comonomer VAQ also led to the formation of internal phase-separated hydrophobic nanodomains in the obtained PNI-xVAQ microgels. The self-regulating color, size, and fluorescence changes of the PNI-xVAQ microgels were reliant on the nonequilibrium redox process of anthraquinone moieties by the addition of sodium dithionite as the chemical fuel to activate the positive feedback that was the reduction of anthraquinone to transient anthraquinone radical anions, following the slow oxidation of anthraquinone radical anions by autonomous "breathing" oxygen in air as the delayed negative feedback. These autonomous self-regulating properties of the PNI-xVAQ microgel were recyclable to a certain extent by repeated feeding of sodium dithionite.

Versatile oligo(ethylene glycol)-based biocompatible microgels for loading/release of active bio(macro)molecules.

The present study aims in the understanding of the effect of oligo(ethylene glycol)-based biocompatible microgels inner structure on the encapsulation/release mechanisms of different types of cosmetic active molecules. For that, multi-responsive microgels were synthesized using three types of cross-linkers: ethylene glycol dimethacrylate (EGDMA), oligo(ethylene glycol) diacrylate (OEGDA) and N,N-methylenebisacrylamide (MBA). The inner morphology of the microgels synthesized was studied by 1H-nuclear magnetic resonance (1H NMR) and small-angle neutron scattering (SANS) techniques and no effect of cross-linker type on microgel microstructure was observed in the case of analysing purified microgel dispersions. Moreover, all the microgels synthesized presented conventional swelling/de-swelling behavior as a function of temperature and pH. Two hydrophobic, one hydrophilic, and one macromolecule as cosmetic active molecules were effectively loaded into different microgel particles via hydrophobic interactions and hydrogen-bonding interactions between -OH groups of active molecules and ether oxygens of different microgel particles. Their release profiles as a function of cross-linker type used and encapsulated amounts were studied by Peppas-Sahlin model. No effect of the cross-linker type was observed due to the similar inner structure of all the microgels synthesized.

Synthesis, characterization and physiochemical investigation of chitosan-based multi-responsive Copolymeric hydrogels

This paper describes the synthesis and physicochemical characterization of Poly(N-isopropylacrylamide)-Chitosan-Poly(Acrylic acid) [PNIPAAm-CS-PAA] based polymeric microgels. Three different samples of multi-responsive (PNIPAAM-CS-PA) microgels were synthesized using various amounts of N Nˡ- Methylene bis-acrylamide (MBA) and Acrylic acid (AA) by free radical emulsion polymerization. The redox initiator Ammonium per sulfate (APS) was used to initiate the reactions while MBA was used as a crosslinking agent. The purified polymeric microgels were then characterized using UV-Visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), Laser light scattering (LLS), Ostwald viscometry, dynamic Rheology and swelling/de-swelling measurements. From the spectroscopic result it was observed that all the reactions have been completed and the resultant microgels were successfully synthesized. The influence of various parameters such as, chemical composition and some external stimuli like temperature and pH on the physicochemical behavior of polymeric microgels was investigated through visual stability test, laser light scattering, viscometry and rheological measurement. The LLS analysis was performed to deduce the size, in the terms of hydrodynamic radius (Rh), of the microgel samples in aqueous media at different pH and temperature. From LLS analysis the microgels were found to be stable at all pH values above the pKa values (4.2) of AA in temperature ranges from 20 °C to 50 °C. With rising in temperature and pH causes aggregation of particles and decrease in stability of microgels due to the decrease in hydrophobicity. From the Rheological measurements, various physiochemical properties such as, elasticity, viscosity, shear stress, storage modulus, loss modulus, phase angle and complex viscosity of the microgels were gathered. The Ostowald viscometry was used to measure the flow viscosity of microgels at different pH and temperatures. The present observations reflect that the prepared samples are multi-responsive and their physicochemical behavior can be tuned very easily by changing their composition and/or varying the external stimuli.

An antibacterial composite system based on multi-responsive microgels hosting monodisperse gold nanoparticles

A multi-responsive microgel having response to pH, temperature, and salt concentration was successfully prepared using a water-soluble monomer. Microgels were readily prepared from 2-(N-morpholino)ethyl methacrylate (MEMA) via emulsion polymerization using glycidyl methacrylate as a comonomer cross-linker. The morpholino groups of MEMA residues of microgels were able to give complexation with metal containing anions such as AuCl4 − in acidic conditions. The reduction of aurate ions with sodium borohydride led to immobilized-gold nanoparticles (AuNP) in the microgel system. Average particle diameters of AuNPs were determined to be 10 ± 2 nm. The resulting AuNP-microgel system was examined as a nanoreactor for catalyst system and determined to be very effective in the reduction of 4-nitrophenol model reaction in aqueous media. AuNPs-microgel composite system had antibacterial properties against several Gram-positive and Gram-negative bacteria similar to amoxicillin. This P(MEMA-co-GMA) microgel is also very useful for different applications such as a host for metal nanoparticle production, a drug carrier or drug delivery system.

