Glycosylated self-assembled nanocarriers for active drug targeting of pediatric patient-derived tumors

Pediatric sarcomas are a heterogeneous group of sugar-avid tumors that account for approximately 10% of childhood solid tumors. Among them, rhabdomyosarcoma is a childhood sarcoma of muscle cells in which overexpression of glucose transporters (GLUTs) has been reported. In addition, glucose uptake is promoted by oncogenic mutations in upstream receptor tyrosine kinases. We hypothesized that the active targeting of ‘molecularly-targeted’ tyrosine kinase inhibitors would enable a significant dose reduction to achieve a similar anti-cancer efficacy with respect to the oral administration. In this work, we report for the first time on a nano-drug delivery system based on glucosylated self-assembled polymeric nanocarriers to actively target the second-generation tyrosine kinase inhibitor dasatinib to glucose-avid pediatric sarcomas by the intravenous route [1]. After a confirming the overexpresssion of GLUT-1 in different pediatric sarcomas, we designed, synthesized and comprehensively characterized the physicochemical properties of a glucosylated polymeric amphiphile. Glucosylation substantially increased the physical stability and the encapsulation capacity of the nanomicelles with respect to the pristine counterpart. In addition, we showed a 9-fold decrease of the half-maximal inhibitory concentration of dasatinib in a rhabdomyosarcoma cell line, Rh30, in vitro. In immunodeficient mice bearing the glucose-avid Rh30 xenograft, we revealed that the glucosylated PMs increased the delivery of dasatinib in the tumor parenchyma with respect to off-target tissue and organs, where the exposure to the drug was minimized. Upon experimental confirmation that most patient-derived xenograft models of pediatric sarcomas overexpress the GLUT-1, we showed the selective accumulation of fluorescent glucosylated micelles in several tumors. In contrast, the reference dose administered by the oral route was not tumor-selective. Finally, the improved nanocarrier pharmacokinetics led to prolonged survival of mice bearing a clinically relevant PDX model of alveolar rhabdomyosarcoma from 19 days for the untreated controls to 27 days for the targeted therapy.

Acknowledgements. This work was funded by the European Union`s - Seventh Framework Programme under grant agreement #612765-MC-NANOTAR.

References

1. Bukchin A, Pascual-Pasto G, Cuadrado-Vilanova M, Castillo-Ecija H, Monterrubio C, Olaciregui NG, Ordeix L, Mora J, Carcaboso A, Sosnik A, Glucosylated nanomicelles target glucose-avid pediatric sarcomas, J Control Release, 276, 59-71 (2018).