Mohammadi, S. O.; LaRocca, M. C.; Yang, C. D.; Jessen, J.; Kenney, M. C.; Lin, K. Y.

Objective: Pulsed ultrasound has been proposed as a tool to enhance ocular drug delivery, but its effects on drug potency are not well understood. Doxorubicin-HCl and cisplatin are two drugs commonly used to treat ocular melanoma. We report the effects of pulsed ultrasound on the cytotoxicity of doxorubicin-HCl and cisplatin in vitro. Methods: Cultured human retinal pigment epithelium cells (ARPE-19) cells were treated with doxorubicin-HCl or cisplatin in the presence or absence of ultrasound. MTT and Trypan blue assays were performed at 24 and 48 hours post-treatment to assess cell metabolism and death. Results: Cells treated with ultrasound plus doxorubicin-HCl demonstrated a significant decrease in metabolism compared to cells treated with doxorubicin-HCl alone. In contrast, cells treated with ultrasound plus cisplatin exhibited a significant increase in metabolism compared to cells treated with cisplatin alone at 48-hours. Cells treated with cisplatin pre-treated with ultrasound (US-Cis) exhibited a significant decrease in metabolism. Cell death was similar in doxorubicin- and cisplatin-treated cells with and without ultrasound. Conclusion: Pulsed ultrasound enhances the cytotoxicity of doxorubicin-HCl at 24- and 48-hours post-treatment but abrogates cisplatin toxicity 48-hours post-treatment. This suggests ultrasound modulates cell-drug interactions in a drug-specific manner. These findings may influence the future development of ultrasound-assisted ocular drug delivery systems. Keywords: therapeutic ultrasound, antineoplastic, microbubbles, sonoporation, ocular drug delivery