Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland.
Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Strasse 5-7, 72076 Tübingen, Germany.
Molecules. 2021 Mar 9;26(5):1492. doi: 10.3390/molecules26051492.
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.
环糊精（CDs）已被广泛用作不同给药系统制剂的药用辅料。最近的研究表明，CDs 能够与多种生物分子（如胆固醇）形成复合物。这为将 CDs 用作某些视网膜疾病（如斯塔加特病和视网膜动脉阻塞）的药物开辟了可能性，在这些疾病中，CDs 可以吸收胆固醇块。然而，关于 CDs 的视网膜毒性的研究有限。本研究旨在研究不同β-（β）CD 衍生物的视网膜毒性及其在视网膜组织内的定位。为此，我们使用野生型小鼠视网膜外植体进行了两种不同的 CD-2-羟丙基-β-CD（HPβCD）和随机甲基化 β-环糊精（RMβCD）的细胞毒性研究，末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）测定和荧光显微镜检查。与 HPβCD 相比，RMβCD 对视网膜外植体的毒性更大，而视网膜可以安全耐受高达 10 mM 的 HPβCD。此外，用相同 CD 的荧光形式进行的研究表明，两种 CD 都可以深入穿透视网膜的内核层，一些被 Müller 细胞摄取。这些结果表明，HPβCD 是用于视网膜药物输送的比 RMβCD 更安全的选择，并可能推进 CDs 在设计用于玻璃体内给药的药物开发中的应用。