Synthesis and multi-responsiveness of poly(N-vinylcaprolactam-co-acrylic acid) core–shell microgels via miniemulsion polymerization

We report herein a facile and large fabrication of multi-responsive poly(N-vinylcaprolactam-co-acrylic acid) microgels with a core–shell structure via seed miniemulsion polymerization. The multi-responsive microgels can reversibly swell and shrink in response to pH and temperature variation.

Biological Imaging and Sensing with Multiresponsive Microgels

Multiresponsive spiropyran-modified poly(N-isopropylacrylamide)-based microgels were synthesized and their response to temperature; UV, visible, and near-infrared radiation; pH; and Cu2+ was investigated. The responses were a result of the spiropyran groups undergoing a reversible isomerization/reaction from a neutral to a charged form. The isomerization process was investigated via experiment and theory. The two-photon excited fluorescence of the spiropyran-modified microgels was also characterized, and their ability to be used to image live cells was determined. Finally, optical devices (etalons) were fabricated using the spiropyran-modified microgels, and the ability of the devices to change color in response to the above-mentioned stimuli was also investigated. We found that the microgel’s responsivity was retained in the etalon, which yielded color tunable devices and sensors. This investigation illustrates the versatility of pNIPAm-based microgels and microgel-based etalons and showcases the clear u...

A review of responsive hybrid microgels fabricated with silver nanoparticles: synthesis, classification, characterization and applications

Multi-responsive microgels loaded with silver nanoparticles have gained much attention in the recent years. Such hybrid system combines responsive behavior of microgels with optical and electronic properties of silver nanoparticles. This composite system shows quick response to slight variation of temperature, pH and ionic strength of medium and concentration of certain biological substances. This review article describes the recent research progress of synthesis, classification, methods of characterization and properties of silver nanoparticles containing microgels. It also covers applications of silver nanoparticles-loaded responsive microgels in catalysis, biomedical field, nanotechnology and degradation of toxic environmental moieties.

Core/Shell Microgels Decouple the pH and Temperature Responsivities of Microgel Films

We investigate the impact of pH on the swelling properties of thermoresponsive microgel layer-by-layer films. Microgels were synthesized from N-isopropylacrylamide and/or N-isopropylmethacrylamide. At pH 3, films composed of traditional (core) microgels, where acrylic acid has been copolymerized throughout the microgel network, have sharp temperature responsivities as observed by increases in the intensity of scattered light. This is contrasted by results at pH 7.4, where responsivity is diminished, likely as a result of deprotonated carboxylic acid groups, which changes the osmotic pressure within the component microgels. To probe this phenomenon further, core/shell microgels were synthesized such that the acidic comonomer was isolated to the shell and the core was purely temperature-responsive. Films assembled from such core/shell microgels exhibited pH-independent temperature responsivities. Temperature controlled in-liquid atomic force microscopy was used to directly measure the thickness of microgel films at pH 3 and 7.4 at ∼26 and 50 °C. Film thickness measurements were predominately in agreement with light scattering data, where decreases in film thickness corresponded with increases in scattered light intensity. Thus, we find that spatially separating the responsivities within multiresponsive microgels can result in more predictive power over the responsivity of microgel assemblies.

Design of smart oligo(ethylene glycol)-based biocompatible hybrid microgels loaded with magnetic nanoparticles.

This article reports a rational strategy for preparing smart oligo(ethylene glycol)-based hybrid microgels loaded with high content of homogeneously distributed preformed magnetic nanoparticles (NPs) (up to 33 wt%). The strategy is based on the synthesis of biocompatible multiresponsive microgels by precipitation copolymerization of di(ethylene glycol) methyl ether methacrylate, oligo(ethylene glycol) methyl ether methacrylate, methacrylic acid, and oligo(ethylene glycol)diac-rylate. An aqueous dispersion of preformed magnetic NPs is straightforwardly loaded into the microgels. Robust monodisperse thermoresponsive magnetic microgels are produced, exhibiting a constant value of the volume phase transition temperature whatever the NPs content. The homogeneous microstructure of the initial stimuli-responsive biocompatible microgels plays a crucial role for the design of unique well-defined ethylene glycol-based thermoresponsive hybrid microgels.

