A Hydrophobic Goldilocks Zone for Cyclodextrin-Lipid-Membrane Interactions: Implications of Drug Hydrophobicity on Kinetics of Cholesterol Removal from Lipid Membranes

Cyclodextrins (CDs) are cyclic oligosaccharides known for their ability to form guest-host complexes with hydrophobic molecules such as cholesterol, making them useful in various biomedical and industrial applications. However, their nonselective cholesterol extraction from cellular membranes raises concerns about cytotoxicity, necessitating a deeper understanding of their interactions with lipid bilayers. In this study, we investigate the role of CD hydrophobicity, as modulated by various substituent chemistries, on cholesterol extraction from supported lipid bilayers (SLBs) using quartz crystal microgravimetry with dissipation monitoring (QCM-D). Our results reveal a hydrophobicity-dependent "Goldilocks Zone" where intermediate hydrophobicity optimizes cholesterol removal while preserving membrane integrity. Additionally, preliminary analyses suggest that CD-membrane binding cooperativity, influenced by hydrophobicity, plays a crucial role in the efficiency and selectivity of cholesterol extraction. CDs with intermediate hydrophobicity exhibit enhanced binding cooperativity and more efficient cholesterol removal, suggesting a synergistic relationship between hydrophobicity and binding dynamics. These findings highlight the importance of CD hydrophobicity and binding cooperativity in designing cyclodextrin-based therapeutics with minimal cytotoxicity.