Crystalline H-aggregate nanoparticles for detecting dopamine release from M17 human neuroblastoma cells.

Dopamine (DA) is an important neurotransmitter, which is essential for transmitting signals in neuronal communications. The deficiency of DA release from neurons is implicated in neurological disorders. There has been great interest in developing new optical probes for monitoring the release behavior of DA from neurons. H-aggregates of organic dyes represent an ordered supramolecular structure with delocalized excitons. In this paper, we use the self-assembly of 3,3'-diethylthiadicarbocyanine iodide (DiSC2(5)) in ammonia solution to develop crystalline H-aggregate nanoparticles, in which DiSC2(5) molecules show long-range π-π stacking. The crystalline H-aggregate nanoparticles are stable in cell culture medium and can serve as an efficient photo-induced electron transfer (PET) probe for the detection of DA with the concentration as low as 0.1 nM in cell culture medium. Furthermore, the crystalline H-aggregate nanoparticle-based PET probe is used to detect the release behavior of DA from the M17 human neuroblastoma cells. We find that the DA release from the cells is enhanced by nicotine stimulations. Our results highlight the potential of crystalline H-aggregate nanoparticle-based PET probes for diagnosing nervous system diseases and verifying therapies.

Microstate feature fusion for distinguishing AD from MCI.

Electroencephalogram (EEG) microstates provide powerful tools for identifying EEG features due to their rich temporal information. In this study, we tested whether microstates can measure the severity of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in patients and effectively distinguish AD from MCI. We defined two features using transition probabilities (TPs), and one was used to evaluate between-group differences in microstate parameters to assess the within-group consistency of TPs and MMSE scores. Another feature was used to distinguish AD from MCI in machine learning models. Tests showed that there were between-group differences in the temporal characteristics of microstates, and some kinds of TPs were significantly correlated with MMSE scores within groups. Based on our newly defined time-factor transition probabilities (TTPs) feature and partial accumulation strategy, we obtained promising scores for accuracy, sensitivity, and specificity of 0.938, 0.923, and 0.947, respectively. These results provide evidence for microstates as a neurobiological marker of AD.

Targeting the resolution pathway of inflammation using Ac2-26 peptide-loaded PEGylated lipid nanoparticles for the remission of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2-26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2-26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn­glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2-26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2-26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.

Injectable Micelle-Incorporated Hydrogels for the Localized Chemo-Immunotherapy of Breast Tumors.

Although immune checkpoint blockade (ICB) holds potential for the treatment of various tumors, a considerable proportion of patients show a limited response to ICB therapy due to the low immunogenicity of a variety of tumors. It has been shown that some chemotherapeutics can turn low-immunogenic tumors into immunogenic phenotypes by inducing a cascade of immune responses. In this paper, we synthesized an injectable micelle-incorporated hydrogel, which was able to sequentially release the chemotherapeutic gemcitabine (GEM) and the hydrophobic indoleamine 2, 3-dioxygenase inhibitor, d-1-methyltryptophan (d-1MT) at tumor sites. The hydrogel was formed via the thiol-ene click reaction between the thiolated chondroitin sulfate and the micelle formed by amphiphilic methacrylated Pluronic F127, in which hydrophobic d-1MT was encapsulated in the core of the F127 micelles and the hydrophilic GEM was dispersed in the hydrogel network. The successive release of chemotherapeutics and immune checkpoint inhibitors at tumor tissues will first promote the infiltration of cytotoxic T lymphocytes and subsequently induce a robust antitumor immune response, ultimately exerting a synergetic therapeutic efficacy. In a 4T1 tumor-bearing mice model, our results showed that the combination of chemotherapy and immunotherapy through the micelle-incorporated hydrogel triggered an effective antitumor immune response and inhibited tumor metastasis to the lung. Our results highlight the potential of the injectable micelle-incorporated hydrogel for the localized chemo-immunotherapy in the treatment of breast tumors.

