title: Doxorubicin and edelfosine lipid nanoparticles are effective acting synergistically against drug-resistant osteosarcoma cancer cells.
abstract: Despite the great advances that have been made in osteosarcoma therapy during recent decades, recurrence and metastases are still the most common outcome of the primary disease. Current treatments include drugs such as doxorubicin (DOX) that produce an effective response during the initial exposure of tumor cells but sometimes induce drug resistance within a few cycles of chemotherapy. New therapeutic strategies are therefore needed to overcome this resistance. To this end, DOX was loaded into lipid nanoparticles (LN) and its efficacy was evaluated in commercial and patient-derived metastatic osteosarcoma cell lines. DOX efficacy was heavily influenced by passage number in metastatic cells, in which an overexpression of P-gp was observed. Notably, DOX-LN overcame the resistance associated with cell passage and improved DOX efficacy fivefold. Moreover, when DOX was co-administered with either free or encapsulated edelfosine (ET), a synergistic effect was observed. This higher efficacy of the combined treatment was found to be at least partially due to an increase in caspase-dependent cell death. The combination of DOX and ET is thus likely to be effective against osteosarcoma.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain; Laboratory of Pediatrics, University Clinic of Navarra, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: González-Fernández
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Imbuluzqueta
authors.affiliation: Laboratory of Pediatrics, University Clinic of Navarra, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Zalacain
authors.affiliation: Laboratory of Cell Death and Cancer Therapy, Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, E-28040, Madrid, Spain.
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
authors.affiliation: Laboratory of Pediatrics, University Clinic of Navarra, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-García
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Irunlarrea 3, 31008, Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D053758:Nanoparticles; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010742:Phospholipid Ethers / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010742:Phospholipid Ethers; C026659:edelfosine; D004317:Doxorubicin
keywords: Doxorubicin; Edelfosine; Lipid nanoparticles; Metastases; Osteosarcoma; Synergy