betadex and Head-and-Neck-Neoplasms

The activity of chlorin e6 (Ce6) in photodynamic therapy of cancers is significantly reduced by its propensity to form aggregates. It was postulated that disaggregation of Ce6 could be achieved with the use of hydroxypropyl-beta-cyclodextrin (HP-β-CD) through solubility enhancement.. An initial phase solubility study of Ce6 was conducted with various concentrations of HP-β-CD at three different pH conditions, i.e. pH 3, pH 5 and pH 7. Solubility-induced disaggregation of Ce6 was illustrated by fluorescence spectroscopy and singlet oxygen generation studies. Interaction between Ce6 and HP-β-CD was further demonstrated by solid-state characterization techniques. Inclusion complex formulations were tested for improved efficacy on squamous cancer cell lines.. Increase in Ce6 solubility was observed, especially at pH 7, indicating the formation of inclusion complex between Ce6 and HP-β-CD. This resulted in disaggregation of Ce6 aggregates illustrated by fluorescence spectroscopy. The mode of binding was predominated by H-bonding supported by temperature-dependent binding studies and molecular simulation work. The inclusion complex demonstrated improved photodynamic efficacy through enhanced singlet oxygen generation and phototoxicity on human oral squamous carcinoma cells.. pH-dependent complexation between Ce6- and HP-β-CD-induced disaggregation of Ce6 aggregates and the resultant formulations facilitated improved PDT efficacy on tested cancer cell lines.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Calorimetry, Differential Scanning; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Chlorophyllides; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Compounding; Head and Neck Neoplasms; Humans; Hydrogen-Ion Concentration; Models, Molecular; Mouth Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Powder Diffraction; Singlet Oxygen; Solubility; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Squamous Cell Carcinoma of Head and Neck; Thermodynamics; Time Factors

Lipid rafts are cholesterol-enriched microdomains in the plasma membrane. They act as molecular platforms that spatially organize membrane receptor molecules and are involved in the transduction of various signaling pathways. We recently reported that in the radiosensitive squamous cell carcinoma SCC61 line, gamma-irradiation results in a rearrangement of the plasma membrane rafts and signaling platforms leading to radiation-induced apoptosis in a ceramide-dependent pathway. By contrast, this reorganization was found to be defective in the radioresistant counterpart cell line, SQ20B. As the cholesterol content of lipid rafts is two times higher in SQ20B compared with SCC61 cells, we investigated the modulation of these microdomains using methyl-beta-cyclodextrin (MbetaCDX), a widely used cholesterol-depleting agent, in order to disrupt raft organization in both cells. Here, we report that MbetaCDX treatment resulted in the triggering of apoptosis in SCC61 cells involving mitochondrial events and associated with the clustering of Fas, the formation of Fas-FADD complexes and the cleavage of procaspase 8. The ligand-independent activation of this death receptor was totally absent in SQ20B cells, which remained resistant to MbetaCDX-triggered apoptosis. However, treatment of SQ20B with MbetaCDX resulted in a ligand-independent activation of the epidermal growth factor receptor (EGFR) survival pathway, as evidenced by an increased tyrosine phosphorylation of EGFR. Taken altogether, our results indicate that lipid raft integrity is intimately involved in the triggering of apoptotic cell death and/or survival pathways in head and neck carcinoma cells.

Topics: Apoptosis; beta-Cyclodextrins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cholesterol; ErbB Receptors; fas Receptor; Head and Neck Neoplasms; Humans; Membrane Microdomains; Signal Transduction

The dissolution rate, the toxicity and the release from chewing gum of miconazole and econazole cyclodextrin products and complexes were investigated. The dissolution rate studies showed that an amorphous miconazole hydroxypropyl-beta-cyclodextrin product gave drug supersaturation, whereas drug supersaturation was not present during dissolution rate testing of an econazole hydroxypropyl-beta-cyclodextrin product. The miconazole hydroxypropyl-beta-cyclodextrin product and genuine cyclodextrin inclusion complexes of miconazole, econazole and clotrimazole were toxic on a human TR146 buccal cell culture model. The toxicity was probably due to drug supersaturation, thereby increasing the bioavailability of the antimycotics. The econazole hydroxypropyl-beta-cyclodextrin product and physical mixtures of miconazole or econazole and beta-cyclodextrin did not give supersaturation and were not as toxic as the above-mentioned compounds. Neat econazole and miconazole, a genuine econazole beta-cyclodextrin complex and the miconazole hydroxypropyl-beta-cyclodextrin product were incorporated in chewing gum. The miconazole hydroxypropyl-beta-cyclodextrin gum had a much higher drug release in vitro than the neat miconazole gum. The genuine econazole beta-cyclodextrin complex only increased the drug release moderately when compared with the release from the neat econazole gum. The release studies were performed on a mastication device.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antifungal Agents; beta-Cyclodextrins; Candida albicans; Carcinoma, Squamous Cell; Cheek; Chewing Gum; Cyclodextrins; Drug Delivery Systems; Econazole; Head and Neck Neoplasms; Humans; Kinetics; Miconazole; Microscopy, Electron, Scanning; Mouth Mucosa; Mouth Neoplasms; Solubility; Tumor Cells, Cultured