Fluorescent H-Aggregate Vesicles and Tubes of a Cyanine Dye and Their Potential as Light-Harvesting Antennae.

H-aggregates of π-conjugated dyes are an ordered supramolecular structure. However, the non-fluorescence behavior of H-aggregates greatly limits their potential applications. In this paper, we report the formation of fluorescent H-aggregates with vesicular and tubular morphologies by the self-assembly of 3,3'-diethylthiacarbocyanine iodide (DiSC2(3)) in ammonia/methanol mixtures. The transition from H-aggregate vesicles to H-aggregate tubes can be achieved by increasing the volume fraction of methanol in the mixtures. H-aggregate vesicles and tubes show two blue-shifted absorption bands and strong fluorescence, which result from the inclined arrangement of DiSC2(3) molecules. Furthermore, light-harvesting complexes are formed by adding dopamine (DA)-quinone (acceptor) in synthetic urine with H-aggregate vesicles or tubes. Our results show that H-aggregate tubes are more efficient than H-aggregate vesicles in transferring excited electrons to DA-quinone acceptors.

Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies.

Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.

Delivery of Ferulic Acid with PEGylated DiphenylalanineBased Nanoparticles for the Treatment of Arthritis in Early Stage.

Ferulic acid (FA), an active component extracted from Chinese medicine, shows excellent anti-inflammatory properties and favorable safety in various animal models. However, the application of FA as an anti-inflammatory drug is hindered by its instability and short half-life in vivo . In this paper, we synthesize PEGylated diphenylalanine nanoparticles by using glutaraldehyde (GTA) as a cross-linker of diphenylalanine NH2 -Phe-Phe-COOH and poly(ethylene glycol) methyl ether amine (PEG5k -NH2). The PEGylated Phe-Phe nanoparticles are used to deliver FA for the treatment of Rheumatoid arthritis (RA). We find that the FA-loaded PEGylated Phe-Phe nanoparticles are biocompatible and inhibit the production of reactive oxygen species (ROS) from cells effectively. After being intravenously administrated in vivo , the FA-loaded PEGylated Phe-Phe nanoparticles show prolonged circulation time and accumulate in arthritic joints. More importantly, we show that the pre-arthritis treatment with the FA-loaded PEGylated Phe-Phe nanoparticles can significantly block the progression of RA.

Dual-Stimuli Responsive Polymeric Micelles for the Effective Treatment of Rheumatoid Arthritis.

The nontargeted distribution and uncontrolled in vivo release of drugs impede their efficacy in the treatment of rheumatoid arthritis (RA). Delivering drugs to arthritic joints and releasing drugs on demand are a feasible solution to achieve the effective treatment of RA. In this paper, we report a facile method to assemble dual-stimuli responsive polymeric micelles from polyethylene glycol-phenylboric acid-triglycerol monostearate (PEG-PBA-TGMS, PPT) conjugates with the aim of delivering dexamethasone (Dex) to arthritic joints and controlling the release of Dex by inflammatory stimuli. We show that the release of Dex from the PPT micelles is accelerated in response to acidic pH and overexpressed matrix metalloproteinases. In an adjuvant-induced arthritis model, the PPT micelles preferentially accumulate in arthritic joints and show an excellent therapeutic efficacy after being intravenously administrated. Our results highlight the potential of the dual stimuli-responsive micelles as a promising therapeutic option for the effective treatment of inflammatory diseases.

Protection of hUC-MSCs against neuronal complement C3a receptor-mediated NLRP3 activation in CUMS-induced mice.

