title: Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer.
abstract: 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.
authors.affiliation: Inserm, U1032, Lyon, F-69424, France.|Inserm, U1033, Lyon, F-69372, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tardoski
authors.affiliation: Inserm, U1032, Lyon, F-69424, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ngo
authors.affiliation: Inserm, U1033, Lyon, F-69372, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Gineyts
authors.affiliation: Inserm, U1033, Lyon, F-69372, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Roux
authors.affiliation: Inserm, U1033, Lyon, F-69372, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.affiliation: Inserm, U1032, Lyon, F-69424, France.|University of Lyon, Villeurbanne, France.|LabEx DEVweCAN, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Melodelima
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D045782:Hemiterpenes / Q000096:biosynthesis; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D007093:Imidazoles / Q000494:pharmacology; D009943:Organophosphorus Compounds; D000069453:Ultrasonic Waves; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins