Copolymer Micelles Research Articles

Nanoimbibition of Essential Oils in Triblock Copolymeric Micelles as Effective Nanosanitizers against Food Pathogens Listeria monocytogenes and Escherichia coli O157:H7

Nanoimbibition of Essential Oils in Triblock Copolymeric Micelles as Effective Nanosanitizers against Food Pathogens <i>Listeria monocytogenes</i> and <i>Escherichia coli</i> O157:H7

Separated Micelles Formation of pH-Responsive Random and Block Copolymers Containing Phosphorylcholine Groups.

The self-assembly of pH-responsive random and block copolymers composed of 2-(N,N-diisopropylamino)ethyl methacrylate and 2-methacryloyloxyethyl phosphorylcholine was investigated in aqueous media. Their pH-responsive behaviors were investigated in aqueous media by dynamic light scattering (DLS) and fluorescence measurements using a pyrene hydrophobic fluorescence probe. In an acidic environment, these copolymers existed as single polymer chains that did not interact with each other. In contrast, upon increasing the pH of the solution above the critical value of ~8, separated micelles were formed in the mixture, which was indicated by bimodal distribution in DLS results with radius of 4.5 and 10.4 nm, corresponding to the random and block copolymer micelles, respectively. Fluorescence resonance energy transfer efficiencies were near to zero in the mixture of the donor labeled block and acceptor labeled random copolymers under both acidic and basic pH. These results demonstrated the coexistence of two distinct micelles.

Aceclofenac-loaded pluronic F108/L81 mixed polymeric micelles: effect of HLB on solubilization

ABSTRACT Pluronic block copolymers have phase behavioural characteristics which are extensively studied for drug delivery applications. In this study, we explored hydrophilic pluronic F108 (HLB = 27), hydrophobic pluronic L81 (HLB = 2) and their mixed micelles acting as solubilising mediums for model drug aceclofenac. The drug solubilisation and interactions have been analysed using UV-visible spectroscopy, Fluorescence spectroscopy, Rheology studies, Fourier-transform infrared spectroscopy, Scanning electron microscope, Dynamic light scattering, Cloud point and partition coefficient measurements. The investigation from UV-spectrophotometry demonstrated that mixed pluronic entrapped greater number of aceclofenac molecules than both the neat pluronics at same concentration. Excimer formation was evidenced from fluorescence spectra with pyrene as a probe. The rheological studies showed difference in viscosity over low shear range. Studies on FTIR demonstrated probable bonding between the aceclofenac and mixed pluronic molecules. The DLS studies on mixed pluronic showed swelling of micellar diameter from 317.6 nm to 413.5 nm. Thermodynamic parameters of the above system revealed higher partition coefficient value for mixed pluronic and spontaneity in drug solubilisation. This study can be exploited to use a hydrophobic copolymeric micelle in mixed pluronic formulation for better drug solubilisation.

Triblock Copolymer Micelles with Tunable Surface Charge as Drug Nanocarriers: Synthesis and Physico-Chemical Characterization.

Polymeric micelles have gained increasing interest as efficient drug delivery systems for cancer treatment and diagnosis. The aim of the present study was to construct and to evaluate novel polymeric nanosized drug carriers with tunable surface charges. Initially, amphiphilic triblock copolymers with predetermined molar mass characteristics were synthesized by applying controlled polymerization techniques. The copolymers self-assembled in aqueous media into core–shell spherical micelles, comprising a biodegradable hydrophobic poly(D,L-lactide) core, positively charged middle layer of poly((2-dimethylamino)ethyl methacrylate), and an outer shell of neutral hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate), with various densities of the short polyether side chains. The block copolymer micelles with average diameters of about 70 nm and surface charges varying from strongly positive to neutral were characterized and loaded with the model, natural, hydrophobic drug curcumin. Characteristics such as drug loading efficiency, in-vitro drug release profiles, and stability under physiological conditions were evaluated and discussed in terms of nanocarriers’ composition. As a result, the most promising candidates for potential application in nanomedicine were identified.

