Controllable Drug-Release Ratio and Rate of Doxorubicin-Loaded Natural Composite Films Based on Polysaccharides: Evaluation of Transdermal Permeability Potential.

In drug delivery systems, it is crucial to develop a drug carrier capable of regulating both the drug-release rate and the drug-release ratio. This study proposes a method for controlling the drug-release ratio/rate using doxorubicin-loaded natural composite films composed of polysaccharides (cellulose, chitin, chitosan, or cellulose nanocrystal) and mineral substances (MMT: montmorillonite). We succeeded in controlling the doxorubicin release ratio from 25 to 88% depending on the natural polysaccharide. Likewise, the reduction rate differed depending on the type of natural polysaccharide, whereas the reduction in release was achieved by mixing MMT. Cellulose had the largest reduction in the drug release ratio, approximately 30%, and cellulose nanocrystals showed little change. Furthermore, we conducted a skin permeation test on the natural polysaccharide film with the highest release rate to confirm its transdermal permeability potential. The polysaccharide doxorubicin-loaded film sustainably released doxorubicin for 2 days, which indicated the potential of a carrier for DDS applications.

Platinum(II) terpyridine-based supramolecular polymer gels with induced chirality.

Metal-ligand binding plays a crucial role in regulating the photophysical properties of supramolecular gels. In this study, we designed 1-Pt complexes comprising a central benzene-1,3,5-tricarboxamide unit functionalized with three terpyridines, which can form supramolecular gels with Pt(II). The resulting supramolecular gel of 1-Pt exhibited strong orange emission, which was attributed to the metal-to-metal ligand charge transfer during gel formation. Furthermore, the temperature-dependent absorption spectrum changes of the supramolecular polymer 1-Pt exhibited a nonsigmoidal transition, following a cooperative pathway involving a nucleation-elongation mechanism. Additionally, the strategy for the co-assembling system involving 1-Pt with chiral molecules (D-form and L-form) induced the helical arrangement of 1-Ptvia chiral additives in supramolecular metallogels.

Controlled Release of Drug-Encapsulated Protein Films with Various Sodium Dodecyl Sulfate Concentrations.

Protein-based drug carriers are ideal drug-delivery platforms because of their biocompatibility, biodegradability, and low toxicity. Many types and shapes of protein-based platforms, including nanoparticles, hydrogels, films, and minipellets, have been prepared to deliver drug molecules. In this study, protein films containing the desired amounts of doxorubicin (DOX) as cancer drugs were developed using a simple mixing method. The release ratio and rate of DOXs were dependent on the surfactant concentration. The drug release ratio was controlled within the range of 20-90% depending on the amount of the surfactant used. The protein film surface was analyzed using a microscope before and after drug release, and the relationship between the degree of film swelling and the drug release ratio was discussed. Moreover, the effects of cationic surfactants on the protein film were investigated. Non-toxic conditions of the protein films were confirmed in normal cells, while the toxicity of the drug-encapsulated protein film was confirmed in cancer cells. Remarkably, it was observed that the drug-encapsulated protein film could eliminate 10-70% of cancer cells, with the extent of efficacy varying based on the surfactant amount.

Drug-Loaded Biocompatible Chitosan Polymeric Films with Both Stretchability and Controlled Release for Drug Delivery.

Chitosan is a natural polysaccharide with the advantageous qualities of biocompatibility and biodegradability, and it has recently been spotlighted as a soft material for a sustainable society. Advantages such as these are in demand for application in various biomaterials. Although extensive studies have been conducted on the preparation of chitosan films, overcoming the problems of weak mechanical properties remains a significant barrier. In the present study, we developed stretchable doxorubicin-loaded biocompatible chitosan films by adding acetic acid in controlled concentrations. The stretchable properties of doxorubicin-loaded chitosan film at various concentrations of acetic acid were measured. Elongation to the point of breakage reached 27% with a high concentration of acetic acid, which could be described as high stretchability. The release ratio of doxorubicin from chitosan film reached 70% with a high acetic acid concentration. The cytotoxicity of doxorubicin-loaded chitosan films was measured, and cancer spheroids had completely collapsed after 7 days. According to the results of skin permeability testing, use of the doxorubicin-loaded chitosan film is a plausible choice for a drug sealant.

Circularly Polarized Luminescence Active Supramolecular Nanotubes Based on PtII Complexes That Undergo Dynamic Morphological Transformation and Helicity Inversion.

