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Background: Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH in vitro and in in vivo and sensitizes tumor cells to radiation and some cancer chemotherapeutics, its toxicity and short in vivo half-life have limited its application to combination anticancer therapies., Objective: To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH., Methods: A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor., Results: The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor., Conclusion: The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The ability of some surfactants to self-assemble in a water/oil bi-phase environment thus forming supramolecular structure leading to the formation of w/o/w multiple emulsions was investigated. The w/o/w multiple emulsions obtained by self-assembling (one-step preparation method) were compared with those prepared following the traditional two-step procedure. Methyl-nicotinate was used as a hydrophilic model drug. The formation of the multiple emulsion structure was evidenced by optical microscopy, which showed a mean size of the inner oil droplets of 6 μm and 10 μm for one-step and two-step multiple emulsions, respectively. The in vitrobiopharmaceutical features of the various w/o/w multiple emulsion formulations were evaluated by means of viscosimetry studies, drug release and in vitro percutaneous permeation experiments through human stratum corneum and viable epidermis membranes. The self-assembled multiple emulsions allowed a more gradual percutaneous permeation (a zero-order permeation rate) than the two-step ones. The in vivotopical carrier properties of the two different multiple emulsions were evaluated on healthy human volunteers by using the spectrophotometry of reflectance, an in vivonon invasive method. These multiple emulsion systems were also compared with conventional emulsion formulations. Our findings demonstrated that the multiple emulsions obtained by self-assembling were able to provide a more sustained drug delivery into the skin and hence a longer therapeutic action than two-step multiple emulsions and conventional emulsion formulations. Finally, our findings showed that the supramolecular micro-assembly of multiple emulsions was able to influence not only the biopharmaceutical characteristics but also the potential in vivotherapeutic response.