Pharmacokinetics and biodistribution of a pGT2-VEGF plasmid DNA after administration in rats.
Intramyocardial administration of gene therapy vectors expressing angiogenic factors have been attempted as an alternative to conventional surgical methods for the management of myocardial ischemia. In this study, we have developed the pGT2-VEGF, a plasmid DNA vector expressing human VEGF165, for the management of ischemic cardiovascular disease and investigated in vivo pharmacokinetics and tissue distribution of pGT2-VEGF after intramyocardial and intravenous administration in rats. A high concentration of pGT2-VEGF was observed in the heart after intramyocardial injection of 300 microg, which is in line with the assumption that direct intramyocardial delivery enables extended localization at the administration site. Leakage of the pGT2-VEGF to the blood circulation was observed after intramyocardial injection, with an area under the curve (AUC) of 3.8 microg min/mL, as compared with 37.3 microg min/mL after intravenous injection of the same dose. The pGT2-VEGF concentration in blood peaked at 5 minutes after intramyocardial administration and declined rapidly to undetectable levels by 2 hours post-administration. In tissue distribution studies, pGT2-VEGF peaked at 5 minutes post-administration in various organs but was undetectable at 2 hours in all organs except heart, lung, and liver. Taken together, the results suggest that intramyocardial-delivered pGT2-VEGF was degraded rapidly in vivo and mainly persisted in target tissues, the heart. In addition, intramyocardial-administered pGT2-VEGF was expressed for longer periods than the persistence of the pGT2-VEGF plasmid DNA in a target tissue. Therefore, a direct myocardial injection of pGT2-VEGF might be useful for local therapeutic angiogenesis.
Son
Mi-Kyung
MK
Research Laboratories, Dong-A Pharm. Co. Ltd., 47-5 Sanggal-ri, Kiheung-up, Yongin-si, Kyunggi-do 449-900, Republic of Korea.
Choi
Jae-Hoon
JH
Lee
Dong-Sop
DS
Kim
Chae-Young
CY
Choi
Seul-Min
SM
Kang
Kyung-Koo
KK
Byun
Jonghoe
J
Kim
Duk-Kyung
DK
Kim
Byong-Moon
BM
D000818:Animals; D001682:Biological Availability; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A