Facile Achievement of Complementary Resistive Switching in Block Copolymer Micelle-Based Resistive Memories.

Interest in resistive random access memory (RRAM) has grown rapidly in recent years for realizing ultrahigh density data storage devices. However, sneak currents in these devices can result in misreading of the data, thus limiting the applicability of RRAM. Complementary resistive switching (CRS) memory consisting of two antiserial RRAMs can considerably reduce sneak currents; however, complicated device architectures and manufacturing processes still remain as challenges. Herein, an effective and simple approach for fabricating CRS memory devices using self-assembled block copolymer micelles is reported. Cu ions are selectively placed in the core of polystyrene-block-poly(2-vinylpyridine) spherical micelles, and a hexagonally packed micelle monolayer is prepared through spin-coating. The micelle monolayer can be a symmetrical resistive switching layer, because the micelles and Cu act as dielectric and active metals in memory devices, respectively. The locally enhanced electric field and Joule heating achieved by the structured Cu atoms inside the micelles promote metal ionization and ion migration in a controlled manner, thus allowing for position selectivity during resistive switching. The micelle-based memory device exhibits stable and reliable CRS behavior, with a nonoverlapping and narrow distribution of threshold voltages. Therefore, this approach is promising for fabricating CRS memory devices for high-performance and ultrahigh-density RRAM applications.

Development of quercetin-loaded PVCL–PVA–PEG micelles and application in inhibiting tumor angiogenesis through the PI3K/Akt/VEGF pathway

Quercetin (Que) exhibits excellent biological activity; however, its clinical development is hindered owing to the poor water solubility. In this study, Que. was loaded on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL–PVA–PEG, Soluplus) micelles through a thin-film hydration process, and their tumor angiogenesis inhibition ability was investigated. The particle size of Soluplus-Que micelles was 55.3 ± 1.8 nm, and the micelles stayed stability within 9 months. Soluplus-Que micelles can enhance the cell uptake of Que. and transport the micelles to intracellular lysosomes and mitochondria. The MTT assay results revealed that Soluplus-Que micelles enhanced the cytotoxicity of Que. on HUVEC cells. Furthermore, Soluplus-Que micelles inhibited migration and invasion of HUVEC cells, as well as inhibited the neovascularization of chick embryo allantoic membrane (CAM). The in vivo study revealed that Soluplus-Que micelles significantly inhibit the growth of H22 solid tumors, with low toxic side effects. Soluplus-Que inhibited the expression of CD31 (a marker of angiogenesis) and the PI3K/Akt/VEGF pathway in tumor tissues, indicating its potential to hold back tumor growth via the inhibition of angiogenesis. Our findings indicated that as a delivery system, Soluplus micelles demonstrate potential for the delivery of poorly soluble drugs for tumor treatment.

Liquid Metal Interfacial Growth and Exfoliation to Form Mesoporous Metallic Nanosheets for Alkaline Methanol Electroreforming

Two-dimensional (2D) materials have spurred great interest in the field of catalysis due to their fascinating electronic and thermal transport properties. However, adding uniform mesopores to 2D metallic materials has remained a great challenge owing to the inherent high surface energy. Here, we introduce a generic liquid metal interfacial growth and exfoliation strategy to synthesize a library of penetrating mesoporous metallic nanosheets. The formation of liquid-metal/water interface promotes the adsorption of metal ion-encapsulated copolymer micelles, induces the self-limiting galvanic replacement reaction, and enables the exfoliation of products under mechanical agitation. These 2D mesoporous metallic nanosheets with large lateral size, narrow thickness distribution, and uniform perforated structure provide facilitated channels and abundant active sites for catalysis. Typically, the generated mesoporous PtRh nanosheets (mPtRh NSs) exhibit superior electroactivity and durability in hydrogen evolution reaction as well as methanol electrooxidation in alkaline media. Moreover, the constructed symmetric mPtRh NSs cell requires only a relative low electrolysis voltage to achieve methanol-assisted hydrogen production compared with traditional overall water electrolysis. The work reveals a specific growth pattern of noble metals at the liquid-metal/water interface and thus introduces a versatile strategy to form 2D penetrating mesoporous metallic nanomaterials with extensive high-performance applications.

