Development of high drug-loading nanomicelles targeting steroids to the brain

Sijia Zheng,1,* Yanqi Xie,1,* Yuan Li,1 Ling Li,1 Ning Tian,1 Wenbo Zhu,2 Guangmei Yan,2 Chuanbin Wu,1 Haiyan Hu1 1School of Pharmaceutical Sciences, 2Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China *These authors contributed equally to this workAbstract: The objective of this research was to develop and evaluate high drug-loading ligand-modified nanomicelles to deliver a steroidal compound to the brain. YC1 (5α-cholestane-24-methylene-3β, 5α, 6β, 19-tetraol), with poor solubility and limited access to the brain, for the first time, has been proved to be an effective neuroprotective steroid by our previous studies. Based on the principle of ‘like dissolves like’, cholesterol, which shares the same steroidal parent nucleus with YC1, was selected to react with sodium alginate, producing amphiphilic sodium alginate–cholesterol derivatives (SACDs). To increase the grafting ratio and drug loading, cholesterol was converted to cholesteryl chloroformate, for the first time, before reacting with sodium alginate. Further, lactoferrin was conjugated on SACDs to provide lactoferrin-SACDs (Lf-SACD), which was established by immune electron microscopy (IEM) and self-assembled into brain-targeting nanomicelles. These nanomicelles were negatively charged and spherical in nature, with an average size of