title: Pharmacokinetics of a Cholesterol-conjugated Aptamer Against the Hepatitis C Virus (HCV) NS5B Protein.
abstract: Hepatitis C virus (HCV) is the major cause of progressive liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Previously, we reported that a 29 nucleotide-long 2'-F pyrimidine modified RNA aptamer against the HCV nonstructural protein 5B efficiently inhibited HCV replication and suppressed HCV infectious virus particle formation in a cell culture system. In this study, we modified this aptamer through conjugation of cholesterol for in vivo availability. This cholesterol-conjugated aptamer (chol-aptamer) efficiently entered the cell and inhibited HCV RNA replication, without any alteration in gene expression profiling including innate immune response-related genes. Moreover, systemic administration of the chol-aptamer was well tolerated without any abnormalities in mice. To evaluate the pharmacokinetics of the chol-aptamer in vivo, dose proportionality, bioavailability, and pharmacokinetic parameters were evaluated by noncompartmental analyses in normal BALB/c mice. Population analysis was performed using nonlinear mixed effects modeling. Moreover, the pharmacokinetics of two different routes (intravenous, IV, versus intraperitoneal, IP) were compared. Cholesterol conjugation showed dose proportionality, extended the time that the aptamer was in the plasma, and enhanced aptamer exposure to the body. Noticeably, the IV route was more suitable than the IP route due to the chol-aptamer remaining in the plasma for a longer period of time.
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Korea.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Korea.
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, California, USA.
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Gyu-Jeong
authors.initials: GJ
authors.lastname: Noh
authors.affiliation: Department of Molecular Biology, Institute of Nanosensor and Biotechnology, and Research Institute of Advanced Omics, Dankook University, Yongin, Korea.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee