J Control Release. 2018 Feb 28. pii: S0168-3659(18)30111-1. [Epub ahead of print]276
59-71
Alexandra Bukchin,
Guillem Pascual-Pasto,
Maria Cuadrado-Vilanova,
Helena Castillo-Ecija,
Carles Monterrubio,
Nagore G Olaciregui,
Monica Vila-Ubach,
Laia Ordeix,
Jaume Mora,
Angel M Carcaboso,
Alejandro Sosnik.
We report for the first time on a nano-drug delivery system based on glucosylated polymeric nanomicelles to actively target the second-generation tyrosine kinase inhibitor dasatinib to glucose-avid pediatric sarcomas by the intravenous route. After a comprehensive physicochemical characterization that confirmed the substantially lower critical micellar concentration and the higher encapsulation capacity of the glucosylated amphiphilic nanocarrier with respect to the pristine counterpart, 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 polymeric nanomicelles increased the delivery of dasatinib in the tumor parenchyma. Conversely, the exposure of off-target tissues and organs to the drug was substantially reduced. Upon experimental confirmation that most patient-derived xenograft (PDX) models of pediatric sarcomas overexpress glucose transporter 1 (GLUT-1), we demonstrated the selective accumulation of dasatinib in a patient-derived rhabdomyosarcoma model in vivo. Conversely, the reference dose administered by the oral route was not tumor-selective. Finally, the improved nanocarrier pharmacokinetics led to prolonged median 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.
Keywords: Dasatinib; Glucose-avid pediatric sarcomas; Glucosylated polymeric nanomicelles; Patient-derived xenografts; Rhabdomyosarcoma; Tumor targeting