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.

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.

Self-assembly of J-aggregate nanotubes and their applications for sensing dopamine.

J-aggregates are an attractive supramolecular structure with interesting excitation properties found in the light-harvesting antenna of green sulfur bacteria. To structurally mimic the light-harvesting antenna, we synthesize J-aggregate nanotubes with a sharp and intense absorption band (J-band) by the coassembly of lithocholic acid (LCA) and 3,3'-dipropylthiadicarbocyanine iodide (DiSC3(5)) in aqueous solution. We show that the J-aggregate nanotubes can be used as a supramolecular probe for the sensitive and selective detection of dopamine (DA) in phosphate buffered saline (PBS) solution with the detection limit of ∼0.4 nM by simply observing the intensity change of the J-band due to the efficient photoinduced electron transfer from the J-aggregate nanotubes to the adsorbed DA.

Bile acid-surfactant interactions at the liquid crystal/aqueous interface.

The interaction between bile acids and surfactants at interfaces plays an important role in fat digestion. In this paper, we study the competitive adsorption of cholic acid (CA) at the sodium dodecyl sulfate (SDS)-laden liquid crystal (LC)/aqueous interface formed with cyanobiphenyl (nCB, n = 5-8) and the mixture of 5CB with 4-(4-pentylcyclohexyl)benzonitrile (5PCH). We find that the critical concentration of CA required to displace SDS from the interface linearly decreases from 160 µM to 16 µM by reducing the alkyl chain length of nCB from n = 8 to n = 5 and from 16 µM to 1.5 µM by increasing the 5PCH concentration from 0 wt% to 19 wt% in the 5PCH-5CB binary mixture. Our results clearly demonstrate that the sensitivity of 5PCH-5CB mixtures for monitoring the interaction between CA and SDS at the LC/aqueous interface can be increased by one order of magnitude, compared to 5CB.

Optical detection of lithocholic acid with liquid crystal emulsions.

The concentration level of bile acids is a clinical biomarker for the diagnosis of intestinal diseases because individuals suffering from intestinal diseases have a sharply increased concentration of bile acids at micromolar levels. Here, we report the detection of lithocholic acid (LCA) in aqueous solution by using surfactant-stabilized 4-n-pentyl-4'-cyanobiphenyl (5CB) liquid crystal droplets as an optical probe. We find that the surfactant adsorbed at the 5CB/water interface can be replaced by LCA, triggering a radial-to-bipolar configuration transition of the 5CB in the droplets. By simply observing the LCA-triggered transition with a polarizing optical microscope, micromolar levels of LCA in aqueous solution can be detected. The detection limit and selectivity of surfactant-stabilized 5CB droplets for LCA depend on the chain length and headgroup of the surfactants used for stabilizing 5CB droplets.

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.

Boojum and stripe textures in long-range orientationally ordered monolayers on solid substrates.

Long-range organization of molecular tilt azimuth is a striking feature in monolayers at the air-water interface. We show that the boojum and stripe textures of pentadecanoic acid (PDA) with the continuous variations of molecular tilt azimuth formed at the air-water interface at temperatures lower than room temperature can be preserved after being transferred to glass substrates at low dipping speeds. The long-range tilt order in the transferred boojums and stripes is resolved by frictional force microscopy at room temperature, suggesting that the tilt order is "frozen" through the interaction of PDA molecules with the glass surface. The transferred stripe structure can be used as a unique alignment layer to induce a continuously azimuthal orientation of nematic liquid crystals.

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.

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.

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.

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.

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.

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.

Director configuration of liquid-crystal droplets encapsulated by polyelectrolytes.

Liquid-crystal 4-n-pentyl-4'-cyanobiphenyl (5CB) droplets dispersed in aqueous solution are prepared by the assembly of poly(styrenesulfonic acid) (PSSH) and poly(styrenesulfonate sodium) (PSSNa) at the 5CB/water interface. The micrometer sized PSSH-coated 5CB droplets in the space confinement formed by two parallel glass slides break up into submicrometer sized droplets under evaporation-induced flow. We find that the size reduction of the PSSH-coated droplets is accompanied by the bipolar-to-radial configuration transition of the 5CB in the droplets, while the PSSNa-coated 5CB droplets show no size-dependent configuration transition in the same size range. Our results suggest that the size-dependent director configuration of liquid-crystal droplets encapsulated by polyelectrolytes can be modulated by changing the interface conditions, which is important in designing liquid-crystal droplets for optical and biological applications.

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.

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.

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.