Comparison of interaction patterns of a triblock copolymer micelle with zwitterionic vs. cationic surfactant: An excited-state proton transfer dynamics investigation

This investigation explored the interaction between a triblock copolymer F127 (poly-(ethylene oxide)101 (PEO101)–poly(propylene oxide)56 (PPO56)–PEO101)) micelle and a zwitterionic sulfobetaine surfactant N-dodecyl-N, N-dimethyl-3-ammoniopropane sulfonate (SB3–12 or SB12), primarily utilizing the excited-state proton transfer (ESPT) dynamics of a photoacid, 8-hydroxy pyrene-1,3,6-trisulfonate (HPTS). We compared the obtained interaction pattern to that of the cationic surfactant, dodecyl trimethylammonium bromide (DTAB or C12TAB), with the same alkyl chains. The two surfactants, irrespective of charge differences, grossly follow the same pattern as manifested by the change in the intensity ratio of the protonated and deprotonated emission bands. For both cases, the ratio first increases above a specific surfactant concentration, attaining a maximum at a particular concentration. The ratio decreases at a high concentration and finally levels off at a very high concentration. Interestingly, the ratio attains maximum for a post-micellar (30–35 mM) concentration (~ 10 times higher than critical micellar concentration or CMC) for SB12 whereas, the maximum occurs at a sub-micellar (6–8 mM) concentration (significantly lower than its CMC) for DTAB. Detailed analysis of the time-dependent emission intensity ratio reveals that ESPT dynamics is slower in the optimum F127-SB12 assembly than in the case of the cationic surfactant. The fluorescence anisotropy decay of 8-methoxypyrene-1,3,6-trisulfonate (MPTS), a methoxy analog of HPTS, also corroborates well with the anomalous pattern; the rotational dynamics become more retarded inside the F127-SB12 assembly than in the case of the cationic surfactant. Thus, although SB12 requires a higher surfactant concentration to acquire the optimum state, it results in a more organized and less hydrated state than the cationic surfactant.

METHOD VALIDATION OF SIMVASTATIN IN PCL-PEG-PCL TRIBLOCK COPOLYMER MICELLES USING UV-VIS SPECTROPHOTOMETRIC FOR SOLUBILITY ENHANCEMENT ASSAY

Objective: This study aims to increase the solubility of simvastatin (SIM), a hydrophobic drug, by incorporating it into PCL-PEG-PCL triblock copolymer micelles and validating the assay method used, namely Uv-Vis spectrophotometric. Methods: The shake flask method was used to determine the increase in solubility experienced by SIM after being incorporated into the micellar system. The values ​​of maximum wavelength (λmax), linearity, LOD, LOQ, accuracy, and precision were used as parameters measured to assess the validity of the assay method used. Results: The results showed that PCL-PEG-PCL triblock copolymer micelles could increase SIM solubility by 9.7 times (89.49±5.75 µg/ml) compared to SIM without modification (9.19±0.24 µg/ml). The validation results show the λmax value of 239 nm, a linear calibration curve with an R-value of 0.9994, LOD and LOQ of 0.33 µg/ml and 1.00 µg/ml, accurate measurement with recovery at concentrations of 80%, 100%, and 120% were 102.93±1.32%, 100.78±0.40%, and 104.58±0.79% and also had good precision ​​with RSD&lt;2%. Conclusion: The PCL-PEG-PCL triblock copolymer micelles can increase SIM solubility and the Uv-Vis spectrophotometric method has been validated successfully for the quantitative analysis of SIM in PCL-PEG-PCL triblock copolymer micelles.