Effect of crosslinker feed content on catalaytic activity of silver nanoparticles fabricated in multiresponsive microgels

We investigated the effect of crosslinking density of poly(N-isopropyl acrylamide-co-acrylic acid) microgels on catalytic activity of silver nanoparticles fabricated hybrid microgels. Multiresponsive poly(N-isopropyl acrylamide-co-acrylic acid) microgels with 2, 4, 6 and 8 mole percentage of N,N-methylene-bis-acrylamide were synthesized by emulsion polymerization. These microgels were characterized by dynamic light scattering and were used as microreactors to synthesize silver nanoparticles. Hybrid system was characterized by ultraviolet-visible spectroscopy. The catalytic activity of hybrid microgels with different crosslinker content was compared by studying the reduction of pnitrophenol as a model reaction. Kinetics of reaction was monitored by spectrophotometry. The value of the apparent rate constant decreases from 0.568 to 0.313min−1, when content of crosslinker are increased from 2 to 8 mole percentage respectively. This decreases in value of apparent rate constant is due to increase in diffusional barrier offered by high crosslinking of polymer network at high mole percentages of N,N-methylene-bis-acrylamide.

Optical Devices Constructed from Multiresponsive Microgels

Novel multiresponsive microgels based on poly(N-isopropylacrylamide) were synthesized to contain triphenylmethane leucohydroxide, and used to construct etalons. The optical properties of the resultant etalons were investigated, and their response to ultraviolet and visible irradiation, solution pH changes, and the presence of a mimic of the nerve agent Tabun characterized. We clearly show that the optical properties of the device depended dramatically on these stimuli. This investigation illustrates the versatility of the microgel-based etalon structure, and showcases the clear utility of such devices for remote actuation, color tunable optics, sensing, and potential remotely triggered drug delivery applications.

Optical Devices Constructed from Multiresponsive Microgels

AbstractNovel multiresponsive microgels based on poly(N‐isopropylacrylamide) were synthesized to contain triphenylmethane leucohydroxide, and used to construct etalons. The optical properties of the resultant etalons were investigated, and their response to ultraviolet and visible irradiation, solution pH changes, and the presence of a mimic of the nerve agent Tabun characterized. We clearly show that the optical properties of the device depended dramatically on these stimuli. This investigation illustrates the versatility of the microgel‐based etalon structure, and showcases the clear utility of such devices for remote actuation, color tunable optics, sensing, and potential remotely triggered drug delivery applications.

Collapse-to-Swelling Transitions in pH- and Thermoresponsive Microgels in Aqueous Dispersions: The Thermodynamic Theory

We present a theory of a conformational collapse-to-swelling transition that occurs in aqueous dispersions of multiresponsive (pH- and thermoresponsive) microgels upon variation of ionic strength, temperature, or pH. Our theory is based on osmotic balance arguments and explicitly accounts for ionization equilibrium inside microgel partices. The theory predicts complex patterns in the dependence of the microgel particle dimensions on the control parameters: An increase in temperature leads to worsening of the solvent quality for the gel forming LCST-polymers and to concomitant decrease in the dimensions of the gel particles. This collapse of the gel particles provoked by an increase in temperature occurs either smoothly (at high or low ionic strength), or may exhibit a jump-wise character at intermediate ionic strength. The theory further predicts that the degree of swelling of microgel particles varies nonmonotonously and exhibits a maximum as a function of salt concentration at a pH close to the pK. This nonmonotonous variation of the particle dimensions occurs continuously at temperatures below or slightly above LCST (good or marginal poor solvent strength conditions, respectively), whereas at higher temperatures the jump-wise swelling of the gel particles is followed by either continuous or jump-wise collapse induced by progressive increase in the salt concentration. A decrease/increase in pH leads to deswelling of the weak polyacid/polybase gel particles, which occurs smoothly at temperatures below LCST, but may exhibit a discontinuity above LCST. These theoretical predictions can be used for design of smart stimuli-responsive microgels.

Novel Multiresponsive Microgels: Synthesis and Characterization Studies

The dispersion polymerization of 2-(N-morpholino)ethyl methacrylate (MEMA) in the presence of ethylene glycol dimethylacrylate (EGDMA) cross-linker and diblock copolymer stabilizer in n-hexane afforded sterically stabilized multiresponsive PMEMA microgels. By changing the reaction parameters, a wide range of particle sizes (120-720 nm) was obtained. Both dynamic light scattering and electron microscopy studies confirmed monodisperse spherical morphologies. These microgels had a response to the solution pH, temperature, and ionic strength. As expected, PMEMA microgels acquired cationic character at low pH because of the protonation of all morpholino groups. Although PMEMA microgels are in a swollen state in both acidic media and at low temperatures, they are in a deswollen state in basic media at high temperatures and in the presence of electrolytes above pH 6. In addition to these multiresponsive behaviors, PMEMA microgels have the ability to swell in various organic solvents. They also interact very well with magnetic particles and gain responsiveness to the magnetic field. Multiresponsive behaviors of PMEMA microgels were investigated by using DLS, UV-vis spectrophotometry, and zeta potentiometry.