Antiblood Cell Adhesion of Mussel-Inspired Chondroitin Sulfate- and Caffeic Acid-Modified Polycarbonate Membranes.

We fabricated a mussel-inspired hemocompatible polycarbonate membrane (PC) modified by the cross-linking of chondroitin sulfate and caffeic acid polymer using CA-CS via a Schiff base and Michael addition reaction and named it CA-CS-PC. The as-fabricated CA-CS-PC membrane shows excellent hydrophilicity with a water contact angle of 0° and a negative surface charge with a zeta potential of -32 mV. The antiadhesion property of the CA-CS-modified PC membrane was investigated by enzyme-linked immunosorbent assay (ELISA), using human plasma protein fibrinogen adsorption studies, and proved to have excellent antiadhesion properties, because of the lower fibrinogen adsorption. In addition, the CA-CS-PC membrane also shows enhanced hemocompatibility. Finally, blood cell attachment tests of the CA-CS-PC membrane were observed by CLSM and SEM, and the obtained results proved that CA-CS-PC effectively resisted cell adhesion, such as platelets and leucocytes. Therefore, this work disclosed a new way to design a simple and versatile modification of the membrane surface by caffeic acid and chondroitin sulfate and apply it for cell adhesion.

Fluorine-Free Superhydrophobic Covalent-Organic-Polymer Nanosheet Coating for Selective Dye and Emulsion Separation.

Covalent organic polymer nanosheets (COPNs) endowed with porous networks and large surface areas in their structures offer great advantages over other materials in addressing environmental problems. In this study, fluorine-free superhydrophobic COPNs were designed and applied to selective dye absorption. Notably, COPNs selectively adsorb dyes with a high hydrophobic index (HI) and reject low HI dyes with maximum adsorption capacities of 361 and 263 mg/g for crystal violet and methylene blue, respectively. The adsorption isotherm model showed that the COPNs follow the Langmuir adsorption isotherm model and pseudo-second-order kinetics. Next, we explored the superhydrophobicity of the COPNs by in situ fabrication with melamine sponge (COPNs-MS), which incorporates the superhydrophobicity of COPNs [water contact angle (WCA) of >150°] with the structure and flexibility of the MS skeleton. The COPNs-MS shows various oil-adsorbing properties with good adsorption capacity (from 60 to 120 g/g) and also effectively separates various surfactant-stabilized emulsions with a separation efficiency of over 99%. The as-fabricated COPNs-MS retains its superhydrophobicity in various solvents and hazardous conditions (WCA ≥ 150°) and exhibits good flame retardancy and excellent compression properties with excellent antifouling property due to the superhydrophobic COPN coating. Furthermore, COPNs-MS also demonstrates excellent recyclability because the strong COPN coating in the MS skeleton retains its hydrophobicity. Therefore, our fluorine-free superhydrophobic COPNs are not only capable of selective dye adsorption but also exhibit very good oil adsorption and surfactant-stabilized emulsion separation performance.

Thioether-terminated triazole-bridged covalent organic framework for dual-sensitive drug delivery application.

A novel thioether-terminated triazole bridge-containing covalent organic framework (TCOF) was constructed via a simple click chemistry between alkyne and azide monomers for dual-sensitive [pH and glutathione (GSH)] anticancer drug delivery systems. The synthesized TCOFs were crystalline in nature with a pore size of approximately 10-30 nm, as confirmed by powder X-ray diffraction spectroscopy and Brunauer-Emmett-Teller technique. Owing to the flexible nature of the synthesized COF, polyethylene glycol (PEG) modification was easily performed to yield a stable TCOF (TCOF-PEG) colloidal solution. Doxorubicin (DOX)-loaded TCOF-PEG (TCOF-DOX-PEG) exhibited sensitivity to lysosomal pH 5 and GSH environments. DOX release was four times higher under GSH environment (relative to pH 7.4) and three times higher under pH 5 condition because of the dynamic nature of triazole. In contrast, DOX-loaded COF without the triazole ring (I-COF) did not show any significant drug release in pH 7.4 and acidic pH; however, drug release was observed in GSH environment. MTT drug internalization data demonstrated sustained release of DOX from TCOF-DOX-PEGs. Finally, we demonstrated the utility of TCOF-PEG as an in vitro drug delivery system in HeLa cells. TCOF-DOX-PEG exhibited time-dependent release of DOX followed by internalization. Thus, the novel TCOF system reported here opens a new window in COF research for sensitive drug carrier systems.

