DNA Nanoparticle Based 2D Biointerface to Study the Effect of Dynamic RGD Presentation on Stem Cell Adhesion and Migration.

The native extracellular matrix (ECM) undergoes constant remodeling, where adhesive ligand presentation changes over time and in space to control stem cell function. As such, it is of interest to develop 2D biointerfaces able to study these complex ligand stem-cell interactions. In this study, a novel dynamic bio interface based on DNA hybridization is developed, which can be employed to control ligand display kinetics and used to study dynamic cell-ligand interaction. In this approach, mesoporous silica nanoparticles (MSN) are functionalized with single-strand DNA (MSN-ssDNA) and spin-coated on a glass substrate to create the 2D bio interface. Cell adhesive tripeptide RGD is conjugated to complementary DNA strands (csDNA) of 9, 11, or 20 nucleotides in length, to form csDNA-RGD. The resulting 3 csDNA-RGD conjugates can hybridize with the ssDNA on the MSN surface, presenting RGD with increased ligand dissociation rates as DNA length is shortened. Slow RGD dissociation rates led to enhanced stem cell adhesion and spreading, resulting in elongated cell morphology. Cells on surfaces with slow RGD dissociation rates also exhibited higher motility, migrating in multiple directions compared to cells on surfaces with fast RGD dissociation rates. This study contributes to the existing body of knowledge on dynamic ligand-stem cell interactions.

Facile Preparation of Hydrogel-Coated Surfaces with Antifouling and Salt Resistance for Efficient Solar-Driven Water Evaporation.

Hydrogel-based evaporators are a promising strategy to obtain freshwater from seawater and sewage. However, the time-consuming and energy-consuming methods used in hydrogel preparation, as well as their limited scalability, are major factors that hinder the development of a hydrogel-based evaporator. Herein, a facile and scalable strategy was designed to prepare a hydrogel-coated evaporator to realize efficient solar-driven water evaporation. The hydrogel coating layer is composed of a robust 3D network formed by tannic acid (TA) and poly(vinyl alcohol) (PVA) through a hydrogen bond. With the assistance of TA surface modifier, carbon black (CB) is uniformly distributed within the hydrogel matrix, endowing the coating with remarkable photothermal properties. In addition, Fe3+ is deposited on the surface of the hydrogel coating through metal coordination with TA, further improving the light absorption of the coating. Due to the synergistic effect of CB and Fe3+, the hydrogel-coated foam exhibited excellent photothermal properties. The water evaporation rate reached 3.64 kg m-2 h-1 under 1 sun irradiation. Because of the hydration ability of PVA hydrogel and the large porous structure of the foam, the hydrogel-coated foam demonstrated excellent antifouling performance and salt resistance. This study provides a facile method for designing and manufacturing high-performance solar-driven water evaporation materials.

Development of Mesoporous Silica Nanoparticle-Based Films with Tunable Arginine-Glycine-Aspartate Peptide Global Density and Clustering Levels to Study Stem Cell Adhesion and Differentiation.

Stem cell adhesion is mediated via the binding of integrin receptors to adhesion motifs present in the extracellular matrix (ECM). The spatial organization of adhesion ligands plays an important role in stem cell integrin-mediated adhesion. In this study, we developed a series of biointerfaces using arginine-glycine-aspartate (RGD)-functionalized mesoporous silica nanoparticles (MSN-RGD) to study the effect of RGD adhesion ligand global density (ligand coverage over the surface), spacing, and RGD clustering levels on stem cell adhesion and differentiation. To prepare the biointerface, MSNs were chemically functionalized with RGD peptides via an antifouling poly(ethylene glycol) (PEG) linker. The RGD surface functionalization ratio could be controlled to create MSNs with high and low RGD ligand clustering levels. MSN films with varying RGD global densities could be created by blending different ratios of MSN-RGD and non-RGD-functionalized MSNs together. A computational simulation study was performed to analyze nanoparticle distribution and RGD spacing on the resulting surfaces to determine experimental conditions. Enhanced cell adhesion and spreading were observed when RGD global density increased from 1.06 to 5.32 nmol cm-2 using highly clustered RGD-MSN-based films. Higher RGD ligand clustering levels led to larger cell spreading and increased formation of focal adhesions. Moreover, a higher RGD ligand clustering level promoted the expression of alkaline phosphatase in hMSCs. Overall, these findings indicate that both RGD global density and clustering levels are crucial variables in regulating stem cell behaviors. This study provides important information about ligand-integrin interactions, which could be implemented into biomaterial design to achieve optimal performance of adhesive functional peptides.

