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.

我们首次报告了基于糖基化聚合物纳米胶束的纳米药物递送系统，以通过静脉内途径积极靶向第二代酪氨酸激酶抑制剂达沙替尼至葡萄糖-avid小儿肉瘤。经过全面的物理化学鉴定，证实相对于原始的对应物而言，胶束化的两亲性纳米载体的临界胶束浓度显着降低，并且包封能力更高，在横纹肌肉瘤细胞系中，达沙替尼的半数最大抑制浓度降低了9倍，Rh30，体外。在携带葡萄糖抗体的Rh30异种移植物的免疫缺陷小鼠中，我们发现糖基化的聚合物纳米胶束增加了dasatinib在肿瘤实质中的递送。相反，脱靶组织和器官暴露于药物的机会大大减少。经实验证实，大多数小儿肉瘤患者来源的异种移植（PDX）模型过表达葡萄糖转运蛋白1（GLUT-1）后，我们证明了达沙替尼在患者来源的横纹肌肉瘤模型中的选择性积累。相反，通过口服途径给予的参考剂量不是肿瘤选择性的。最后，改良的纳米载体药代动力学可以使携带临床相关PDX牙槽性横纹肌肉瘤的小鼠的中位生存期从未治疗对照的19天延长到靶向治疗的27天。