Delivering Crocetin across the Blood-Brain Barrier by Using γ-Cyclodextrin to Treat Alzheimer’s Disease
Ka Hong Wong, Yuning Xie, Xiao Li Huang, Kazunori Kadota, Xin‐Sheng Yao, Yang Yu, Xiaoyu Chen, Aiping Lü, Zhijun Yang
Abstract
Abstract Crocetin (CRT) has shown various neuroprotective effects such as antioxidant activities and the inhibition of amyloid β fibril formation, and thus is a potential therapeutic candidate for Alzheimer’s disease (AD). However, poor water solubility and bioavailability are the major obstacles in formulation development and pharmaceutical applications of CRT. In this study, a novel water-soluble CRT-γ-cyclodextrin inclusion complex suitable for intravenous injection was developed. The inclusion complex was nontoxic to normal neuroblastoma cells (N2a cells and SH-SY5Y cells) and AD model cells (7PA2 cells). Furthermore, it showed stronger ability to downregulate the expression of C-terminus fragments and level of amyloid β in 7PA2 cell line as compared to the CRT free drug. Both inclusion complex and CRT were able to prevent SH-SY5Y cell death from H 2 O 2 -induced toxicity. The pharmacokinetics and biodistribution studies showed that CRT-γ-cyclodextrin inclusion complex significantly increased the bioavailability of CRT and facilitated CRT crossing the blood-brain barrier to enter the brain. This data shows a water-soluble γ-cyclodextrin inclusion complex helped to deliver CRT across the blood-brain barrier. This success should fuel further pharmaceutical research on CRT in the treatment for AD, and it should engender research on γ-cyclodextrin with other drugs that have so far not been explored.