Retinoblastoma (RB) makes up about 3% of all childhood malignancies. Chemotherapy is commonly applied for RB treatment, while the clinical effectiveness varies significantly due to the cancer therapeutic resistances. Hypoxic tumor microenvironment, a hallmark of all tumors, is strongly associated with malignant progress and therapeutic resistances. The hypoxia mainly promotes the angiogenesis by upregulating pro-angiogenetic pathways. In this work, polymeric micelles are used as the carrier to deliver celastrol and siRNA to RB cells for achieving synergistic anti-tumor and antiangiogenesis effects. The micelle vectors have shown effective cellular internalization and release of loaded-celastrol and HIF-1 siRNA. The co-delivery system specifically and synergistically inhibits the expression of HIF-1α and VEGF in RB cells, suppresses the HIF-1α /VEGF/VEGFR signaling pathway, and impedes the proliferation, migration, and invasion of vascular endothelial cells. The polymer micellar carrier that co-delivers HIF-1α siRNA and celastrol is used for antiangiogenic and antitumor therapy of RB. Altogether, the results show that our polymeric micelle delivery system can be used to overcome barriers of drug resistance induced by angiogenesis and develop new drug/siRNA combinatory therapies.

中文翻译：

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缺氧诱导因子-1αsiRNA和Celastrol共递送Nanomicelles对视网膜母细胞瘤的抗血管生成和抗肿瘤治疗。

视网膜母细胞瘤（RB）约占所有儿童恶性肿瘤的3％。化学疗法通常用于RB治疗，而临床效果由于癌症的治疗抗性而有很大差异。缺氧肿瘤微环境是所有肿瘤的标志，与恶性进展和治疗耐药性密切相关。缺氧主要通过上调促血管生成途径来促进血管生成。在这项工作中，高分子胶束被用作载体，将celastrol和siRNA传递至RB细胞，以实现协同的抗肿瘤和抗血管生成作用。胶束载体已显示有效的细胞内在化和负载的Celastrol和HIF-1 siRNA的释放。共递送系统特异性和协同抑制RB细胞中HIF-1α和VEGF的表达，抑制HIF-1α/ VEGF / VEGFR信号通路，并抑制血管内皮细胞的增殖，迁移和侵袭。共递送HIF-1αsiRNA和Celastrol的聚合物胶束载体可用于RB的抗血管生成和抗肿瘤治疗。总之，结果表明我们的聚合物胶束递送系统可用于克服由血管生成引起的耐药性障碍，并开发新的药物/ siRNA组合疗法。