Improvement of in vitro antioxidant activity of kaempferol by encapsulation in copolymer micelles

Antioxidant capacity of poorly soluble natural antioxidant kaempferol, in particular free or loaded in two types of cationic micelles, was studied on non-enzyme induced lipid peroxidation (LPO) in vitro. The micelles were based on triblock copolymers - poly(2-(dimethylamino)ethyl methacrylate-b-poly(propylene oxide)-b-poly(2-(dimethylamino)ethyl methacrylate (PDMAEMA-PPO-PDMAEMA) and poly(2-(dimethylamino)ethyl methacrylate-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate (PDMAEMA-PCL-PDMAEMA). The lipid peroxidation was induced by incubating of rat liver microsomes with iron sulphate and ascorbic acid (Fe2+/AA). The effect of free and micellar kaempferol (at concentrations 25, 50 and 75 μg/ml) was assessed after 20 min incubation time. In the non-enzyme lipid peroxidation model, the kaempferol-loaded micelles significantly decreased the formation of malondialdehyde (MDA). The effect of kaempferol loaded in PDMAEMA-PCL-PDMAEMA micelles was more pronounced, showing an improved antioxidant activity in the conditions of oxidative stress and lipid peroxidation in vitro.

Ultrasound-Induced Release of Nimodipine from Drug-Loaded Block Copolymer Micelles: In Vivo Analysis

Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm2). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm2) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44–61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83–91%) of their baseline diameter, which was significant (p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model.Graphical abstract

Comparative Thermodynamic Studies of the Micellization of Amphiphilic Block Copolymers before and after Cyclization.

The enthalpy and entropy of micellization in water, ΔHmic and ΔSmic, respectively, of three linear amphiphilic BAB block copolymers consisting of either poly(methyl acrylate) (Mn ∼ 1200 and 700 Da) or poly(ethyl acrylate) (Mn ∼ 800 Da) as hydrophobic (B) segments and poly(ethylene oxide) (PEO) as the hydrophilic (A, Mn ∼ 3000 Da) segment were determined by isothermal titration calorimetry (ITC). The ΔHmic and ΔSmic of the cyclic AB block copolymers obtained by cyclization of the linear triblock copolymers were determined under the same conditions. The ΔHmic value of the cyclic copolymers was smaller than that of their linear precursors. The ΔSmic value showed the same trend, but the relative difference between the cyclized and linear copolymers was less pronounced. The hydrodynamic diameter (Dh), critical micelle concentration (CMC), molecular weight (Mw-mic), and second virial coefficient (A2) of the micelles were determined. The Dh value of the cyclic copolymer micelles was smaller than the linear counterpart. On the other hand, the CMC value became larger, whereas the A2 value was comparable or increased by cyclization. Overall, the results suggest that, in the unimer state, the hydrophobic segments of the cyclized copolymers form a tightly coiled structure to minimize contact with water, resulting in the smaller ΔHmic value. Contrary to the linear copolymer micelles, the cyclic copolymer micelles have no "dangling chains", which may explain the topology-driven slight difference in the ΔSmic value.

White-emitting film of diblock copolymer micelles with perovskite nanocrystals.

Perovskite nanocrystals are synthesized in diblock copolymer micelles to improve their processability and stability. The copolymer micelle approach allows fluorescence from a stretchable or flexible substrate by coating processes, and stable emission in water by protecting the nanocrystals in the micelles. Fluorescent films in three primary colors of blue, green, and red are also produced with the assistance of anion exchange reactions for perovskite nanocrystals in the micelles. Then, by stacking films in three primary colors, we are able to produce a white-emitting film of copolymer micelles containing only perovskite nanocrystals without the support of other kinds of emissive materials.

