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Molecules 2018, 23(5), 1228; https://doi.org/10.3390/molecules23051228

Cyclodextrins: Assessing the Impact of Cavity Size, Occupancy, and Substitutions on Cytotoxicity and Cholesterol Homeostasis

1
Cyclolab Cyclodextrin Research and Development Laboratory Ltd., H-1097 Budapest, Hungary
2
Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA
3
Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA
4
Department of Chemistry, University of California-Davis, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Received: 26 April 2018 / Revised: 11 May 2018 / Accepted: 17 May 2018 / Published: 20 May 2018
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Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides; the most common CDs contain six, seven, or eight glucose units called α-CDs, β-CDs, and γ-CDs, respectively. The use of CDs in biomedical research is increasing due to their ability to interact with membrane lipids as well as a wide variety of poorly water-soluble molecules. We assessed the impact of CD cavity size, occupancy, and substitutions on cytotoxicity and cholesterol homeostasis. The potency of CD-mediated cytotoxicity was in the order of β-CDs, α-CDs, and γ-CDs. Substitutions with hydroxypropyl or carboxymethyl group attenuated cytotoxicity compared with the native CDs, whereas CDs substituted with methyl groups exhibited cytotoxicity that was similar to that of the native CDs. The lipid components in blood exerted remarkable hemolysis-alleviating effects in methyl-β-CD-induced hemolysis. Occupancy of the CD cavity with cholesterol or a structurally related lipid molecule abrogated the cytotoxic capacity of the CDs. Interestingly, hydroxypropyl-γ-CD (HPγCD) was able to reduce intracellular cholesterol accumulation in Niemann–Pick disease type C (NPC) patient-derived fibroblasts as efficiently as HPβCD. Proteomic study indicated that HPβCD and HPγCD treatments altered the expression pattern of cellular proteins, suggesting that some of the CD-induced cellular proteins may play an important function in modulating intracellular cholesterol homeostasis. View Full-Text
Keywords: cholesterol; cyclodextrin; lipids; Niemann–Pick disease type C; occupancy cholesterol; cyclodextrin; lipids; Niemann–Pick disease type C; occupancy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Szente, L.; Singhal, A.; Domokos, A.; Song, B. Cyclodextrins: Assessing the Impact of Cavity Size, Occupancy, and Substitutions on Cytotoxicity and Cholesterol Homeostasis. Molecules 2018, 23, 1228.

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