title: A focal adhesion kinase inhibitor 16-hydroxy-cleroda-3,13-dien-16,15-olide incorporated into enteric-coated nanoparticles for controlled anti-glioma drug delivery.
abstract: 16-Hydroxy-cleroda-3,13-dien-16,15-olide (HCD) which is extracted from a medicinal plant, Polyalthia longifolia, was shown to exhibit anticancer activity through apoptosis and FAK inhibition in our previous study. To improve its solubility and efficacy, a novel HCD delivery system using copper-substituted mesoporous silica nanoparticles (MSNs) was designed as a delivery vehicle, and the outer surfaces of MSNs were further coated with enteric polymers to prevent the drug from leaching in the stomach acid. All the data regarding synthesis and physical characterization, including Zeta potential, FT-IR spectra, N2 adsorption-desorption isotherms (BET), drug loading, powder X-ray diffraction, Thermo gravimetric analysis (TGA), Transmission electron microscopy (TEM), and Scanning electron microscopy (SEM) were well characterized. The non-coated MSN-HCD exposed to acidic pH (1.2) showed a rapid degradation of the drug, whereas the enteric-coated samples presented a sustained release profile in the gastrointestinal pHs. Cell cytotoxicity was further confirmed by the MTT-C6 Glioma cell line, in vitro. When compared with the control and pure HCD, the MSN-HCD revealed a potential anti-proliferation effect via the synergistic effect of the drug and the MSN vehicle. Additionally, this MSN-HCD had the effect of increasing the reactive oxygen species (ROS) levels and altered the Mitochondria membrane potential (MMP) in C6 cell line. The in vivo anti-tumor efficacy of enteric-coated MSN-HCD was evaluated by C6 Glioma bearing xenograft nude mice, and enteric-coated MSN-HCD clearly exhibited the greatest anti-glioma activity, as compared to the pure HCD and the untreated control. In terms of the effective treatment of brain glioma, this study provides conclusive evidence of the successful development of the anti-cancer agent HCD conjugated with enteric-coated MSN as a delivery control mechanism with enhanced dissolution characteristics.
authors: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors: Varadharajan
authors: V
authors: Thiyagarajan
authors: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors: Shi-Xiang
authors: SX
authors: Lin
authors: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan.
authors: Chia-Hung
authors: CH
authors: Lee
authors: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan. Electronic address: cfweng@mail.ndhu.edu.tw.
authors: Ching-Feng
authors: CF
authors: Weng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D005910:Glioma / Q000188:drug therapy*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011109:Polymethacrylic Acids / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012822:Silicon Dioxide / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013818:Thermogravimetry; D014961:X-Ray Diffraction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020099:Coated Materials, Biocompatible; D003692:Delayed-Action Preparations; D004224:Diterpenes; D004337:Drug Carriers; D011109:Polymethacrylic Acids; D047428:Protein Kinase Inhibitors; C038300:methylmethacrylate-methacrylic acid copolymer; D012822:Silicon Dioxide; C072581:16-hydroxycleroda-3,13(14)-dien-15,16-olide; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: 16-Hydroxy-cleroda-3,13-dien-16,15-olide; Cytotoxicity; Drug delivery; Mesoporous silica nanoparticles; Reactive oxygen species