Lipid nanoparticles for paediatric osteosarcoma treatment

Osteosarcoma (OS) is the most common primary malignant bone tumour diagnosed in the paediatric population. It appears in the metaphysial area of long bones of the extremities, such as femur or tibia; however, at the time of diagnose 30% of patients present visible metastasis in the lungs and for the remaining, micro-metastases are assumed. For that reason, the treatment of choice for OS is based on the combination of systemic multi-agent chemotherapy together with the resection of the primary tumour. With this therapeutic approach, a five year-survival rate close to 70% is achieved for patients with localized tumour, nonetheless this rate drastically drops to 20% for patients with metastatic disease. Within that context, the present work aims to improve the therapeutic success of primary and metastatic OS by using drug delivery systems (particularly lipid nanoparticles, LN) to encapsulate conventional anti-osteosarcoma drugs, such as methotrexate and doxorubicin. Moreover, the anti-tumour potential of the alkyl-lysophospholipid edelfosine was also assessed. As described along the manuscript, methotrexate, doxorubicin and edelfosine were successfully loaded into LN. The loaded drugs were able to decrease the growth of patient-derived and ATCC®-commercial OS cells. Importantly, edelfosine internalization and efficacy was higher in metastatic than in primary-patient derived OS cells. Afterwards, and based on previous findings in the bibliography that reported a synergistic activity of edelfosine and doxorubicin against Ewing sarcoma cells, whether the combination of doxorubicin and edelfosine could be synergistic against OS cells was analyzed. Results showed a synergistic activity between the drugs. For that reason, in vivo studies of the single-agents and combined drugs in orthotopic OS tumour models were assessed. Edelfosine monotherapy, either free-administered or loaded into LN, was able to slow down the progression of the primary tumour. Most notably, only edelfosine loaded into LN avoided the metastatic spread of OS cells from the primary tumour to lungs. In conclusion, these LN appear to be promising systems for the future therapy of OS.