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 μg, 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 μg min/mE, as compared with 37.3 μg 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, pGT ₂-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 pGT ₂-VEGF was degraded rapidly in vivo and mainly persisted in target tissues, the heart. In addition, intramyocardial-administered pGT ₂-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.