Cholesterol-siRNA conjugates

This was the basis for the development of a second generation DPC, named ARC-520, which is currently in phase II clinical trial for the treatment of hepatitis B (Table 14.2). In ARC-520, the previous endosomolytic PBAVE polymer was replaced with a melittin-like peptide (MLP) with a well-defined structure. In addition, there is no chemical link between the siRNA and the polymer. Thus, ARC-520 consists of two individual components cholesterol-siRNA conjugates and hepatocyte-targeting membrane-active peptides linked to the MLP polymer. 

Conjugation of cholesterol to siRNA has been demonstrated to improve serum protein binding, improve pharmacokinetics. 

Tremendous efforts have been made to overcome these challenges, cationic liposome and positively charged polymers are currently being used as the most common method to complex with negatively charged siRNA for systemic delivery [30, 36]. Other in vivo delivery approaches include conjugation with cholesterol, aptamer, peptide complexation with antibody-protamine fusion protein or encapsulation in cyclodextrin nanoparticles [35, 37-39]. 

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