PAMAM G4.5 dendrimers for targeted delivery of ferulic acid and paclitaxel to overcome P-glycoprotein-mediated multidrug resistance.

In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared with PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells.

Electroactive polypyrrole-molybdenum disulfide nanocomposite for ultrasensitive detection of berberine in rat plasma.

Electroactive polypyrrole-molybdenum disulfide (MoP) nanocomposites were synthesized and used for modifying screen-printed carbon electrodes (SPCEs) for ultrasensitive detection of berberine, an anticancer drug, in rat plasma. The electroactive nanocomposites were fabricated by exfoliating MoS2 followed by pyrrole polymerization. The effect of polypyrrole in the MoP nanocomposite was evaluated by varying the pyrrole concentration during polymerization, and the resulting nanocomposites prepared with pyrrole concentrations of 10, 20, 30 µL were named as MoP-1, MoP-2, and MoP-3, respectively. The electrochemical characterization of the three MoP nanocomposite sensors revealed that MoP-2/SPCE exhibited the highest electroactivity. The detection of berberine by the three MoP-coated SPCEs revealed that MoP-2/SPCE exhibited the highest activity against berberine due to a two-electron transfer mechanism on the MoP-2/SPCE electrode surface. The detection limit of berberine using the MoP-2/SPCE sensor was found to be about 0.05 µM, which is remarkably lower than the reported detection limits. The interference study proved the selectivity of the MoP-2/SPCE sensor toward berberine in the presence of other bioactive molecules and metal ions. The designed MoP-2/SPCE sensor retained 92% of its initial activity after 15 days of storage at room temperature, with RSD values of about 2.95% and 3.68% for the repeatability and reproducibility studies. Finally, the detection limit of berberine in a rat plasma sample determined using the MoP-2/SPCE sensor was found to be about 5 µM.

Radioprotective effect of self-assembled low molecular weight Fucoidan-Chitosan nanoparticles.

Fucoidan, a sulphated polysaccharide, plays a vital role in reducing cellular oxidative damage by exerting potential antioxidant activity. However, because of the negative surface charges of oligofucoidan, it shows poor oral intestinal absorption. To overcome this drawback, the oligofucoidan polysaccharides self-assembled with opposite charge based polysaccharides (chitosan) to form the chitosan-fucoidan polysaccharides (C1-F3P) nanoparticles (NPs) of 190-230 nm in size. The oligofucoidan and C1-F3P NPs were studied for their radioprotective property using mice exposed to 5 Gy radiation. The C1-F3P NPs prevents radiation induced lipid peroxidation and restores intestinal enzymatic and non-enzymatic antioxidants (p < 0.05) status. In addition, hematoxylin-eosin staining revealed the radioprotective effect of oligofucoidan and C1-F3P NPs by mitigating the loss of crypt and villi in the small intestine. Thus, the present study demonstrated that C1-F3P NPs can be considered as a radioprotective agent that can be used for the prevention and treatment of Gy-radiation-induced intestine injury.

Amino acid-modified PAMAM dendritic nanocarriers as effective chemotherapeutic drug vehicles in cancer treatment: a study using zebrafish as a cancer model.

