Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDVTM) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high; SH-SY-5Y, low] were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EGFREDVTM. In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox-treated animals compared to control, doxorubicin, or non-EGFR EDVTMDox. There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDVTMDox. Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther; 17(5); 1012–23. ©2018 AACR.

中文翻译：

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用于治疗神经母细胞瘤的靶向阿霉素的细菌衍生纳米细胞

晚期神经母细胞瘤是一种侵袭性疾病，对耐药肿瘤患者的治疗选择有限。小儿癌症的靶向化疗有望提高治疗效果并降低与全身化疗相关的毒性。EnGeneIC Dream Vector (EDVTM) 是一种纳米细胞，它可以通过将双特异性蛋白附着在纳米细胞表面来包装化疗药物和靶向肿瘤。成人难治性肿瘤的 I 期试验显示出可接受的安全性。在此，我们研究了靶向 EGFR 和负载阿霉素的 EDVTM (EGFREDVTMDox) 治疗神经母细胞瘤的活性。两种独立的神经母细胞瘤细胞系，EGFR 蛋白 [SK-N-BE(2)，高；使用 SH-SY-5Y，低]。与对照、多柔比星或非多柔比星加载的 EGFREDVTM 相比，EGFREDVTMDox 在这些细胞中诱导细胞凋亡。在三维肿瘤球体中，成像和荧光寿命显微镜显示，与单独使用多柔比星相比，EGFREDVTMDox 具有显着增强的多柔比星渗透，与非 EGFR 靶向 EDVTMDox 相比具有更好的渗透性，增强的球体渗透导致细胞凋亡增加。在两个独立的原位人类神经母细胞瘤异种移植模型中，与对照、多柔比星或非 EGFR EDVTMDox 相比，荷瘤小鼠的短期研究（28 天）导致 EGFREDVTMDox 治疗动物的肿瘤大小显着减小。与对照、多柔比星或非 EGFR EDVTMDox 相比，第 28 天肿瘤的 TUNEL 染色增加。而且，与对照相比，用 EGFREDVTMDox 治疗的神经母细胞瘤小鼠的总生存期增加（P < 0007）。载药双特异性抗体靶向 EDVsTM 为治疗侵袭性儿科恶性肿瘤（如神经母细胞瘤）提供了一种极具前景的方法。摩尔癌症治疗; 17(5); 1012-23。©2018 AACR。