Ultrasmall Cu3(PO4)2 Nanoparticles Reinforced Hydrogel Membrane for Super-antifouling Oil/Water Emulsion Separation.

Membrane fouling is a persistent and crippling challenge for oily wastewater treatment due to the high susceptibility of membranes to contamination. A feasible strategy is to design a robust and stable hydration layer on the membrane surface to prevent contaminates. A hydrogel illustrates a distinct category of materials with outstanding antifouling performance but is limited by its weak mechanical property. In this research, we report a reinforced hydrogel on a membrane by in situ growing ultrasmall hydrophilic Cu3(PO4)2 nanoparticles in a copper alginate (CuAlg) layer via metal-ion-coordination-mediated mineralization. The embeddedness of hydrophilic Cu3(PO4)2 nanoparticle with a size of 3-5 nm endows the CuAlg/Cu3(PO4)2 composite hydrogel with enhanced mechanical property as well as reinforced hydrate ability. The as-prepared CuAlg/Cu3(PO4)2 modified membrane exhibits a superior oil-repulsive property and achieves a nearly zero flux decline for separating surfactant stabilized oil-in-water emulsions with a high permeate flux up to ∼1330 L m-2 h-1 bar-1. Notably, it is capable of keeping similar permeate flux for both pure water and oil-in-water emulsions during filtration, which is superior to the currently reported membranes, indicating its super-antifouling properties.

DNA modified MSN-films as versatile biointerfaces to study stem cell adhesion processes.

A significant bottleneck in the clinical translation of stem cells remains eliciting the desired stem cell behavior once transplanted in the body. In their natural environment, stem cell fate is regulated by their interaction with extracellular matrix (ECM), mainly through integrin-mediated cell adhesion. 2D biointerfaces that selectively present ECM-derived ligands can be used as valuable tools to study and improve our understanding on how stem cells interact with their environment. Here we developed a new type of biointerface based on mesoporous silica nanoparticles (MSN) which are interesting nanomaterials for biointerface engineering because they allow close control over surface physiochemical properties. To create the platform, DNA functionalized MSN (MSN-ssDNA) with varying PEG linker length were developed. Cell adhesion tripeptide RGD was conjugated to a complementary DNA strand, which could specifically bind to MSN-ssDNA to create MSN-dsDNA-RGD films. We showed that MSN-dsDNA-RGD films could promote hMSCs adhesion and spreading, whereas MSN-dsDNA films without RGD resulted in poor cell spreading with round morphology, and low cell adhesion. In addition, we showed that cell adhesion to the films is PEG length-dependent. The design of the platform allows easy incorporation of other and multiple ECM ligands, as well as soluble cues, making MSN-ssDNA based biointerfaces a novel tool to study ligand-stem cell interactions.

Effect of ultrasound on the preparation of soy protein isolate-maltodextrin embedded hemp seed oil microcapsules and the establishment of oxidation kinetics models.

In this study, microcapsules were prepared by spray drying and embedding hemp seed oil (HSO) with soy protein isolate (SPI) and maltodextrin (MD) as wall materials. The effect of ultrasonic power on the microstructure and characteristics of the composite emulsion and microcapsules was studied. Studies have shown that ultrasonic power has a significant impact on the stability of composite emulsions. The particle size of the composite emulsion after 450 W ultrasonic treatment was significantly lower than the particle size of the emulsion without the ultrasonic treatment. Through fluorescence microscopy observation, HSO was found to be successfully embedded in the wall materials to form an oil/water (O/W) composite emulsion. The spray-dried microcapsules showed a smooth spherical structure through scanning electron microscopy (SEM), and the particle size was 10.7 µm at 450 W. Fourier transform infrared (FTIR) spectroscopy analysis found that ultrasonic treatment would increase the degree of covalent bonding of the SPI-MD complex to a certain extent, thereby improving the stability and embedding effect of the microcapsules. Finally, oxidation kinetics models of HSO and HSO microcapsules were constructed and verified. The zero-order model of HSO microcapsules was found to have a higher degree of fit; after verification, the model can better reflect the quality changes of HSO microcapsules during storage.

