title: Evaluation of cholesterol depletion as a marker of nephrotoxicity in vitro for novel β-cyclodextrin derivatives.
abstract: 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 (HP(3)-SBE(2)-β-CD and HP(2)-SBE(3)-β-CD) and compared their effects to sulfobutyl ether-β-cyclodextrin (SBE(7)-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 HP(3)-SBE(2)-β-CD or HP(2)-SBE(3)-β-CD on cell viability, membrane damage, and the induction of apoptosis and necrosis resembled that of SBE(7)-β-CD, whereas the effects were significantly lower for M-β-CD or DM-β-CD. HP(3)-SBE(2)-β-CD and HP(2)-SBE(3)-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.
authors.affiliation: Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, Nanjing Normal University, Wenyuan Road 1, Nanjing 210046, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Xie
authors.forename: Fengyi
authors.initials: F
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Tao
authors.forename: Yina
authors.initials: Y
authors.lastname: Zou
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhou
authors.forename: Shuqin
authors.initials: S
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000172:deficiency* / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D047392:beta-Cyclodextrins / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D047392:beta-Cyclodextrins; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; C031215:betadex