Study of the relationship between lipid binding properties of cyclodextrins and their effect on the integrity of liposomes

It is well known that cyclodextrins are able to extract lipids constituting membranes, increasing their fluidity and permeability. This behaviour towards biological membranes is directly linked to the toxicological effects of methylated cyclodextrins. However, confusion is currently made in the literature between the different methylated cyclodextrin derivatives. Moreover, a new methylated cyclodextrin derivative recently occurred in the market, the Crysmeb®. We wanted to compare and understand the effect of the most currently used cyclodextrins on a model membrane. We studied the influence of natural cyclodextrins (βCD and γCD), methylated derivatives (2,6-dimethyl-βCD (Dimeb), 2,3,6-trimethyl-βCD (Trimeb) and randomly methylated-βCD (Rameb), as well as the new derivative Crysmeb), hydroxypropylated derivatives (HPβCD of different substitution degrees and HPγCD) and the sulfobutylated derivative (SBEβCD) on the release of a fluorescent marker encapsulated in the inner cavity of liposomes. It was shown that the observed effect on calcein release can be directly related to the affinity of cyclodextrins for both lipid components of liposomes, cholesterol and phosphatidylcholine. From this relationship, we were able to determine, for each cyclodextrin, a theoretical concentration giving rise to 50% or 100% calcein release. This theoretical concentration was confirmed experimentally. We have also showed that cyclodextrins which provoke calcein release also induce large structure modifications of liposomes.