[Positron emission tomography (PET) imaging of small interfering RNA (siRNA) delivery in drug development]

Pharmacokinetic studies of nanoparticles have provided significant information by which advanced delivery systems have been designed. On the other hand, pharmacokinetics of RNA interference (RNAi) effectors such as small interfering RNA (siRNA) is poorly understood. We have synthesized [(18)F]-labeled siRNA for a pharmacokinetic study using positron emission tomography (PET). PET is a noninvasive bioimaging modality applicable to a microdosing study that is designed to evaluate pharmacokinetics of drug candidates in human at an early stage of drug development. We have demonstrated that the resulting PET images clearly show the biodistribution of siRNA in mice. Naked [(18)F]-siRNA accumulates in the bladder immediately after intravenous administration due to rapid degradation. [(18)F]-siRNA formulated in cationic liposomes rapidly accumulates in the lungs due to positive surface charge of the cationic liposomes. [(18)F]-siRNA formulated in PEGylated liposomes shows long circulation in the bloodstream. Thus, the biodistribution of [(18)F]-siRNA is reflected by the characteristics of each liposomal biodistribution. Importantly, it has been demonstrated that accumulation of siRNA in tumors is able to be evaluated using [(18)F]-siRNA/PET. In addition, [(18)F]-siRNA/PET is also found to be useful to evaluate the effect of chemical modification of siRNA on its biodistribution. Cholesterol-conjugated [(18)F]-siRNA shows long half-life in the bloodstream and accumulates in the liver compared with naked [(18)F]-siRNA. Our findings indicate that the pharmacokinetic PET study of siRNA provides important insights into the development of RNAi medicine.