Biocompatible thermoresponsive N-isopropyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide-based random copolymer: synthesis and studies of its composition dependent properties and anticancer drug delivery efficiency.

A new acrylamide monomer, N-isopropyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide (M3i), consisting of both isopropyl and isopropylamidopropyl moieties, has been synthesized from isopropylamine and N-isopropylacrylamide via an aza-Michael addition reaction followed by amidation with acryloyl chloride. The homopolymer of M3i (polyM3i) and a series of random copolymers of M3i and poly(ethylene glycol)methyl ether acrylate (PEGA: CH2CHCO2(CH2CH2O)nMe, Mn = 480, n = 9 on average) with varying compositions have been synthesized via reversible addition-fragmentation chain transfer polymerization using 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT) as well as 1-phenylethyl phenyl dithioacetate (PEPD) as a RAFT agent. These polymers have been characterized by 1H NMR, FTIR, GPC, UV-Vis, fluorescence, TGDTA, DSC, DLS, and TEM techniques. A lower critical solution temperature (LCST) and glass transition temperature (Tg) for polyM3i prepared using DDMAT were observed at 17 and 133 °C, respectively, while for a polymer formed using PEPD, no LCST was observed until 0 °C and its observed Tg was found at 127.3 °C. The polymers are thermally stable up to 300 °C. Upon an increase in the M3i content in the copolymers, LCST decreases, Tg increases, and the apparent hydrodynamic diameter decreases. Moreover, the effects of concentration and the addition of urea and sodium chloride on the LCST of the copolymer with an LCST close to body temperature were studied. Owing to the incorporation of PEGA, a higher critical micellar concentration and larger TEM particle size of this copolymer were observed with respect to those of polyM3i. The usefulness of the micelles of the copolymers as nano-carriers for the drug doxorubicin was explored. The in vitro tumoricidal activity of the micelles of the doxorubicin-loaded copolymers was also assessed against Dalton's lymphoma cells.

Self-assembly of micelles with pH/ROS dual-responsiveness and mitochondrial targeting for potential anti-tumor applications

A series of mitochondria-targeting and pH/ROS-responsive copolymer micelles was developed for the potential tumor-triggered targeted delivery of DOX.

The effect of Gd-DOTA locations within PLGA-b-PEG micelle encapsulated IR-1061 on bimodal over-1000 nm near-infrared fluorescence and magnetic resonance imaging.

Multimodal imaging is attractive in biomedical research because it can provide multidimensional information about objects that individual techniques cannot accomplish. In particular, combining over one-thousand-nanometer near-infrared (OTN-NIR) fluorescence and magnetic resonance (MR) imaging is promising for detecting lesions with high sensitivity and structural information. Herein, we describe the development of a bimodal OTN-NIR/MRI probe from gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) conjugated poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer (PLGA-b-PEG) micelle encapsulated IR-1061 at two different locations. One configuration contains Gd-DOTA at the end of the PEG of the hydrophilic shell and the other contains Gd-DOTA at the border of PLGA/PEG. The two structures show remarkable differences in fluorescence and R1 relaxation rates in biological environments; the structure with Gd-DOTA at the border of PLGA/PEG exhibits stable fluorescence and T1 signal distribution in live mice. The introduction ratio of Gd-DOTA to PEG is significant for controlling the properties of both structures; a higher Gd-DOTA ratio is preferable for the contrast enhancement effect. We found that Gd-DOTA ratios higher than 10% degraded the fluorescence intensity when Gd-DOTA was bound to the end of PEG. In contrast, the introduction of 70% Gd-DOTA at the border of PLGA/PEG did not exhibit a degraded signal, and the structural stability was enhanced with higher ratios of Gd-DOTA. In conclusion, we confirmed that the location of Gd-DOTA is a crucial factor in designing high-performance probes. The overall properties improve when Gd-DOTA is set on the border of PLGA/PEG. These improvements in the properties by controlling the probe structures are promising for future biomedical applications.

