Ewing's sarcoma (EwS) is the second most common bone cancer in children and adolescents. Current chemotherapy regimens are mainly ineffective in patients with relapsed disease and cause long-term effects in survivors. Therefore, we have developed a combinatorial therapy based on a novel drug candidate named ML111 that exhibits selective activity against EwS cells and synergizes with vincristine. To increase the aqueous solubility of hydrophobic ML111, polymeric nanoparticles (ML111-NP) were developed. In vitro data revealed that ML111-NP compromise viability of EwS cells without affecting non-malignant cells. Furthermore, ML111-NP exhibit strong synergistic effects in a combination with vincristine on EwS cells, while this drug pair exhibits antagonistic effects towards normal cells. Finally, animal studies validated that ML111-NP efficiently accumulate in orthotopic EwS xenografts after intravenous injection and provide superior therapeutic outcomes in a combination with vincristine without evident toxicity. These results support the potential of the ML111-based combinatorial therapy for EwS.

尤文氏肉瘤 (EwS) 是儿童和青少年中第二常见的骨癌。目前的化疗方案主要对疾病复发的患者无效，并对幸存者造成长期影响。因此，我们开发了一种基于名为 ML111 的新型候选药物的组合疗法，该候选药物对 EwS 细胞具有选择性活性，并与长春新碱具有协同作用。为了增加疏水性 ML111 的水溶性，开发了聚合物纳米颗粒 (ML111-NP)。体外数据显示，ML111-NP 会损害 EwS 细胞的活力，但不会影响非恶性细胞。此外，ML111-NP 与长春新碱组合对 EwS 细胞表现出强烈的协同作用，而该药物对对正常细胞表现出拮抗作用。最后，动物研究证实，静脉注射后，ML111-NP 可在原位 EwS 异种移植物中有效积累，并与长春新碱组合提供优异的治疗效果，且无明显毒性。这些结果支持基于 ML111 的 EwS 组合疗法的潜力。