Development of gene drug delivery systems based on pharmacokinetic studies.
A series of pharmacokinetic studies following systemic or local administration for the development of delivery systems for gene drugs, such as plasmid DNA and oligonucleotides, are reviewed. The pharmacokinetics of gene drugs after intravenous injection into mice was evaluated based on clearance concepts. Pharmacokinetic analysis revealed that the overall disposition characteristics of the gene drug itself were determined by the physicochemical properties of its polyanionic DNA. Based on these findings, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. On the other hand, the pharmacokinetics of gene drugs after intratumoral injection were assessed in a tissue-isolated tumor perfusion system. The relationship between the physicochemical properties of gene drug delivery systems and intratumoral pharmacokinetics was determined and the therapeutic effect was also discussed in relation to pharmacokinetics. Collectively, it was demonstrated that a rational design of gene drug delivery systems that can control their in vivo disposition is possible by means of pharmacokinetic studies at whole body, organ and cellular levels.
Takakura
Y
Y
Department of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan.
Nishikawa
M
M
Yamashita
F
F
Hashida
M
M
D000818:Animals; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010957:Plasmids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000502:physiology
D004337:Drug Carriers; D009841:Oligonucleotides; D011108:Polymers