Circularly polarized luminescence (CPL) with tunable chirality is currently a challenging issue in the development of supramolecular nanomaterials. We herein report the formation of helical nanoribbons which grow into helical tubes through dynamic helicity inversion. For this, chiral PtII complexes of terpyridine derivatives, namely S-trans-1 and R-trans-1, with respective S- and R-alanine subunits and incorporating trans-double bonds in the alkyl chain were prepared. In DMSO/H2 O (5 : 1 v/v), S-trans-1 initially forms a fibrous self-assembled product, which then undergoes dynamic transformation into helical tubes (left-handed or M-type) through helical ribbons (right-handed or P-type). Interestingly, both helical supramolecular architectures are capable of emitting CPL signals. The metastable helical ribbons show CPL signals (glum =±4.7×10-2 ) at 570 nm. Meanwhile, the nanotubes, which are the thermodynamic products, show intense CPL signals (glum =±5.6×10-2 ) at 610 nm accompanied by helicity inversion. This study provides an efficient way to develop highly dissymmetric CPL nanomaterials by regulating the morphology of metallosupramolecular architectures.

In Situ Supramolecular Gel Formed by Cyclohexane Diamine with Aldehyde Derivative.

Low-molecular-weight gels have great potential for use in a variety of fields, including petrochemicals, healthcare, and tissue engineering. These supramolecular gels are frequently metastable, implying that their properties are kinetically controlled to some extent. Here, we report on the in situ supramolecular gel formation by mixing 1,3-cyclohexane diamine (1) and isocyanate derivative (2) without any catalysis at room temperature in various organic solvents. A mixture of building blocks 1 and 2 in various organic solvents, dichloromethane, tetrahydrofuran, chloroform, toluene, and 1,4-dioxane, resulted in the stable formation of supramolecular gel at room temperature within 60-100 s. This gel formation was caused by the generation of urea moieties, which allows for the formation of intermolecular hydrogen-bonding interactions via reactions 1 and 2. In situ supramolecular gels demonstrated a typical entangled fiber structure with a width of 600 nm and a length of several hundred µm. In addition, the supramolecular gels were thermally reversible by heating and cooling. The viscoelastic properties of supramolecular gels in strain and frequency sweets were enhanced by increasing the concentration of a mixed 1 and 2. Furthermore, the supramolecular gels displayed a thixotropic effect, indicating a thermally reversible gel.

Kahweol Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting the Src/mTOR/STAT3 Signaling Pathway.

Kahweol, a coffee-specific diterpene, induces apoptosis in human cancer cells, and some targets of kahweol-mediated apoptosis have been identified. However, the specific apoptotic effects and mechanism of action of kahweol in hepatocellular carcinoma (HCC) cells are unknown. This study was performed to investigate the molecular mechanism by which kahweol induces apoptosis in HCC cells. The Src pathway is associated with apoptosis in cancer. In this study, we found that kahweol induces apoptosis by inhibiting phosphorylation of Src, and also inhibiting p-mTOR and p-STAT3. Therefore, we suggest that kahweol is a potent inhibitor of HCC cell growth.

Simple Formation of Cancer Drug-Containing Self-Assembled Hydrogels with Temperature and pH-Responsive Release.

The purpose of a drug delivery system is to efficiently deliver drugs to a desired target, while simultaneously reducing the side effects caused by these drugs and maximizing their efficacy. However, in the manufacture of a drug delivery system, it is difficult to control the amount of drug encapsulation. In this study, we developed a simple formation process of self-assembled hydrogels that made it easier to package the desired amount of anticancer drugs. A self-assembled hydrogel was prepared by simply mixing transferrin, dithiothreitol, and an anticancer drug in a salt solvent. The structural conditions of the hydrogel were determined in order to control the concentration of the transferrin protein, dithiothreitol, and salt in the solvent. The self-assembled hydrogels contained the desired amount of anticancer drugs. With this system, changes in pH and temperature control the release rate and the release ratio of anticancer drugs. The cytotoxicity of the drug-loaded hydrogel was evaluated, which showed that 80% of the treated cells had been killed following 48 h of incubation.

Beryllium-Ion-Selective PEDOT Solid Contact Electrode Based on 9,10-Dinitrobenzo-9-Crown-3-Ether.

