Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications

During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAFV600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles

Site-Specific Introduction of O-6-Methylguanine into the 12th Codon of the Human Ha-Ras Oncogene and Examination of Its Mutagenic Properties

Journal URL: http://www.sciencedirect.com/science/journal/0165116

Genetically modified foods: The effect of information

Journal URL: http://www.emeraldinsight.com/Insight/viewContainer.do;jsessionid=1567D45BA73033EECD46E6387A120D96?containerType=Journal&containerId=13

Molecular mechanism of methylating agent-induced apoptosis: identification of novel chemosensitivity markers

Journal URL: http://www.blackwell-synergy.com/loi/ej

Oil-In-Water Microemulsions as Hosts for Benzothiophene-Based Cytotoxic Compounds: An Effective Combination

Targeted delivery of chemotherapeutics in order to overcome side effects and enhance chemosensitivity remains a major issue in cancer research. In this context, biocompatible oil-in-water (O/W) microemulsions were developed as matrices for the encapsulation of DPS-2 a benzothiophene analogue, exhibiting high cytotoxicity in various cancer cell lines, among them the MW 164 skin melanoma and Caco-2 human epithelial colorectal adenocarcinoma cell lines. The microemulsion delivery system was structurally characterized by dynamic light scattering (DLS) and electron paramagnetic resonance (EPR) spectroscopy. The effective release of a lipophilic encapsulated compound was evaluated via confocal microscopy. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay. When encapsulated, DPS-2 was as cytotoxic as when dissolved in dimethyl sulfoxide (DMSO). Hence, the oil cores of O/W microemulsions were proven effective biocompatible carriers of lipophilic bioactive molecules in biological assessment experiments. Further investigation through fluorescence-activated cell sorting (FACS) analysis, comet assay, and Western blotting, revealed that DPS-2, although non-genotoxic, induced S phase delay accompanied by cdc25A degradation and a nonapoptotic cell death in both cell lines, which implies that this benzothiophene analogue is a deoxyribonucleic acid (DNA) replication inhibitor

Colloidal nanodispersions for the topical delivery of Ibuprofen: Structure, dynamics and bioperformances

Colloidal liquid-in-liquid nanodispersions such as micro- and nanoemulsions were developed, characterized and compared as potential carriers for the topical administration of ibuprofen. Both colloidal systems were based on water as the continuous phase, limonene as the dispersed phase and a mixture of pharmaceutically acceptable surfactants (Pluronic® L-35, Labrasol®, Tween 80). To improve their properties regarding penetration efficacy, an aqueous solution of chitosan was used as continuous phase in both systems. Micro- and nanoemulsions were structurally studied applying Dynamic Light Scattering (DLS), Electron Paramagnetic Resonance (EPR) spectroscopy and viscometry. Microemulsions with mean droplet diameter of 41 nm and PdI < 0.3 were obtained in the absence and presence of either chitosan or ibuprofen. Nanoemulsions were developed by high-pressure homogenization using the same ingredients at different concentrations. Unlike thermodynamically stable microemulsions, nanoemulsions showed storage stability for 2 months, higher droplet size (174 nm) and lower PdI (<0.15). In the presence of Ibuprofen droplet size and stability of the nanoemulsions were not affected. EPR spectroscopy revealed ibuprofen’s location in the oil cores and gave information about the rigidity of the surfactants’ monolayer. In both cases an outer compact configuration of the interfacial layer and a more flexible inner one was observed. The cytotoxicity of both systems towards human melanoma cell line WM 164 was relatively low. Interestingly, ibuprofen was released more promptly from the microemulsions (prospectively, systemic exposure increase), however the ex vivo studies, regarding skin uptake and penetration, revealed that the nanoemulsions are more appropriate as nanocarriers for the topical administration of ibuprofen

Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: A structure and biological assessment study

Hypothesis: Lipophilic cannabidiol can be solubilized in oil-in water nanoemulsions, which can then be impregnated into chitosan hydrogels forming another colloidal system that will facilitate cannabidiol's release. The delivery from both systems was compared, alongside structural and biological studies, to clarify the effect of the two carriers' structure on the release and toxicity of the systems. Experiments: Oil-in-water nanoemulsions (NEs) and the respective nanoemulsion-filled chitosan hydrogels (NE/HGs) were formulated as carriers of cannabidiol (CBD). Size, polydispersity and stability of the NEs were evaluated and then membrane dynamics, shape and structure of both systems were investigated with EPR spin probing, SAXS and microscopy. Biocompatibility of the colloidal delivery systems was evaluated through cytotoxicity tests over normal human skin fibroblasts. An ex vivo permeation protocol using porcine ear skin was implemented to assess the release of CBD and its penetration through the skin. Findings: Incorporation of the NEs in chitosan hydrogels does not significantly affect their structural properties as evidenced through SAXS, EPR and confocal microscopy. These findings indicate the successful development of a novel nanocarrier that preserves the NE structure with the CBD remaining encapsulated in the oil core while providing new rheological properties advantageous over NEs. Moreover, NE/HGs proved to be more efficient as a carrier for the release of CBD. Cell viability assessment revealed high biocompatibility of the proposed colloids

Polar, Functionalized Guanine-O6 Derivatives Resistant to Repair by O6-Alkylguanine-DNA Alkyltransferase: Implications for the Design of DNA-modifying Drugs.

NoThe protein O6-alkylguanine-DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance