A novel class of specifically engineered, dimerized cyclodextrin nanostructures was developed for the encapsulation of toxic biomolecules such as 7-ketocholesterol (7KC). 7KC accumulates over time and causes dysfunction in many cell types, linking it to several age-related diseases including atherosclerosis and age-related macular degeneration (AMD). Presently, treatments for these diseases are invasive, expensive, and show limited benefits.
Here, a combination of in silico, in vitro, and ex vivo methods is used to implement a synergistic rational drug design strategy for developing CDs to remove atherogenic 7KC from cells and tissues. Mechanisms by which CDs encapsulate sterols are discussed, and it was concluded that covalently linked head-to-head dimers of βCDs have substantially improved affinity for 7KC compared to monomers. It was found that inclusion complexes can be stabilized or destabilized in ways that allow the design of CD dimers with increased 7KC selectivity while maintaining an excellent safety profile. These CD dimers are being developed as therapeutics to treat atherosclerosis and other debilitating diseases of aging.
Amelia M. Anderson, Tamari Kirtadze, Milo Malanga, Darren Dinh, Carolyn Barnes, Angielyn Campo, Daniel M. Clemens, Rebeca Garcia-Fandiño, Ángel Piñeiro, Matthew S.O’Connor (2021) Cyclodextrin dimers: a versatile approach to optimizing encapsulation and their application to therapeutic extraction of toxic oxysterols. nternational Journal of Pharmaceutics
Available online 9 April 2021, 120522. https://doi.org/10.1016/j.ijpharm.2021.120522