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

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.

Cyclodextrins in Drug Delivery Systems and Their Effects on Biological Barriers

“…Latter has no ability to complex cholesterol, that is why there should be another mechanism to explain this phenomenon. It was supposed that cyclodextrins can induce cellular signaling routes to facilitate intracellular cholesterol trafficking [124,125]. To achieve the above-mentioned effects, HPBCD molecule must enter the cells.…”

Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis

“…As positive controls, 70% ethanol, 2HPBCD, and MBCD, known to dissolve cholesterol 17,18,24 , was included in this experiment. CCs were dissolved by incubation with ACD and 2HPBCD after 2-48 h incubation (Fig.…”

Cytotoxic Activity Evaluation on Breast Cells of Guest-host Complexes Containing Artemisinin

“…In the formation of guest-host inclusion complexes the nonpolar molecule enters the internal lipophilic cavity of the CDs and thus, the carrier molecules are widely used as to improve drug solubility and stability [21]. Because the methylation of hydroxyl groups can enhance the hydrophobic cavity, methylated CDs are used in drug delivery processes to improve bioavailability and cellular distribution [29,30], especially Heptakis (2,3,6-tri-Omethyl)-β-cyclodextrin which is considered the most soluble in comparison to natural CDs [31].…”