Authors: P. Botella, C. Muniesa, V. Vicente, K. Fabregat, A. Cabrera
Affilation: Instituto de Tecnología Química (UPV-CSIC), Spain
Pages: 347 - 350
Keywords: cancer therapy, drug delivery, disulfide cleavage, mesoporous silica nanoparticles, glutathione
Direct coupling of camptothecin (CPT) to nanoparticles is circumvented by the reduced therapeutic activity of its structure-modified derivatives. To negotiate this problem, we have developed a novel CPT nanoplatform based in a mercapto-functionalized silica hybrid containing a non-porous core and a mesoporous shell. (Pyridin-2-yldisulfanyl)alkyl carbonate derivatives of CPT have been attached over the pores of the thiol-modified inorganic nanoparticles by disulfide bridge. This bond is sensitive to intracellular reducing compounds as glutathione (GSH), releasing free CPT after an intramolecular cyclization. We present here the in vitro evaluation of these materials in HeLa cells, stating their cytotoxicity and intracellular release mechanism. Results indicate that lateral chain length determines the release of free CPT after disulfide bridge cleavage. Co-localization experiments by confocal microscopy with LysoTracker® show nanoparticles within lysosomes, but also in the cytosol. Evidence of GSH role in CPT release mechanism was studied by MTT assay in the presence of GSH inhibitors like L-buthionine sulfoximine (BSO) or chloroquine (CLQ). In both cases, significant increase of cell resistance to the nanomedicine was found. This novel CPT-containing nanoparticulated system combines therapeutic activity and imaging at subcellular level, imposing controlled intracellular release of the active principle under the reducing activity of GSH.
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