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

Manisha Prajapati,Thorsteinn Loftsson,Gustav Christensen,François Paquet-Durand

doi:10.3390/molecules26051492

Manisha Prajapati, Thorsteinn Loftsson + Show 2 more

Open Access

https://doi.org/10.3390/molecules26051492

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Abstract

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-(β)CD derivatives and their localization within retinal tissues. To this end, we performed cytotoxicity studies with two different CDs—2-hydroxypropyl-βCD (HPβCD) and randomly methylated β-cyclodextrin (RMβCD)—using wild-type mouse retinal explants, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and fluorescence microscopy. RMβCD was found to be more toxic to retinal explants when compared to HPβCD, 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 Müller cells. These results suggest that HPβCD is a safer option than RMβCD for retinal drug delivery and may advance the use of CDs in the development of drugs designed for intravitreal administration.

Highlights

Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4-)-linked α-Dglucopyranose units with a hydrophobic central cavity and a hydrophilic outer surface
randomly methylated β-cyclodextrin (RMβCD) was found to be more toxic to retinal explants when compared to HPβCD, which the retina can safely tolerate at levels as high as 10 mM
These results suggest that HPβCD is a safer option than RMβCD for retinal drug delivery and may advance the use of CDs in the development of drugs designed for intravitreal administration

Summary

Introduction

Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4-)-linked α-Dglucopyranose units with a hydrophobic central cavity and a hydrophilic outer surface. They can form water-soluble inclusion complexes with numerous lipophilic drugs provided that their structure (or part of it) fits in the CD cavity. The complexation affects many physicochemical properties of drugs, such as their aqueous solubility and chemical stability [2]. CDs have undergone extensive safety studies and have been approved by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for pharmaceutical use and in dietary supplements [3,4]. CDs have been the subject of numerous review publications [5,6,7,8,9,10,11,12,13]

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