Current Development of siRNA Bioconjugates: From Research to the Clinic

In this study, it was shown that the main factor determining the nature of the biodistribution of conjugates is their lipophilicity. Conjugates of siRNA with lower lipophilicity; i.e., derivatives of retinoic acid, lithocholic acid, and docosahexanoic acid with greater efficiency than cholesterol conjugates accumulated in the kidneys, bladder, and lungs of the mouse after subcutaneous injection (Biscans et al., 2018). This fact is consistent with previous data that showed that more lipophilic conjugates bind more efficiently to serum components, and thus are not excreted by the kidneys (Wolfrum et al., 2007; Osborn et al., 2018). Lipophilic derivatives after subcutaneous or intravenous injection do not penetrate the blood-brain barrier (BBB) (Biscans et al., 2018). Therefore, attempts were made to directly inject derivatives into the brain of the mouse to suppress gene expression in the brain (Alterman et al., 2015; Nikan et al., 2016, 2017). Since docosahexaenoic acid is the most common polyunsaturated fatty acid in the mammalian brain, conjugation of siRNA with docosahexaenoic acid more effectively suppressed the expression of the target gene (Nikan et al., 2016) than other lipophilic conjugates (Alterman et al., 2015). Injection of the siRNA-docosahexaenoic acid conjugate into the brain striatum of the mouse (~1.25 mg/kg) caused a decrease in the mRNA level of the target gene (Htt) not only in the striatum (73%) but also in the cortex (52%) of the corresponding he...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research