A beryllium(II)-ion-selective poly(ethylenedioxythiophene) (PEDOT) solid contact electrode comprising 9,10-dinitrobenzo-9-crown-3-ether was successfully developed. The all-solid-state contact electrode, with an oxygen-containing cation-sensing membrane combined with an electropolymerized PEDOT layer, exhibited the best response characteristics. The performance of the constructed electrode was evaluated and optimized using potentiometry, conductance measurements, constant-current chronopotentiometry, and electrochemical impedance spectroscopy (EIS). Under optimized conditions, which were found for an ion-selective membrane (ISM) composition of 3% ionophore, 30% polyvinylchloride (PVC), 64% o-nitro phenyl octyl ether (o-NPOE), and 3% sodium tetraphenylborate (NaTPB), the fabricated electrode exhibited a good performance over a wide concentration range (10-2.5-10-7.0 M) and a wide pH range of 2.0-9.0, with a Nernstian slope of 29.5 mV/D for the beryllium (II) ion and a detection limit as low as 10-7.0 M. The developed electrode shows good selectivity for the beryllium(II) ion over alkali, alkaline earth, transition, and heavy metal ions.

Kahweol activates the Nrf2/HO-1 pathway by decreasing Keap1 expression independently of p62 and autophagy pathways.

Kahweol is a diterpene found in coffee beans and unfiltered coffee drinks. Several studies have demonstrated that kahweol induces the nuclear factor erythroid-2 related factor 2/ hemeoxygenase-1 (Nrf2/HO-1) pathway; however, the mechanisms involved are currently unknown. Kelch-like ECH-associated protein 1 (Keap1) is a major regulator of Nrf2 expression and is degraded mostly by autophagy. The p62 protein enhances binding to Keap1 and contributes to the activation of Nrf2. Here, we examined the role of Keap1 regulation in the effect of kahweol on the Nrf2/HO-1 pathway in hepatocytes. In AML12 cells and primary mouse hepatocytes, kahweol increased the levels of Nrf2 and HO-1 protein without increasing expression of the Nrf2 mRNA. In addition, kahweol reduced Keap1 protein levels significantly without decreasing Keap1 mRNA levels. Although regulation of the Keap1-Nrf2-pathway by p62-dependent autophagy is well known, we confirmed here that the reduction of Keap1 protein levels by kahweol does not involve p62-dependent autophagy degradation or ubiquitination. In conclusion, kahweol increases the expression of Nrf2 in hepatocytes by inhibiting translation of the Keap1 mRNA.

Bispicolyamine-Based Supramolecular Polymeric Gels Induced by Distinct Different Driving Forces with and Without Zn2.

Metal-coordination polymeric gels are interesting areas as organic/inorganic hybrid supramolecular materials. The bispicolylamine (BPA) based gelator (1) showed excellent gelation with typical fibrillar morphology in acetonitrile. Upon complexing 1 with Zn2+, complexes ([1 + Zn + ACN]2+ and [1 + zinc trifluoromethanesulfonate (ZnOTf)]+) with four coordination numbers were formed, which determine the gel structure significantly. A gel-sol transition was induced, driven by the ratio of the two metal complexes produced. Through nuclear magnetic resonance analysis, the driving forces in the gel formation (i.e., hydrogen-bonding and π-π stacking) were observed in detail. In the absence and the presence of Zn2+, the intermolecular hydrogen-bonds and π-π stacking were the primary driving forces in the gel formation, respectively. In addition, the supramolecular gels exhibited a monolayer lamellar structure irrespective of Zn2+. Conclusively, the gels' elasticity and viscosity reduced in the presence of Zn2+.

Monodisperse Micelles with Aggregation Numbers Related to Platonic Solids.

Recent studies show that calix[4]arene-based micelles are monodisperse with defined Nagg values chosen from 4, 6, 8, 12, 20, and 32. Interestingly, all these numbers coincide with the face numbers of Platonic solids, so they are called "Platonic micelles." As long as a certain geometric condition is fulfilled, any amphiphilic molecule can form a Platonic micelle. The preferred Nagg values are explained in relation to the mathematical Tammes problem, namely, how to obtain the best coverage of a sphere's surface with multiple identical circles. The coverage ratio can be calculated and produces maxima at 4, 6, 12, 20, and 32, coinciding with the observed Nagg values. In this feature article, Platonic micelles as well as their morphological transition by controlling pH, salt, temperature, and electrostatic interactions are summarized.