BACKGROUND: Hyperactivation of complement C3 and inflammation-related activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome are implicated in the etiology of stress-related disorders. Studies have shown that human umbilical cord mesenchymal stromal cells (hUC-MSCs) have immunomodulatory and anti-inflammatory effects; however, the mechanism remains unclear. METHODS: hUC-MSCs were administered to chronic unpredictable mild stress (CUMS) model mice once a week for four weeks. After the administration of hUC-MSCs, several parameters were assessed, including behavioral performance, synapse-related proteins, complement C3 receptors (C3aR) in neurons, and the NLRP3 inflammasome. Then, CUMS mice were injected with SB290157, a complement C3aR antagonist, and the behavioral index and NLRP3 inflammasome activation were tested. RESULTS: The open-field and forced swimming behavioral tests showed an improvement in depression-like behaviors in the CUMS-exposed mice after the administration of hUC-MSCs. Treatment with hUC-MSCs significantly decreased the neuronal C3aR levels and alleviated synaptic damage. Furthermore, the levels of the NLRP3 inflammasome and inflammatory factors were reduced after hUC-MSC administration. In particular, treatment with a C3aR antagonist also decreased NLRP3 inflammasome expression and inflammation, which was consistent with the observed improvements after hUC-MSC treatment. CONCLUSION: hUC-MSCs can attenuate NLRP3 activation in CUMS-induced mice, which may be correlated with C3aR in neurons.

Davydov Split Aggregates of Cyanine Dyes on Self-Assembled Nanotubes.

The Davydov splitting of dye aggregates represents unique molecular excitons. In this paper, we report the formation of Davydov split aggregates of 3,3'-diethylthiacarbocyanine iodide (DiSC2 (3)) and 3,3'-diethylthiadicarbocyanine iodide (DiSC2 (5)) templated by the helical nanotubes of lithocholic acid (LCA). The templated Davydiv split aggregates show a strong J-band and a weak H-band in the adsorption spectra. As the LCA helical nanotubes transform into a straight shape, the relative intensities of the J-band and the H-band of the templated Davydov split aggregates become roughly equal. The twisted angle change of the transition moment of DiSC2 (3) and DiSC2 (5) molecules in the templated Davydov split aggregates in response to the helical-to-straight shape transformation of LCA nanotubes is estimated. The templated Dvaydov split aggregates with well-defined shapes and molecular excitons are of interest for artificial light-harvesting and optoelectronic devices.

Colorimetric Detection of Dopamine with J-Aggregate Nanotube-Integrated Hydrogel Thin Films.

The deficiency of dopamine (DA) is clinically linked to several neurological diseases. The detection of urinary DA provides a noninvasive method for diagnosing these diseases and monitoring therapies. In this paper, we report the coassembly of lithocholic acid (LCA) and 3,3'-diethythiadicarbocyanine iodide (DiSC2(5)) at the equimolar ratio in ammonia solution into J-aggregate nanotubes. By integrating the J-aggregate nanotubes into transparent agarose hydrogel films formed on the wall of quartz cuvettes, we fabricate a portable and reproducible sensor platform for the optical detection of DA in synthetic urine. The J-band intensity of the integrated J-aggregate nanotubes is found to linearly decrease with the increase of DA concentrations from 10 to 80 nM, giving the limit of detection of ∼7 nM. The detection mechanism is based on the photoinduced electron transfer (PET) from the excited J-aggregate nanotubes to adsorbed DA-quinone. The PET process used in the sensor platform can reduce the interference of ascorbic acid and uric acid in the detection of DA in synthetic urine. The high sensitivity of the sensor platform is contributed by the delocalized exciton of J-aggregate nanotubes.

Improving the anti-inflammatory efficacy of dexamethasone in the treatment of rheumatoid arthritis with polymerized stealth liposomes as a delivery vehicle.

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints of the body. Although liposomes are a promising drug delivery vehicle, there is still a challenge of using conventional liposomes for the treatment of RA due to their short circulation time and physicochemical instability in blood vessels. Here, we report the formation of polymerized stealth liposomes composed of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) with a thin-film hydration method, in which DC8,9PC molecules are cross-linked in the bilayer of the liposomes by UV irradiation and the PEG chains present at the surface of the liposomes provide a stealth layer. We demonstrate that the polymerized stealth liposomes are stable and show long circulation time in blood vessels. They can be internalized by cells without significant toxicity. After being injected into arthritic rats, the polymerized stealth liposomes with loaded dexamethasone (Dex) show long blood circulation time and accumulate preferentially in inflamed joints, consequently suppressing the level of proinflammatory cytokines (TNF-α and IL-1ß) in joint tissues, reducing the swelling of inflamed joints and alleviating the progression of RA. We believe that polymerized stealth liposomes can be used as a promising drug delivery vehicle for various therapeutic applications.

