Effectiveness of localized ultrasound-targeted microbubble destruction with doxorubicin liposomes in H22 mouse hepatocellular carcinoma model

Objective: In order to increase local drug concentration and reduce systemic side effects of liver cancer chemotherapy, it is desirable to develop novel non-invasive technologies for drug targeting, such as ultrasound-targeted microbubble destruction (UTMD).

Methods: H22 hepatocellular carcinoma (HCC) xenograft transplantation model was generated in UTMD study. BALB/c mice were randomly divided into six groups: doxorubicin HCl liposomal injection (DOX), DOX?+?US, UTMD, DOX?+?UTMD, H22 liver tumor control (CH control) and blank control group. The therapeutic schedule started on day 4 after tumor inoculation.

Results: Average survival time of the animal model was approximately 18?d. The UTMD therapy parameters were optimized in the H22 mouse model to be: microbubble (MB) diameter, 2.30?±?0.25?μm; MB density, 4.0?×?10⁹ bubbles/ml; treatment dose, 0.2?ml per 20?g mouse body weight; sonication frequency, 1.3?MHz; and sonication power, 2.06?W/cm². Mice treated with DOX?+?UTMD had the smallest tumor volume and weight (p?<?0.001), and the highest tumor inhibition rate (p?<?0.01), intratumoral DOX concentration (p?<?0.001) and survival rate among all tumor-burden groups (p?<?0.001). Cell viability in different treatment groups was also assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Conclusion: An improved antitumor effect was observed with the combination therapy of DOX and UTMD, as compared with treatment with DOX, DOX?+?US or UTMD, which implicates a novel approach for HCC treatment.