Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumour-associated macrophages and cancer cells.
Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumour-associated macrophages and cancer cells.
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DOI：
10.1002/adfm.201501283
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发表时间：
2015-07-15
影响因子：
19
通讯作者：
Tian F
中科院分区：
文献类型：
--
作者：
Conde J;Bao C;Tan Y;Cui D;Edelman ER;Azevedo HS;Byrne HJ;Artzi N;Tian F
肺癌与非常差的预后相关，并且被认为是全球死亡的主要原因之一。在这里，我们提出了高度有效和选择性的生物杂交RNAi肽纳米颗粒，可以通过肿瘤环境的免疫调节结合肿瘤抑制作用，在炎症性肿瘤相关巨噬细胞（TAM）中诱导特异性和持久的基因治疗。我们的数据证明，使用常规RNAi NP可以在癌细胞中实现被动基因沉默。当与免疫调节TAM细胞群的基于M2肽的靶向免疫疗法组合时，可以观察到协同效应和长寿命的肿瘤根除，同时沿着增加的小鼠存活。在多次和长期给药系统中用低剂量siRNA（ED 50 0.0025-0.01 mg/kg）治疗显著减少了肺肿瘤组织中炎性TAM的募集，减小了肿瘤大小（约95%）并增加了小鼠的动物存活率（约75%）。我们的研究结果表明，沉默肿瘤细胞及其在肿瘤微环境中的支持免疫细胞（如TAM）中的重要基因的组合可能会极大地改善癌症临床结果。
Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, we present highly potent and selective bio-hybrid RNAi-peptide nanoparticles that can induce specific and long-lasting gene therapy in inflammatory tumour associated macrophages (TAMs), via an immune modulation of the tumour milieu combined with tumour suppressor effects. Our data prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide-based targeted immunotherapy that immuno-modulates TAMs cell-population, a synergistic effect and long-lived tumour eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED50 0.0025-0.01 mg/kg) in a multi and long-term dosing system substantially reduced the recruitment of inflammatory TAMs in lung tumour tissue, reduced tumour size (∼95%) and increased animal survival (∼75%) in mice. Our results suggest that it is likely that the combination of silencing important genes in tumour cells and in their supporting immune cells in the tumour microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.