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Chitosan oligosaccharide-arachidic acid (CSOAA) conjugate was successfully synthesized and used for the development of self-assembled nanoparticles for doxorubicin (DOX) delivery. The molar substitution of AA on CSO and critical micelle concentration (CMC) of CSOAA were measured. Physicochemical properties of DOX-loaded CSOAA-based nanoparticles, such as particle size, zeta potential and morphology, were also characterized. The DOX-loaded CSOAA-based nanoparticles showed spherical shape with a mean diameter of 130 nm and positive charge. According to the result of in vitro release test, DOX-loaded CSOAA-based nanoparticles exhibited sustained and pH-dependent drug release profiles. The CSOAA showed negligible cytotoxicity in FaDu, human head and neck cancer, cells. Cellular uptake of DOX in FaDu cells was higher in the nanoparticle-treated group compared to the free DOX group. The anti-tumor efficacy of DOX-loaded nanoparticles was also verified in FaDu tumor xenografted mouse model. These results suggested that synthesized amphiphilic CSOAA might be used for the preparation of self-assembled nanoparticles for anti-cancer drug delivery., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The heparin-Pluronic (HP) conjugate was coupled via redox-sensitive disulfide bond and contains a vinyl sulfone (VS) group with high reactivity to some functional groups such as thiol group. Heparin was conjugated with cystamine and the terminal hydroxyl groups of Pluronic were activated with the VS group, followed by coupling of VS groups of Pluronic with cystamine of heparin. The chemical structure, heparin content and VS group content of the resulting product were determined by (1)H NMR, FT-IR, toluidine blue assay and Ellman's method. The HP conjugate formed a type of nanogel in an aqueous medium, showing a critical micelle concentration of approximately 129.35 mg L(-1), a spherical shape and the mean diameter of 115.7 nm, which were measured by AFM and DLS. The release test demonstrated that HP nanogel was rapidly degraded when treated with glutathione. Cytotoxicity results showed a higher viability of drug-free HP nanogel than that of drug-loaded one. Cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGDfC) peptide was efficiently conjugated to VS groups of HP nanogel and exhibited higher cellular uptake than unmodified nanogels. All results suggest a novel multi-functional nanocarrier delivery and effective release of proteins to the intracellular region in a redox-sensitive manner.

Biocompatibility studies of all-trans-retinoic acid (RA)-loaded microspheres were carried out after they were subcutaneously injected into rats. To characterize the inflammatory response to these microspheres, tissue reactions at the implantation site and cell types in the interstices of the microspheres were evaluated for 180 days. On the 15th day, the cross-sectional area of the fibrous capsules surrounding the implantation site of the RA-loaded microspheres was four times larger than that of the control microspheres. The size of the fibrous capsules surrounding the implantation site of the RA-loaded microspheres decreased significantly over a period of 75 days, while the size of the fibrous capsules surrounding the implantation site of the control microspheres remained almost constant throughout the entire course of 180 days. The tissue response to the RA-loaded microspheres was more intensified by the increased extensive cellular infiltration of macrophages, granulation tissue, and fibrosis than that to the control microspheres. The difference in the inflammatory response between the RA-loaded microspheres and the control microspheres was significant for 75 days after implantation. It was suggested that the released RA from the microspheres stimulated inflammatory responses. However, no further enhanced inflammation reactions were detected after RA had been completely released from the microspheres.

Abstract: To achieve rapid onset of action and improved bioavailability of udenafil, a microemulsion system was developed for its intranasal delivery. Phase behavior, particle size, transmission electron microscope (TEM) images, and the drug solubilization capacity of the microemulsion were investigated. A single isotropic region was found in pseudo-ternary phase diagrams developed at various ratios with CapMul MCM L8 as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol (1:0.25, v/v) as a cosurfactant. Optimized microemulsion formulations with a mean diameter of 120–154nm achieved enhanced solubility of udenafil (>10mg/ml) compared with its aqueous solubility (0.02mg/ml). An in vitro permeation study was performed in human nasal epithelial (HNE) cell monolayers cultured by the air–liquid interface (ALI) method, and the permeated amounts of udenafil increased up to 3.41-fold versus that of pure udenafil. According to the results of an in vivo pharmacokinetic study in rats, intranasal administration of udenafil-loaded microemulsion had a shorter T max value (1min) compared with oral administration and improved bioavailability (85.71%) compared with oral and intranasal (solution) administration. The microemulsion system developed for intranasal administration may be a promising delivery system of udenafil, with a rapid onset of action and improved bioavailability. [Copyright &y& Elsevier]

Abstract: Heparin is available to patients only by parenteral administrations due to its low oral bioavailability. For the oral delivery of low molecular weight heparin (LMWH), LMWH–DOCA was synthesized by chemical conjugation of LMWH and deoxycholic acid (DOCA) and this conjugate was formulated in a microemulsion system. The coupling ratios of DOCA to LMWH for LD1 and LD2 were 1.33 and 2.37, respectively. The microemulsion was composed of tricaprylin, surfactant mixture (Tween® 80 and Span® 20) and LMWH–DOCA in water, and their volume ratio was 5:3:1:1. Pharmacokinetic parameters of LMWH were not significantly changed by conjugation with DOCA; however, when LMWH–DOCA in tricaprylin microemulsion was orally administered in mice, its bioavailability was increased up to 1.5%. Furthermore, the enhancing effect of the conjugated DOCA in the tricaprylin microemulsion on the absorption of LMWH in the intestine was more significantly increased in monkey than in mice. Since the tricaprylin microemulsion could dissolve LMWH–DOCA, this formulation could maximize the enhancing effect of the conjugated DOCA on the absorption of LMWH in the intestine. Finally, it was expected that 20 mg/kg of LMWH–DOCA in the tricaprylin microemulsion was enough to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE). [Copyright &y& Elsevier]