PLA2-Triggered Release of Drugs from Self-Assembled Lipid Tubules for Arthritis Treatments.

Environment-responsive drug delivery is a promising approach for tailoring the drug release in drug therapy. In this study, we develop lipid tubules by the self-assembly of 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). These lipid tubules are capable of encapsulating hydrophobic dexamethasone (Dex) and hydrophilic dexamethasone sodium phosphate (DSP) simultaneously. In vitro studies show that the lipid tubules can be internalized by cells with no significant toxicity. We find that phospholipase (PLA2) is able to slowly digest the lipid tubules and trigger the sustained release of Dex and DSP. After being subcutaneously administrated to the inflammatory sites of arthritic rats, we show that a single dose of drug-loaded lipid tubules can remarkably inhibit the degree of joint swelling at the inflammatory sites and suppress the content of proinflammatory cytokines in inflamed tissues for a long time by this sustained release of both Dex and DSP triggered by the highly expressed PLA2 at the inflamed sites. Our results highlight the potential of using PLA2-responsive lipid tubules as on-demand carriers for treating inflammatory diseases.

Matrix Metalloproteinase-Responsive PEGylated Lipid Nanoparticles for Controlled Drug Delivery in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder. It causes inflammation, swelling, and pain in the joints of the human body. Overexpressed matrix metalloproteinases (MMPs) at the inflammatory sites of RA are a target in the construction of inflammation-responsive drug delivery vehicles for enhancing the therapeutic effect of anti-inflammatory drugs in the treatment of RA. In this paper, we report MMP-responsive PEGylated lipid nanoparticles through the co-assembly of triglycerol monostearate (TGMS) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) in which the ester bond of TGMS is cleavable by MMPs and the PEG chain provides a stealth layer. The lipid nanoparticles show high biocompatibility, extended blood circulation, and preferential distribution in the inflammatory joints of RA. The loaded dexamethasone (Dex) can be rapidly released from the lipid nanoparticles in response to MMPs. After being intravenously administered to arthritic rats, Dex-loaded MMP-responsive PEGylated lipid nanoparticles significantly reduce the degree of joint swelling and inhibit the production of TNF-α and IL-1ß in joint tissues. These results demonstrate that MMP-responsive PEGylated lipid nanoparticles are a smart drug vehicle for the treatment of RA with improved therapeutic efficacy.

Morphology Transformation of Supramolecular Structures in Aqueous Mixtures of Two Oppositely Charged Amphiphiles.

The co-assembly of oppositely charged amphiphiles provides a fascinating approach for forming complex supramolecular structures, which are interesting from both fundamental and technological viewpoints. Here, we report a stepwise morphology transformation of co-assembled supramolecular structures in the aqueous mixture of lithocholic acid (LCA) and cetyltrimethylammonium bromide (CTAB) at mixed molar ratios of 1:1 and 2:1. The co-assembly of LCA and CTAB initially forms multilamellar vesicles followed by the spontaneous growth of membrane tubes from the vesicles. The vesicle-to-tube transition is accompanied by a fluidic-to-crystalline phase transition. After being aged, the membrane tubes twist into left-handed helices, which then intertwine into left-handed double helices and multihelix bundles. The single handedness of these supramolecular structures is a reflection of the amplification of the chirality of LCA. An understanding of the co-assembly mechanism and pathway is a key step toward producing supramolecular structures with distinguished morphologies.

