Author: Tardoski S1,2,3,4, Ngo J1,3,4, Gineyts E2,3,4, Roux JP2,3,4, Clézardin P2,3,4, Melodelima D1,3,4
Affiliation: <sup>1</sup>Inserm, U1032, Lyon, F-69424, France.
<sup>2</sup>Inserm, U1033, Lyon, F-69372, France.
<sup>3</sup>University of Lyon, Villeurbanne, France.
<sup>4</sup>LabEx DEVweCAN, Lyon, France.
Conference/Journal: Sci Rep.
Date published: 2015 Nov 18
Other:
Volume ID: 5 , Pages: 16354 , Special Notes: doi: 10.1038/srep16354. , Word Count: 205
Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability 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 bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that 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 bisphosphonate from 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 bisphosphonate anticancer activity in bone metastases and in primary tumors.
PMID: 26578234 PMCID: PMC4649676 DOI: 10.1038/srep16354