No abstract

Purpose. An oil/water nanoemulsion was developed in the present study to enhance the solubility, stability and anti-tumor activity of a novel 10-methoxy-9-nitrocamptothecin (MONCPT). Materials and Methods. MONCPT nanoemulsion was prepared using Lipoid E80 and cremophor EL as main emulsifiers by microfluidization. The droplet size of the nanoemulsion was measured by dynamic light scattering. In vitro drug release was monitored by membrane dialysis. Kinetics of MONCPT transformed into carboxylic salt was performed in phosphate buffer at different pH. Hemolysis of MONCPT nanoemulsion was conducted in rabbit erythrocytes. Solubilization character of MONCPT in nanoemulsion was experimented using Nile red as a solvatochromic probe. In vitro cytotoxicity of the nanoemulsion was measured in A549 and S180 cells using Sulforhodamine B protein stain method, and suppression rate of tumor growth was investigated in S180-bearing mice. The cell cycle effects of MONCPT nanoemulsion on S180 cells were analyzed by flow cytometry. Distribution of the nanoemulsion in A549 cells and S180-bearing mice were also investigated by fluorescence image. Results. MONCPT is incorporated in the nanoemulsion in form of lactone with concentration of 489 µg/ml, more than 200 folds higher than that in water. Experiments using Nile red as a solvatochromic probe indicated that more MONCPT might be located in the interfacial surfactant layer of the nanoemulsion than that in discrete oil droplet or continuous aqueous phase. Nanoemulsion could release MONCPT in a sustained way, and it was further shown to notably postpone the hydrolysis of MONCPT with longer hydrolysis half-life time (11.38 h) in nanoemulsion at pH 7.4 than that of MONCPT solution (4.03 h). No obvious hemolysis was caused by MOCPT nanoemulsion in rabbit erythrocytes. MONCPT nanoemulsion showed a marked increase in cytotoxic activity, 23.6 folds and 28.6 folds in S180 cells and A549 cells respectively via arresting the cell at G2 phase, compared to that induced by MONCPT injection. It correlated well to the in vivo anti-tumor activity of MONCPT nanoemulsion with suppression rate of 93.6%, while that of MONCPT injection was only 24.2% at the same dosage. Moreover, nanoemulsion exhibited enhanced capability of delivering drug into malignant cell's nucleus in vitro and induced drug accumulation in tumor in S180-bearing mice using in vivo imaging. Conclusion. The nanoemulsion prepared exhibited an improved MONCPT solubility, stability and antitumor activity, providing a promising carrier for cancer chemotherapy using MONCPT.

a 4-Anilinoquinazoline ureas were envisaged according to the hybrid-design approach based upon two privileged pharmacophores in kinase drug discovery, i.e. 4-anilinoquinazoline and unsymmetrical diaryl urea. In our structure-activity relationships (SAR) campaign, title compounds were synthesized and profiled in biochemical assay for their kinase inhibitory activity. Title compounds 18-20 were found to be multikinase inhibitors with profound activity against BRAF, BRAF V600E, VEGFR-2 and EGFR.Molecular docking into DFG-out conformations of BRAF and VEGFR-2 suggested that they might be type II inhibitors.

Background:The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line. Methods: A novel composite doxorubicin-loaded micelle consisting of polyethylene glycolpolycaprolactone/Pluronic P105 was developed, and carrier-mediated doxorubicin accumulation and release from multicellular spheroids was evaluated. We used confocal laser scanning microscopy and flow cytometry to study the accumulation and efflux of doxorubicin from A549 multicellular spheroids. Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems. Results: Confocal laser scanning microscopy and quantitative flow cytometry studies both verified that, for equivalent doxorubicin concentrations, composite doxorubicin-loaded micelles significantly enhanced cellular doxorubicin accumulation and inhibited doxorubicin release. Colony-forming assays demonstrated that composite doxorubicin-loaded micelles are radiosensitive, as shown by significantly reduced survival of cells treated by radiation + composite micelles compared with those treated with radiation + free doxorubicin or radiation alone. The multicellular spheroid migration area and growth ability verified higher radiosensitivity for the composite micelles loaded with doxorubicin than for free doxorubicin. Conclusion: Our composite doxorubicin-loaded micelle was demonstrated to have radiosensitization. Doxorubicin loading in the composite micelles significantly increased its cellular uptake, improved drug retention, and enhanced its antitumor effect relative to free doxorubicin, thereby providing a novel approach for treatment of cancer.