Soft-Templated Synthesis of Lightweight, Elastic, and Conductive Nanotube Aerogels.

Conductive polymer (CP) nanotubes are fascinating nanostructures with high electrical conductivity, fast charge/discharge capability, and high mechanical strength. Despite these attractive physical properties, progress in the synthesis of CP nanotube hydrogels is still limited. Here, we report a facile and effective approach for the synthesis of polypyrrole (PPy) nanotube hydrogels by using the weakly interconnected network of self-assembled nanotubes of lithocholic acid as a soft template. The PPy nanotube hydrogels are then converted to aerogels by freeze drying, in which PPy nanotubes form elastic and conductive networks with a density of 38 mg/cm3 and an electrical conductivity of 1.13 S/m. The PPy nanotube aerogels are able to sustain a compressive strain as high as 70% and show an excellent cyclic compressibility due to their robust nanotube networks and hierarchically porous structures, which allow the compressive stress to be easily dissipated. Furthermore, PPy nanotube aerogels show negative strain-dependent electrical resistance changes under compressive strains. The lightweight, elastic, and conductive PPy nanotube aerogels may find potential applications in strain sensors, supercapacitors, and tissue scaffolds.

Preparation of multi-layer nylon-6 nanofibrous membranes by electrospinning and hot pressing methods for dye filtration.

We report the formation of multi-layer nylon-6 (PA-6) nanofibrous membranes by electrostatic spinning coupled with a hot pressing process. The structure and porosity of multi-layer PA-6 nanofibrous membranes were characterized using a scanning electron microscope and the N2 nitrogen adsorption and desorption isotherms. We show that multi-layer PA-6 nanofibrous membranes can be used for efficient and continuous indigo dye filtration. Under the condition of constant pressure at the 0.1 MPa dead end filtration, continuous filter for a period of time, the filtration efficiency for indigo dye increases with the increase of the number of layers in PA-6 nanofibrous membranes. The 10 layer PA-6 nanofiber membrane can completely remove the indigo dye, and early filtration flux was high, with extended time, the filtration flux decline and gradually stabilized.

Formation of Spherulitic J-Aggregates from the Coassembly of Lithocholic Acid and Cyanine Dye.

Supramolecular aggregates of organic dyes through noncovalent interactions have attracted great interest because they exhibit collective optical and excitonic properties. We report the formation of spherulitic J-aggregates from the coassembly of lithocholic acid (LCA) and 3,3'-diethylthiacarbocyanine iodide (DiSC2(3)) in ammonia solution. Each spherulite contains a core, which serves as a nucleus for the growth of radially oriented J-aggregate fibrils. We find that the growth of spherulitic J-aggregates exhibits a sigmoidal kinetic curve with an initial lag time, followed by a period of rapid growth and a finally slow approach to equilibrium.

Liquid Crystal Droplet-Embedded Biopolymer Hydrogel Sheets for Biosensor Applications.

The development of simple, portable, and low-cost biosensing platforms is of great interest in the clinical diagnosis of disease. Here, we report liquid crystal (LC) droplet-embedded chitosan (CHI) hydrogel films formed by the Ag(+) ion-triggered fast gelation of the CHI/surfactant complex-stabilized LC emulsion which is cast on substrates. The small sheets cut from the LC droplet-embedded hydrogel films combine the advantages of both hydrogels and LC droplets, offering a portable and label-free sensing platform for the real-time detection of bile acids in a small amount of solution. We find that the response time and detection limit of LC droplet-embedded hydrogel sheets for bile acids depend on their chemical structures.

Design of ß-CD-surfactant complex-coated liquid crystal droplets for the detection of cholic acid via competitive host-guest recognition.

ß-CD-C14TAB complex-coated 5CB droplets are designed by the adsorption of ß-CD-C14TAB complexes at the 5CB/aqueous interface. We show that the 5CB droplets can be used as an optical probe for the selective detection of cholic acid in aqueous solution containing uric acid and urea via competitive host-guest recognition.