Oxidation of quantum dots encapsulated in block copolymer micelles as a function of polymer terminal charge.

Most high-quality quantum dots (QDs) are synthesized in the organic phase, and are often coated with polymers for use in aqueous biological environments. QDs can exhibit fluorescence losses during phase transfer, but evaluating underlying mechanisms (e.g., oxidation, surface etching, loss of colloidal stability) can be challenging because of variation in synthesis methods. Here, fluorescence stability of QDs encapsulated in block co-polymer (BCP) micelles was investigated as a function of BCP terminal functionalization (i.e., -OH, -COOH, and -NH2 groups) and synthesis method (i.e., electrohydrodynamic emulsification-mediated selfassembly (EE-SA), sonication, and manual shaking). Fluorescence losses, fluorescence intensity, energy spectra, and surface composition were assessed using spectrofluorometry and cathodoluminescence spectroscopy (CL) with integrated X-ray photoemission spectroscopy (XPS). QDs passivated using charged BCPs exhibited 50-80% lower fluorescence intensity than those displaying neutral groups (e.g., -OH), which CL/XPS revealed to result from oxidation of surface Cd to CdO. Fluorescence losses were higher for processes with slow formation speed, but minimized in the presence of poly(vinyl alcohol) (PVA) surfactant. These data suggest slower BCP aggregation kinetics rather than electrostatic chain repulsion facilitated QD oxidation. Thus, polymer coating method and BCP structure influence QD oxidation during phase transfer and should be selected to maximize fast aggregation kinetics.

Unexpected toroidal micelles formed from St/MMA gradient copolymers.

Toroidal micelles are of great interest and rarely observed in gradient copolymer systems. Herein, we report massive toroidal micelles formed from styrene (St)/methyl methacrylate (MMA) gradient copolymers using a common solvent mixing method followed by a cooling-heating procedure. Furthermore, we demonstrate that the obtained toroidal morphology is sensitively dependent on a heat treatment procedure. Solely spherical micelles are obtained by a common solvent mixing method. These spherical micelles could be transformed into toroidal micelles via vesicles during a cooling-heating process. When a reverse heating-cooling process is adopted, no toroidal micelles formed. Thus, these results add new members to the family of toroidal micelles and reveal pathway dominating morphologies in gradient copolymer micelles.

Realizing shape and size control for the synthesis of coordination polymer nanoparticles templated by diblock copolymer micelles.

The combination of polymers with nanoparticles offers the possibility to obtain customizable composite materials with additional properties such as sensing or bistability provided by a switchable spin crossover (SCO) core. For all applications, a precise control over size and shape of the nanomaterial is highly important as it will significantly influence its final properties. By confined synthesis of iron(II) SCO coordination polymers within the P4VP cores of polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) micelles in THF we are able to control the size and also the shape of the resulting SCO nanocomposite particles by the composition of the PS-b-P4VP diblock copolymers (dBCPs) and the amount of complex employed. For the nanocomposite samples with the highest P4VP content, a morphological transition from spherical nanoparticles to worm-like structures was observed with increasing coordination polymer content, which can be explained with the impact of complex coordination on the self-assembly of the dBCP. Furthermore, the SCO nanocomposites showed transition temperatures of T1/2 = 217 K, up to 27 K wide hysteresis loops and a decrease of the residual high-spin fraction down to γHS = 14% in the worm-like structures, as determined by magnetic susceptibility measurements and Mössbauer spectroscopy. Thus, SCO properties close or even better (hysteresis) to those of the bulk material can be obtained and furthermore tuned through size and shape control realized by tailoring the block length ratio of the PS-b-P4VP dBCPs.

Environmentally Responsive Multilayer Films Based on Block Copolymer Micelles and Natural Peptides for Controlled Release of Favipiravir

Environmentally Responsive Multilayer Films Based on Block Copolymer Micelles and Natural Peptides for Controlled Release of Favipiravir