Cytotoxicity of β-Cyclodextrins in Retinal Explants for Intravitreal Drug Formulations

Cyclodextrins (CDs) have been widely used as pharmaceutical excipients for formulation purposes for different delivery systems. Recent studies have shown that CDs are able to form complexes with a variety of biomolecules, such as cholesterol. This has subsequently paved the way for the possibility of using CDs as drugs in certain retinal diseases, such as Stargardt disease and retinal artery occlusion, where CDs could absorb cholesterol lumps. However, studies on the retinal toxicity of CDs are limited. The purpose of this study was to examine the retinal toxicity of different beta-(beta)CD derivatives and their localization within retinal tissues. To this end, we performed cytotoxicity studies with two different CDs-2-hydroxypropyl-beta CD (HP beta CD) and randomly methylated beta-cyclodextrin (RM beta CD)-using wild-type mouse retinal explants, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and fluorescence microscopy. RM beta CD was found to be more toxic to retinal explants when compared to HP beta CD, which the retina can safely tolerate at levels as high as 10 mM. Additionally, studies conducted with fluorescent forms of the same CDs showed that both CDs can penetrate deep into the inner nuclear layer of the retina, with some uptake by Muller cells. These results suggest that HP beta CD is a safer option than RM beta CD for retinal drug delivery and may advance the use of CDs in the development of drugs designed for intravitreal administration.