Nanoparticle delivery of pooled siRNA for effective treatment of non-small cell lung cancer.
Nanoparticle delivery of pooled siRNA for effective treatment of non-small cell lung cancer.
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DOI：
10.1021/mp300152v
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发表时间：
2012-08-06
影响因子：
4.9
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Yang Y;Hu Y;Wang Y;Li J;Liu F;Huang L
非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因。为了探索小干扰RNA （siRNA）治疗非小细胞肺癌的潜力，我们开发了以氨酰胺为靶点的LCP，将siRNA有效地递送到表达sigma受体的非小细胞肺癌细胞的细胞质中。在体外A549细胞中，靶向LCP的siRNA递送效率比非靶向LCP高9倍。为了同时靶向多种致癌机制，我们共同配制了三个靶向HDM2、c-myc和VEGF癌基因的siRNA序列，并在体外研究了它们对A549和H460细胞的杀伤效果。结果表明，靶向LCP共递送的siRNA可有效同时下调HDM2、c-myc和VEGF的表达，显著抑制肿瘤细胞生长。用靶向LCP配制的德州红标记siRNA静脉注射A549异种移植肿瘤小鼠后，siRNA成功递送至肿瘤细胞内并在肿瘤细胞内浓缩。反复静脉注射靶向LCP配制的混合siRNA小鼠，A549和H460肿瘤的体内非小细胞肺癌生长均明显受损（p < 0.01），表明治疗A549肿瘤的ED50为~0.2 mg/kg。抑制HDM2/c-myc/VEGF可抑制肿瘤增殖和血管生成，同时诱导肿瘤凋亡，从而增强抗肿瘤活性。我们的研究结果表明，靶向LCP是一种很有前途的载体，可以将汇集的siRNA传递到肿瘤中并实现多靶点阻断。这可能是人类非小细胞肺癌基因治疗的一种有效的治疗方式。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. To explore the potential of small interfering RNA (siRNA) therapy for NSCLC, we have developed anisamide-targeted LCP to efficiently deliver siRNA into the cytoplasm of sigma receptor-expressing NSCLC cells. Targeted LCP demonstrated a 9-fold higher siRNA delivery efficiency compared to non-targeted LCP in A549 cells in vitro. To simultaneously target multiple oncogenic mechanisms, we co-formulated three siRNA sequences targeting HDM2, c-myc and VEGF oncogenes, and investigated their efficacy of cell-killing in A549 and H460 cells in vitro. The results indicated that the pooled siRNA co-delivered by the targeted LCP could effectively and simultaneously knock down HDM2, c-myc and VEGF expressions and significantly inhibit tumor cell growth. After i.v. injection of mice bearing A549 xenografted tumor with Texas Red-labeled siRNA formulated in the targeted LCP, siRNA was successfully delivered to and concentrated in the tumor cells. Repeated intravenous injections of mice with pooled siRNA formulated in the targeted LCP significantly impaired NSCLC growth in vivo (p < 0.01) for both A549 and H460 tumors, demonstrating an ED50 for the treatment of ~0.2 mg/kg in A549 tumors. The enhanced anti-tumor activity is due to the fact that the silencing of HDM2/c-myc/VEGF could inhibit tumor proliferation and angiogenesis and also simultaneously induce tumor apoptosis. Our results demonstrate that the targeted LCP is a promising vector to deliver pooled siRNA into tumors and to achieve multiple target blocking. This is potentially a valid therapeutic modality in the gene therapy of human NSCLC.
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影响因子：
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作者：
Cheang, Tuck-yun;Wang, Sheng-ming;Xu, An-Wu
通讯作者：
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