Soybean Oil Treatment Using the Dissolving Curve Equation of Hydrogen.

The solubility of hydrogen in n-hexane was determined using a homemade reactor. The solubility of hydrogen in soybean oil was established using the Peng-Robinson (PR) equation of state and the van der Waals mixing rule. The curve equation established a linear relationship between the solubility of hydrogen in oil and the number of moles of hydrogen in the reactor. Under the optimal temperature and catalyst, the relationship between the hydrogen consumption of the hydrogenation of oil and fat and the TFAs formed in the oil was determined. When the reaction pressure exceeded 3.0 MPa, the hydrogenation of oil was consumed. The amount of hydrogen, the rate of hydrogenation, and the change in the TFAs all stabilized. Therefore, the pressure of the general hydrogenation reaction should not exceed 3.0 MPa. This result provides a quick and simple method for controlling TFAs in oils and fats for industrial applications.

2D biointerfaces to study stem cell-ligand interactions.

Stem cells have great potential in the field of tissue engineering and regenerative medicine due to their inherent regenerative capabilities. However, an ongoing challenge within their clinical translation is to elicit or predict the desired stem cell behavior once transplanted. Stem cell behavior and function are regulated by their interaction with biophysical and biochemical signals present in their natural environment (i.e., stem cell niches). To increase our understanding about the interplay between stem cells and their resident microenvironments, biointerfaces have been developed as tools to study how these substrates can affect stem cell behaviors. This article aims to review recent developments on fabricating cell-instructive interfaces to control cell adhesion processes towards directing stem cell behavior. After an introduction on stem cells and their natural environment, static surfaces exhibiting predefined biochemical signals to probe the effect of chemical features on stem cell behaviors are discussed. In the third section, we discuss more complex dynamic platforms able to display biochemical cues with spatiotemporal control using on-off ligand display, reversible ligand display, and ligand mobility. In the last part of the review, we provide the reader with an outlook on future designs of biointerfaces. STATEMENT OF SIGNIFICANCE: Stem cells have great potential as treatments for many degenerative disorders prevalent in our aging societies. However, an ongoing challenge within their clinical translation is to promote stem cell mediated regeneration once they are transplanted in the body. Stem cells reside within our bodies where their behavior and function are regulated by interactions with their natural environment called the stem cell niche. To increase our understanding about the interplay between stem cells and their niche, 2D materials have been developed as tools to study how specific signals can affect stem cell behaviors. This article aims to review recent developments on fabricating cell-instructive interfaces to control cell adhesion processes towards directing stem cell behavior.

Erratum: Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma.

The authors informed the journal that an error occurred in their manuscript. Figure 2D was mistakenly overlooked by the authors during the galley proof stage. Reference: 1. Zhang X, Zhao L, Zhai G, Ji J, Liu A. Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma. Med Sci Monit, 2019; 25: 9737-9751. doi: 10.12659/MSM.918899.

Multifunctional Polyethylene Glycol (PEG)-Poly (Lactic-Co-Glycolic Acid) (PLGA)-Based Nanoparticles Loading Doxorubicin and Tetrahydrocurcumin for Combined Chemoradiotherapy of Glioma.

BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.

Triamcinolone acetonide-chitosan coated liposomes efficiently treated retinal edema as eye drops.

Macular edema (ME), which is present in various retinal diseases, leads to permanent retinal structural damage and threatens vision. The intravitreal/periocular injection of triamcinolone acetonide (TA) can improve the prognosis of ME; however, further exploration of noninvasive delivery systems is essential. Therefore, as a continuation of our previous study using TA-chitosan coated liposomes (TA-CHLs) as a topical drug delivery system, the present study aimed to determine the drug safety, stability, permeability, and bioavailability of TA-CHLs. The study was based on detecting the delivery of a fluorescent dye to the retina using optical coherence tomography angiography in rats. Marked cellular uptake was observed in cell lines. TA-CHL toxicity was investigated in cell culture. Clinical ocular safety was evaluated by measuring the corneal thickness and intraocular pressure. In preclinical studies on a laser-induced retinal edema rat model, the TA-CHL eye drops had dramatic therapeutic effect in remission of retinal edema over 10 days. These results demonstrated that TA-CHL was nontoxic and had good bioavailability in vitro and in vivo. The results of the present study indicated that this formulation could be an effective therapeutic approach and the TA-CHL eye drops may represent a new option for retinal diseases.

