Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonateshave demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonateshave anticancer activity. However, bisphosphonatesexhibit a high affinity for bone mineral, which reduces their bioavailibity for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonatezoledronate (ZOL) in combination with US. In a bone metastasismodel, mice treated with ZOL+US had osteolytic lesionsthat were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonatefrom the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonateanticancer activity in bone metastases and in primary tumors.