Alveolar rhabdomyosarcoma (ARMS) are aggressive soft tissue tumors harboring specific fusion transcripts, notably PAX3-FOXO1 (P3F). Current therapy concepts result in unsatisfactory survival rates making the search for innovative approaches necessary: targeting PAX3-FOXO1 could be a promising strategy. In this study, we developed integrin receptor-targeted Lipid–Protamine-siRNA (LPR) nanoparticles using the RGD peptide and validated target specificity as well as their post-silencing effects. We demonstrate that RGD-LPRs are specific to ARMS in vitro and in vivo. Loaded with siRNA directed against the breakpoint of P3F, these particles efficiently down regulated the fusion transcript and inhibited cell proliferation, but did not induce substantial apoptosis. In a xenograft ARMS model, LPR nanoparticles targeting P3F showed statistically significant tumor growth delay as well as inhibition of tumor initiation when injected in parallel with the tumor cells. These findings suggest that RGD-LPR targeting P3F are promising to be highly effective in the setting of minimal residual disease for ARMS.

中文翻译：

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靶向PAX3-FOXO1的RGD脂质体-鱼精蛋白-siRNA（LPR）纳米颗粒用于肺泡横纹肌肉瘤治疗

肺泡横纹肌肉瘤（ARMS）是具有特定融合转录本的侵略性软组织肿瘤，尤其是PAX3-FOXO1（P3F）。当前的治疗方案导致存活率不令人满意，因此寻求创新方法成为必要：靶向PAX3-FOXO1可能是一种有前途的策略。在这项研究中，我们使用RGD肽开发了针对整合素受体的脂质-鱼精蛋白-siRNA（LPR）纳米颗粒，并验证了靶标特异性及其沉默后的作用。我们证明，RGD-LPRs在体外和体内对ARMS是特异性的。这些粒子装有针对P3F断裂点的siRNA，有效地下调了融合转录本并抑制了细胞增殖，但并未诱导实质性的细胞凋亡。在异种移植ARMS模型中，当与肿瘤细胞平行注射时，靶向P3F的LPR纳米颗粒显示出统计学上显着的肿瘤生长延迟以及对肿瘤起始的抑制。这些发现表明，针对P3F的RGD-LPR有望在设置ARMS的最小残留疾病方面非常有效。