Background/Main objective: Neuroblastoma, a solid tumor of the childhood, is the cause of 15% of deaths by cancer in children under the age of 15. Survival of advanced stage neuroblastoma patients remains poor (around 30%), because these tumors rapidly develop resistance to conventional treatments. The poor penetration of chemotherapy agents to the target tumor cells is considered one of the main mechanisms of drug resistance in solid malignancies. Therefore, the main objective of this project is to design pharmacological treatments that circumvent some of the resistance mechanisms and penetrate more efficiently to the neuroblastoma tumor cells.
Methodology: We hypothesize that the penetration and activity of the genotoxic drug SN-38 in neuroblastoma tumor xenografts will be improved by its formulation as micelles and by the administration of concomitant nutlin and vandetanib (two new drugs with remarkable anti-neuroblastoma effect). To address this hypothesis, we will prepare SN-38 micelles by the self-assembly of amphiphilic polymers in water. To evaluate the penetration of SN-38 micelles to neuroblastoma xenografts, we will apply a microdialysis technique to sample the extracellular fluid of the tumors and we will analyze drug concentrations in the dialyzates. We will evaluate the effect of nutlin and vandetanib on the tumor penetration and activity of SN-38. Finally, we will test the efficacy of our treatments in a neuroblastoma tumor model and will correlate drug concentrations in plasma and tumor with the observed antineoplastic activity.
Expected results: We will identify more effective therapies than the currently available for the treatment of neuroblastoma. We expect that our research will be able to rapidly be translated to the clinic and help rationally design clinical trials for the multidrug resistant neuroblastoma.
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