Synthesis and characterization of nanoemulsion-mediated core crosslinked nanoparticles, and in vivo pharmacokinetics depending on the structural characteristics.

For designing nanoparticles as drug carriers, a covalently crosslinked structure is necessary for the structural stability in vivo. In this study, we prepared core crosslinked nanoparticles through the formation of nanoemulsions stabilized by poly(ethylene glycol) (PEG)-bearing surfactants. The structural characteristics of these particles were carefully evaluated using small-angle scattering techniques including dynamic, static, X-ray, and neutron scattering. The particles demonstrated high stability even in vivo, with the suppression of premature drug release owing to the crosslinked structure. Interestingly, the ability to retain encapsulated molecules was dependent on the molecular weight of PEG in vivo, presumably due to the difference in the crowding density of PEG chains at the outermost surface. This suggests that conferring structural stability via a core crosslinked structure is surely important, but we also need to consider controlling the crowding density of the hydrophilic polymer chains in the particle shell when designing drug carriers.

Structural Polymorphism of Resorcinarene Assemblies.

In 1997, a study based on X-ray crystallography revealed that resorcinarenes adopt a hexameric capsule-like structure. The function of resorcinarenes has been discussed on the basis of this structure; however, our recent study showed that the hexamer may be only one of resorcinarenes' polymorphic members. Here, we present the solvent dependence of the aggregation number of C-undecylresorcinarene in water-saturated toluene and chloroform using small-angle neutron and X-ray scattering and analytical ultracentrifugation measurements. We found that a new octamer was formed in toluene where the eight resorcinarene units were placed at the vertices of a regular cube; this contrasts to the previous structure in chloroform, namely, a hexamer with the six resorcinarenes located at the vertices of a regular octahedron that has a cavity inside where chloroform molecules are pooled.

Bundling Process of Citrulline Polypeptides upon UCST-Type Phase Separation.

Ureido-modified poly(l-citrulline) (l-ornithine-co-l-citrulline denoted by PlOC) shows UCST-type phase separation behavior even under physiologically relevant conditions, which forms an α-helix structure above its phase separation temperature (Tp) but transforms into a solid-like aggregation composed of regular hexagonal packed cylinders below the Tp. This morphological transformation is characteristic of the phase separation behavior, but the mechanism behind it has remained incompletely understood. Here, we studied the phase separation behavior using small-angle X-ray scattering (SAXS) measurements. To analyze the SAXS data, we employed the modified unified model proposed previously, which decomposes the scattering profile into each structural element, such as the α-helices and their aggregation formed via hydrogen-bonding interactions between the ureido groups. The aggregation level is dependent on the temperature (T) and grouped into three classes: (1) mass-fractal aggregation composed of the α-helix (T > Tp), (2) spherical aggregation composed of the hexagonal packed cylinder (T < Tp), and (3) micro-order agglomeration formed by mutual fusion of the spherical aggregation, which appears as a solid-like aggregation. The SAXS analysis suggested that the transformation from the dispersed state as the α-helix to the agglomeration containing hierarchical structures occurs in a stepwise manner when the temperature falls below the Tp, which might also be transition behavior similar to the process of protein folding through folding intermediates.

Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connetive Tissue Growth Factor.

The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor ß (TGF-ß)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.

Clusterin Attenuates Hepatic Fibrosis by Inhibiting Hepatic Stellate Cell Activation and Downregulating the Smad3 Signaling Pathway.

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis.

Finely Controlled Circularly Polarized Luminescence of a Mechano-Responsive Supramolecular Polymer.

Finely controlled circularly polarized luminescence (CPL) supramolecular polymerization based on a tetraphenylethene core with four l- or d-alanine branch side chains (l-1 and d-1) in the solution state is presented, resulting from the tuning of mechanical stimulus. Weak, green emissions of l-1 and d-1 in tetrahydrofuran (THF) were converted into strong blue emissions by tuning the mechanical stimulus. The strong blue emissions were caused by an aggregation-induced emission (AIE) effect during the formation of a supramolecular polymer. Lag time in the supramolecular polymerization was drastically reduced by the mechanical stimulus, which was indicative of the acceleration of the supramolecular polymerization. A significant enhancement of circular dichroism (CD) and CPL signals of l-1 and d-1 was observed by tuning the rotational speed of the mechanical stimulus, implying that the chiral supramolecular polymerization was accelerated by the mechanical stimulus.