Interactions between cyclodextrins and cellular components: Towards greener medical applications?

Leclercq, Loïc

The results prove that the native CDs are the most toxic (γ-CD < β-CD < α-CD). As expected, lipid effluxes on the brain capillary endothelial cells in the presence of native CDs reveal that α-CD extracts only phospholipids whereas β-CD is able to remove phospholipids and cholesterol. In contrast, γ-CD is less lipid-selective than the other native CDs. This differential effect compared to the order of magnitude of hemolytic activity (γ-CD < α-CD < β-CD) could be ascribed to the lower cholesterol content in blood-brain barrier cells compared to erythrocytes. Indeed, the cholesterol fraction is markedly higher in erythrocytes than in other cells. As for hemolysis, the presence of hydrophilic substituents (e.g., 2-hydroxypropyl and sulfobutyl ether) annihilates the cytotoxicity while the presence of methyl residues induces cell death of various cells (Caco-2, TR146, PC-12, etc.) [76] [77] [78] . For instance, cell death induced by DM-β-CD is caused by a marked apoptosis mechanism (i.e., a process by which cells trigger their self-destruction in response to a signal which leads to cell changes prior to death) for NR8383, A549 and Jurkat cells [79] . This apoptosis process results from cholesterol extraction leading to inhibition of the activation of PI3K-Akt-Bad pathway. The presence of DM-α-CD had repercussions that were totally opposite to the DM-β-CD. Indeed, the cell death results from a non-apoptotic mechanism (i.e., necrosis). This differential effect could be attributed to a dissimilarity of interaction between the methylated CDs with the cholesterol-rich lipid rafts and with the sphingomyelin-rich domains for DM-β-CD and DM-α-CD, respectively. These results suggest that lipid rafts of cell membranes would be involved in cell death and cellular function.