In vivo tissue pharmacokinetics of ERBB2‐specific binding oligonucleotide‐based drugs by PET imaging

Although aptamers have shown excellent target specificity in preclinical and clinical studies either by themselves or as aptamer‐drug conjugates, their in vivo tissue pharmacokinetic (PK) analysis is still problematic. We aimed to examine the utility of image‐based positron emission tomography (PET) to evaluate in vivo tissue PK, target specificity, and applicability of oligonucleotides. For this, fluorine‐18‐labeled aptamers with erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐specific binding were synthesized by base‐pair hybridization using a complementary oligonucleotide platform. To investigate the PKs and properties of in vivo tissue, usefulness of in vivo PET imaging in the development of an oligonucleotide‐based drug as an assessment tool was evaluated in normal and tumor xenografted mice. ERBB2‐cODN‐idT‐APs‐[(18)F]F ([(18)F]1), injected intravenously showed significant and rapid uptake in most tissues except for the initial brain and muscle; the uptake was highest in the heart, followed by kidneys, liver, lungs, gall bladder, spleen, and stomach. The main route of excretion was through the renal tract ~77.8%, whereas about 8.3% was through the biliary tract of the total dose. The estimated effective dose for an adult woman was 0.00189 mGy/MBq, which might be safe. ERBB2‐positive tumor could be well visualized in the KPL4 xenograft animal model by in vivo PET imaging. Consequently, the distribution in each organ including ERBB2 expression could be well determined and quantified by PET with fluorine‐18‐labeled aptamers. In vivo PK parameters such as terminal half‐life, time to maximum concentration, area under the curve, and maximum concentration, were also successfully estimated. These results suggest that image‐based PET with radioisotope‐labeled aptamers could be provide valuable information on properties of oligonucleotide‐based drugs in drug discovery of targeted therapeutics against various diseases.