A more efficient ocular delivery system of triamcinolone acetonide as eye drop to the posterior segment of the eye.

As a leading cause of vision impairment of the retina, macular edema (ME) has one of the highest clinical demands for treatment. Current treatment of ME relies heavily on invasive techniques resulting in complications and poor patient compliance. To enhance the efficiency of triamcinolone acetonide as eye drop to the posterior segment of the eye, we developed and characterized a novel formulation, namely, triamcinolone acetonide chitosan-coated liposomes (TA-CHL), prepared by the calcium acetate gradient method with some modifications. TA-CHL provided the mean particle size of 135.46 ± 4.49 nm and high entrapment efficiency (90.66 ± 3.21%), exhibited a sustained release profile, excellent physical stability, and no significant toxicity on cornea, conjunctiva, and retina. Optical coherence tomography system (OCT) was used to detect pharmacokinetics of CHL in vivo, indicating that CHL had good potency for drug delivery. Cellular uptake experiments showed CHL had the higher transduction efficiency into HCEC and ARPE-19 than liposomes. TA-CHL was shown to be potentially effective eye drop to contribute to the posterior segment of the eye.

Heparin-reduced graphene oxide nanocomposites for curcumin delivery: in vitro, in vivo and molecular dynamics simulation study.

Graphene-based nanomaterials (GBNMs) have great potential in drug delivery and photothermal therapy owing to their unique physicochemical properties. However, inferior water solubility and biocompatibility related issues greatly restricted their further applications. Herein, to rectify the obstructive problems, we prepared uniform and smaller sized graphene oxide (GO) nanosheets (∼85 nm) via a modified Hummers' method, which exhibited significantly improved hemocompatibility compared to random large sized GO nanosheets prepared by a common method. Then, we grafted unfractionated heparin (UFH) onto reduced graphene oxide (rGO) covalently using adipic acid dihydrazide (ADH) as a linker to fabricate biocompatible nanocomposites for the cellular delivery of curcumin (Cur). The novel nanocomposites showed quite a small size of 42 nm in average lateral dimension and exhibited a significantly stronger photothermal effect than GO nanosheets. Besides, in vitro cell experiments verified that the potential anticancer efficacy of Cur-loaded vehicles and cytotoxicity of rGO-UFH/Cur against MCF-7 and A549 cells could be further enhanced under 808 nm irradiation, suggesting the possibility of combinational chemotherapy and photothermal therapy. Moreover, consistent with the in vitro sustained drug release performance, an in vivo pharmacokinetics study also indicated that the retention time of Cur could be significantly prolonged when loaded on rGO-UFH nanocomposites than in free Cur solution. Notably, we firstly discussed the interaction between rGO and Cur, and demonstrated the meliorative biocompatibility of uniform rGO compared to GRO via a molecular dynamics simulation (MD) study. Thus, the in vitro, in vivo and computational study demonstrated that the small sized rGO-UFH nanocomposites had wide application prospects as drug delivery vehicles.

The enhanced effect of tetrahydrocurcumin on radiosensitivity of glioma cells.

OBJECTIVES: To evaluate the effects of tetrahydrocurcumin (THC) on the radiosensitivity of glioma cells and the possible molecular mechanism. METHODS: MTT assay, colony forming and wound healing assays were performed to detect the proliferation, radiosensitivity and migration of cells with various treatments. Cell apoptosis, cell cycle and GHS level were determined for exploring potent sensitization mechanism of THC. Meanwhile, protein expressions of cyclin D1 and PCNA were also measured. Furthermore, both orthotopic C6 mouse models and C6 subcutaneously grafted mouse models were established to test the tumour inhibitory effects of combined treatment in vivo. KEY FINDINGS: Cells treated with combined THC and radiation demonstrated lower cell viability and higher apoptosis rate as compared to radiation group. Moreover, the intracellular GSH was also decreased in the THC co-treated C6 cells. More importantly, combinatorial treatment group significantly induced G0/G1 cell cycle arrest and a decrease in the S phase cell through the down-regulation of cyclin D1 and PCNA. The in-vivo therapeutic efficacy assay indicated that the growth of tumour was greatly inhibited in combinatorial group. CONCLUSIONS: Tetrahydrocurcumin can synergistically enhance the radiosensitivity of glioma cells by inhibiting the expressions of cyclin D1 and PCNA.