The use of nanomaterials for drug delivery offers many advantages including the targeted delivery of drugs and their controlled release. Nonetheless, entry into the target cells remains a challenge for many nanomaterials used for drug delivery. Moreover, cellular uptake limits the therapeutic efficiency of many anticancer drugs. An important goal is to increase the specific accumulation of these nanoparticles (NPs) at the desired cancerous tissues. Notably, cancer cells show a high demand for some amino acids and we have used this knowledge to develop novel carrier systems. In this study, drug carriers were produced by the conjugation of multiple amino acids such as l-histidine (H) and l-cysteine (C) or single amino acids such as only H with the G4.5 dendrimers (G) to produce GHC aggregates and GH NP carriers, respectively. Doxorubicin was loaded into the G4.5, GH, and GHC dendrimers (G/DOX, GH/DOX and GHC/DOX, respectively) and the release mechanism was demonstrated at pH 7.4 and pH 5.0. GH/DOX and GHC/DOX showed better stability under physiological conditions than the dendrimer alone (G/DOX). GH/DOX and GHC/DOX exhibited higher inhibition of HeLa cell proliferation in in vitro and in vivo studies in zebrafish, confirming the early release of DOX by disrupting the endosomal membrane and triggering the destabilization of carriers at a lower pH of 5.0.

Fabrication of electroactive polypyrrole-tungsten disulfide nanocomposite for enhanced in vivo drug release in mice skin.

The present study focused on the development of electric stimuli drug release carrier based on transition metal dicgalcogenides. First, tungsten disulfide (WS2) was exfoliated and functionalized using thiol chemistry with various thiol-terminated ligands such as thioglycolic acid (TGA), mercaptosuccinic acid (MSA), and 2-ethanethiol (2ET). The exfoliated WS2 underwent non-covalent coating with an electrically conductive polypyrrole (PPy) for functionalization, of which MSA-WS2-PPy achieved the highest 5-FU (anticancer drug) loading. An electrically-stimulated drug release experiment showed that TGA-WS2-PPy achieved a higher drug release (90%) than MSA-WS2-PPy (70%) and 2ET-WS2-Ppy (35%). The TGA-WS2-PPy exhibited swelling/recombination between PPY and MSA-WS2 substrate under electrical stimulation, resulting in the highest 5-FU release. From the MTT assay result, there was no significant toxicity observed for TGA-WS2-PPy-FU on HaCaT cells, indicating the biocompatibility of TGA-WS2-PPy-FU in the absence of electrical stimulation. However, HaCaT cells died when incubated with TGA-WS2-PPy-FU under electrical stimulation. Finally, Raman mapping studies for TGA-WS2-PPy drug release in the skin of nude mice demonstrated that the carrier penetrated deeper into the skin of the mice while other systems failed to exhibit significant effects under electrical stimulation. The present study offers a novel approach in developing a non-invasive electrically-stimulated drug release system based on WS2 and an externally-controlled delivery model.

Synthesis of "Dahlia-Like" Hydrophilic Fluorescent Carbon Nanohorn as a Bio-Imaging PROBE.

Carbon nanohorns (CNH) were synthesized by a simple conventional hydrothermal method in this study. The CNHs were prepared by the chemical oxidation from the carbonation of Nafion (catalyst) with heparin (carbon resource). The formation of CNH involved two major steps, as described followed. First, the formation of carbon nanorice (CNR) was achieved by carbonation and self-assembly of heparin inside the Nafion structure. Second, the further oxidation of CNR resulted the heterogeneous and porous micelle domains showed at the outer layer of the CNR particles. These porous domains exhibited hydrophobic carbon and resulted self-assembly of the CNR to form the structure of CNHs. The resulting CNHs aggregated into a "dahlia-like" morphology with fluorescence in a diameter of 50-200 nm. The "dahlia-like" CNH showed better fluorescence (450nm) than CNR particles because of the presence of more structural defect. These findings suggest that the hydrophilic fluorescent carbon nanohorns (HFCNHs) synthesized in this study have the potential to be used for in vitro bio-imaging.

Pluronic F127 self-assembled MoS2 nanocomposites as an effective glutathione responsive anticancer drug delivery system.

