Oral edelfosine lipid nanoparticles caused the regression of lung metastases in pre- clinical osteosarcoma animal models

lipid nanoparticles caused the regression of lung metastases in pre- clinical osteosarcoma ABSTRACT Osteosarcoma (OS) is the most frequent paediatric bone cancer, responsible for 9% of all cancer-related deaths in children. In this paper, a new strategy based on delivering edelfosine (ET) in lipid nanoparticles (LN) was explored in order to target the primary tumor and eliminate metastases. The in vitro and in vivo efficacy of the free drug, drug loaded into lipid nanoparticles (ET-LN) and doxorubicin (DOX) against osteosarcoma (OS) cells was analysed. ET and ET-LN decreased the growth of OS cells in vitro in a time and dose-dependent manner. Interestingly, the uptake of ET and ET-LN was lower when OS cells were pre-treated with DOX. In vivo investigations revealed that ET and ET-LN slowed down the primary tumour growth in two OS models. However, the combination of both drugs showed no additional antitumour effect. Importantly, ET-LN successfully prevented the metastatic spread of OS cells from the primary tumour to the lungs. On the whole, the ET-LN is a promising candidate for OS chemotherapy.

[1]  C. Nunes,et al.  Daunorubicin and doxorubicin molecular interplay with 2D membrane models. , 2017, Colloids and surfaces. B, Biointerfaces.

[2]  M. Heymann,et al.  The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. , 2017, Cellular immunology.

[3]  A. Patiño-García,et al.  Doxorubicin and edelfosine lipid nanoparticles are effective acting synergistically against drug-resistant osteosarcoma cancer cells. , 2017, Cancer letters.

[4]  M. Heymann,et al.  Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis , 2016, International journal of molecular sciences.

[5]  David M. Shaw,et al.  Defining Nano, Nanotechnology and Nanomedicine: Why Should It Matter? , 2016, Sci. Eng. Ethics.

[6]  M. Heymann,et al.  Drugs in early clinical development for the treatment of osteosarcoma , 2016, Expert opinion on investigational drugs.

[7]  M. Heymann,et al.  The Challenges of Detecting Circulating Tumor Cells in Sarcoma , 2016, Front. Oncol..

[8]  D. Heymann,et al.  Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation. , 2016, Clinical chemistry.

[9]  A. Patiño-García,et al.  Lipid nanoparticles enhance the efficacy of chemotherapy in primary and metastatic human osteosarcoma cells , 2015 .

[10]  A. Patiño-García,et al.  Antitumoral-Lipid-Based Nanoparticles: a Platform for Future Application in Osteosarcoma therapy. , 2015, Current pharmaceutical design.

[11]  Z. Qian,et al.  Development of individualized anti-metastasis strategies by engineering nanomedicines. , 2015, Chemical Society reviews.

[12]  Tamer Refaat,et al.  Cancer active targeting by nanoparticles: a comprehensive review of literature , 2015, Journal of Cancer Research and Clinical Oncology.

[13]  M. Blanco-Prieto,et al.  Lipid nanoparticles protect from edelfosine toxicity in vivo. , 2014, International journal of pharmaceutics.

[14]  E. Kleinerman,et al.  Aerosol interleukin‐2 induces natural killer cell proliferation in the lung and combination therapy improves the survival of mice with osteosarcoma lung metastasis , 2014, Pediatric blood & cancer.

[15]  Kanghua Li,et al.  EMT transcription factors: implication in osteosarcoma , 2013, Medical Oncology.

[16]  Mark B. Jones,et al.  Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice , 2012, Breast Cancer Research and Treatment.

[17]  F. Mollinedo,et al.  Comparative study of A HPLC-MS assay versus an UHPLC-MS/MS for anti-tumoral alkyl lysophospholipid edelfosine determination in both biological samples and in lipid nanoparticulate systems. , 2009, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[18]  W. Blackwelder,et al.  Phase I/II and Phase II Studies of Targeted Gene Delivery In Vivo: Intravenous Rexin-G for Chemotherapy-resistant Sarcoma and Osteosarcoma , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  F. Mollinedo,et al.  Lipid nanoparticles for alkyl lysophospholipid edelfosine encapsulation: development and in vitro characterization. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[20]  H. Maeda,et al.  Exploiting the enhanced permeability and retention effect for tumor targeting. , 2006, Drug discovery today.

[21]  I. Holen,et al.  Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells , 2005, International journal of cancer.

[22]  P. Workman,et al.  Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids. , 1995, British Journal of Cancer.

[23]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[24]  T. Bumgarner Pediatric And Adolescent Osteosarcoma , 2016 .

[25]  P. Meyers,et al.  Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma. , 2014, Advances in experimental medicine and biology.

[26]  E. Kleinerman,et al.  Genetically modified T cells targeting interleukin-11 receptor α-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. , 2012, Cancer research.