Tumor targeting strategies for chitosan-based nanoparticles.

Currently, targeted nanoparticles (NPs) are rapidly being developed to overcome various bottlenecks of antitumor agents, such as poor solubility in aqueous solution, poor pharmacokinetics, a lack of selectivity and undesirable side effects in healthy tissues. In recent years, chitosan, a cationic polysaccharide, has been widely explored for the targeted delivery of antitumor agents due to its unique physicochemical and biological properties, such as biocompatibility, biodegradability, mucoadhesive feature, absorption enhancement and active functional groups for chemical modifications. This article reviews the recent developments in various target-specific nanoparticles based on chitosan and its derivatives, including passive, active and stimuli-sensitive targeting strategies. In addition, the target mechanisms and the key efficacy factors are illuminated.

Paliperidone protects SK-N-SH cells against glutamate toxicity via Akt1/GSK3ß signaling pathway.

Schizophrenia is a heterogeneous psychotic illness and its etiology remains poorly understood. Recent studies have suggested that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics appear to slow progressive morphological brain changes. In addition, the atypical antipsychotics were reported to have a superior therapeutic efficacy in treating schizophrenia and have a low incidence of extrapyramidal side effects (EPS) compared to typical antipsychotics. However, the mechanisms of atypical antipsychotics in treating schizophrenia and the basis for differences in their clinical effects were still totally unknown. In the present study, we investigated whether paliperidone shows protective effects on SK-N-SH cells from cell toxicity induced by exposure to glutamate. We examined the effects of the drugs on cell viability (measured by MTT metabolism assay and lactate dehydrogenase (LDH) activity assay), apoptosis rate, ROS levels and gene expression and phosphorylation of Akt1 and GSK3ß. The results showed that paliperidone significantly increases the cell viability by MTT and LDH assays (p<0.05), in contrast to the typical antipsychotic (haloperidol), which had little neuroprotective activity. Moreover, paliperidone retarded the glutamate-mediated promotion of ROS and the rate of apoptosis (p<0.05). In addition, paliperidone also effectively reversed glutamate-induced decreases of gene expression and phosphorylation of Akt1 and GSK3ß (both p<0.05). Our results demonstrated that paliperidone could effectively protect SK-N-SH cells from glutamate-induced damages via Akt1/GSK3ß signaling pathway.

Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3ß signaling pathway.

Recent studies have suggested that neurodegeneration is involved in the pathogenesis of schizophrenia, and some atypical antipsychotics appear to prevent or retard progressive morphological brain changes. However, the underlying molecular mechanisms are largely unknown. Whether changes in intracellular signaling pathways are related to their neuroprotective effects remains undefined. In the present study, we used mouse embryonic prefrontal cortical neurons to examine the neuroprotection of paliperidone against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. Paliperidone inhibited MK-801 induced neurotoxicity both in MTT metabolism assay (p<0.01) and in lactate dehydrogenase (LDH) activity assay (p<0.01). Time course studies revealed that paliperidone effectively attenuated the elevation of intracellular free calcium concentration ([Ca(2+)]i) induced by exposure to MK-801 (p<0.01). Moreover, paliperidone could significantly retard MK-801-mediated inhibition of neurite outgrowth (p<0.01) and reverse MK-801-induced decreases of gene expression and phosphorylation of Akt1 and GSK3ß (both p<0.01). Furthermore, these protective effects of paliperidone were blocked by pretreatment with a PI3K inhibitor LY294002. Taking together, our results demonstrated that paliperidone could protect prefrontal cortical neurons from MK-801-induced damages via Akt1/GSK3ß signaling pathway.