Shuqin Yu - Evaluation of cholesterol depletion as a marker of nephrotoxicity in vitro for Novel β-Cyclodextrin Derivatives

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        Cyclodextrins (CDs) have been shown to improve physicochemical   and biopharmaceutical properties of drugs when low solubility and   low safety limit their use in the pharmaceutical field. Recently,   we have developed new multi-substituted-β-CDs,   hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HPn-SBEm-β-CD).   HPn-SBEm-β-CD exhibit low hemolysis, good solubility, strong   inclusion ability, and an appropriate average molecular weight.   In this study, we chose two products of HPn-SBEm-β-CD   (HP3-SBE2-β-CD   and HP2-SBE3-β-CD)   and compared their effects to sulfobutyl ether-β-cyclodextrin   (SBE7-β-CD),   methyl-β-cyclodextrin (M-β-CD) and 2,6-di-O-methyl-β-cyclodextrin   (DM-β-CD). We evaluated viability, membrane damage, induction of   apoptosis and necrosis, cholesterol depletion, and morphological   changes in human embryonic kidney 293A cells (HEK293A)    in vitro.   CDs caused a reduction of cell viability and increased LDH levels   in a concentration-dependent manner. The effect of   HP3-SBE2-β-CD   or HP2-SBE3-β-CD   on cell viability, membrane damage, and the induction of   apoptosis and necrosis resembled that of SBE7-β-CD,   whereas the effects were significantly lower for M-β-CD or   DM-β-CD. HP3-SBE2-β-CD   and HP2-SBE3-β-CD   exhibited morphological changes at high concentrations. In   conclusion, the results showed that cholesterol depletion may be   as a marker for evaluating the cytotoxicity of novel β-CD   derivatives. These results will provide useful information for   HPn-SBEm-β-CD as a promising safe adjuvant for intravenous   administration in the future.

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      Address (URL): http://www.sciencedirect.com/science/article/pii/S0278691511000950