In this study, bio-responsive polymeric MoS2 nanocomposites were prepared for use as a drug carrier for cancer therapy. Herein, we report the synthesis and demonstrate the self-assembly of pluronic F127 (PF127) on a cystamine-glutathione-MoS2 (CYS-GSH-MoS2) system, which can be used for GSH-triggered drug release under biological reducing conditions. The reduction-sensitive disulfide bond containing CYS was incorporated between the amphiphilic copolymer PF127 and GSH-MoS2 to achieve feasible drug release. Percent drug loading capacity and encapsulation efficiency were 51.3% and 56%, respectively. In addition, when the MoS2-GSH-CYS-PF127 nanocomposite was incubated in a GSH environment, the morphology of the nanocomposite tended to change, ultimately leading to drug release. The drug-loaded PF127-CYS-GSH-MoS2 polymeric nanocomposites efficiently released 52% of their drug content after 72 h of incubation in a GSH reduction environment. The HeLa cells treated with DOX loaded MoS2-GSH-CYS-PF127 showed 38% toxicity at drug concentration of 40 µg, which indicated that the successfully released of drug from carrier and caused the cell death. Further, fluorescence microscopy images of HeLa cells revealed the potential behavior of the MoS2-GSH-CYS-PF12 nanocomposite during the 2- and 4 h incubation periods; the nanocomposite was only found in the cytoplasm of HeLa cells. Interestingly, after 6 h of incubation, the drug was slowly released from the nanocomposite and could enter the nucleus as confirmed by fluorescence imaging of HeLa cells. Altogether, our synthesized PF127-coated MoS2 nanocomposite could be effectively adopted in the near future as a GSH-sensitive drug carrier.

Fabrication of silver seeds and nanoparticle on core-shell Ag@SiO2 nanohybrids for combined photothermal therapy and bioimaging.

In this study, two core-shell nanohybrids of different morphologies, namely SiO2-coated silver (Ag) with surface-exposed silver seeds (Ag@SiO2@Agseed) and SiO2-coated Ag with surface-exposed Ag nanoparticles (Ag@SiO2@AgNPs), were fabricated using the Stober method. Potential applications in bioimaging and photothermal therapy (PTT) of the two fabricated nanohybrids were also explored. Upon exposure to visible light (400 nm), Ag@SiO2@Agseed with surface-exposed Ag seeds exhibited greater photothermal conversion efficiency than Ag@SiO2@AgNPs. In vitro MTT assays in the dark and subsequent bioimaging using HeLa cells proved the potential biocompatibility of the fabricated core-shell nanohybrids. PTT applications of the two fabricated core-shell nanohybrids were studied by incubating HeLa cells with the nanohybrids, exposure to 400 nm laser, and subsequent staining with annexin V and propidium iodide (PI), and the two core-shell nanohybrids gave distinctively different PI staining results. Interestingly, Ag@SiO2@Agseed caused higher cell death upon light exposure compared to Ag@SiO2@AgNPs as the former generated more heat within the cells. These results demonstrated potential bioimaging and PPT applications of the fabricated core-shell nanohybrids and offer a novel candidate for phototherapy-based biomedical applications.

MoS2-Gd Chelate Magnetic Nanomaterials with Core-Shell Structure Used as Contrast Agents in in Vivo Magnetic Resonance Imaging.

Despite their frequent usages as contrast agents for in vivo MRI imaging, paramagnetic molecules continue to suffer from low resolution, physicochemical instability, and high toxicity. Herein, we present a molybdenum disulfide and gadolinium complex, as an alternative core-shell magnetic nanomaterial that exhibits enhanced paramagnetic property; 4.5-times longer water proton spin-lattice relaxation time (T1) when compared to commercial gadolinium contrast agents; as well as lowered toxicity, extended blood circulation time, increased stability, and desirable excretion characteristic. Transmission electron microscopy (TEM) revealed smooth core-shell nanoparticles 100 nm in size with a shell width of approximately 10 nm. These findings suggest that the synthesized nanomaterial possesses high potential as a positive contrast agent for the enhancement of MRI imaging.