In-vivo Sonoporation Effect Under the Presence of a Large Amount of Micro-Nano Bubbles in Swine Liver

Abstract

Sonoporation as a method of intracellular drug and gene delivery has not yet progressed to being used in vivo. This is likely because the cavitation effect is too small to reach a level practical for in vivo use. The aim of this study was to prove the feasibility of sonoporation at a level practical for use in vivo by injecting a large amount of carbon dioxide micro-nanobubbles into swine livers and applying ultrasound irradiation. Nine swine placed under general anesthesia were used. The carbon dioxide micro-nanobubbles and drug were injected through a catheter into the hepatic artery. The carbon dioxide micro-nanobubbles and 100 mg of cisplatin were intraarterially injected over a period of 10 minutes, and ultrasound irradiation was performed from the surface of the liver under laparotomy during the intraarterial injection. The swine were euthanized immediately after the intraarterial injection, after which ultrasound-irradiated and non-irradiated liver tissues were immediately excised. Cross-sections of the excised liver tissue were examined with the naked eye for any abnormalities. Increased cisplatin concentration was evaluated as increased platinum concentration. Tissue platinum concentration was measured using inductively coupled plasma mass spectrometry. Liver tissue platinum concentrations were compared between the irradiated tissue and non-irradiated tissue using the Wilcoxon signed-rank test. The mean (± SD) liver tissue platinum concentration was 6.260*103 ± 2.070 ng/g in the irradiated liver tissue and 3.280*103 ± 0.430 ng/g in the non-irradiated liver tissue, showing significantly higher concentrations in the irradiated tissue than in the non-irradiated tissue (p = 0.004). No abnormal macroscopic findings were seen in the liver tissue harvested from any of the specimens. In conclusion, increasing the tissue concentration of administered cisplatin in the livers of living swine through the effect of sonoporation was possible by performing ultrasound irradiation of these livers in the presence of a large amount of micro-nanobubbles. A sonoporation effect practical for use in vivo can be achieved if a large amount of micro-nanobubbles is present.