用于癌症治疗中有效基因沉默的双靶向树枝状聚合物介导的 siRNA 递送系统,Journal of the American Chemical Society

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用于癌症治疗中有效基因沉默的双靶向树枝状聚合物介导的 siRNA 递送系统
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-10-22 , DOI: 10.1021/jacs.8b10021
Yiwen Dong ₁ , Tianzhu Yu ₂ , Ling Ding ₂ , Erik Laurini ₃ , Yuanyu Huang _{4,

5} , Mengjie Zhang ₄ , Yuhua Weng ₄ , Shuting Lin ₁ , Peng Chen ₁ , Domenico Marson ₃ , Yifan Jiang ₂ , Suzanne Giorgio ₂ , Sabrina Pricl ₃ , Xiaoxuan Liu _{1,

2} , Palma Rocchi ₆ , Ling Peng ₂

Affiliation

小干扰 RNA (siRNA) 正在成为治疗各种疾病的新疗法，前提是可以提供安全有效的递送。特别是，特异性递送至靶细胞对于在降低毒性的同时实现高治疗效果至关重要。由于树枝状聚合物的多价协同性与脂质载体的自组装特性，两亲性树枝状聚合物正在成为 siRNA 递送的新型有希望的载体。在这里，我们报告了一种将 siRNA 靶向递送到癌细胞的弹道方法，该方法使用配备有带有 RGDK 弹头的双靶向肽的两亲树枝状聚合物。根据分子设计，两亲性树枝状聚合物有望有效传递siRNA，而靶向肽的目的是通过其弹头与癌细胞上的整合素和神经纤维蛋白-1受体的相互作用来定位肿瘤。通过静电相互作用将带正电荷的 siRNA/树枝状聚合物递送复合物与带负电荷的靶向肽段包被，形成小而稳定的纳米颗粒，能够保护 siRNA 免于降解，同时保持 RGDK 靶向癌细胞的可及性，并保持siRNA 从内体中逃逸。与非靶向或基于共价树枝状聚合物的系统相比，靶向系统具有增强的 siRNA 传递、更强的基因沉默和更有效的抗癌活性。此外，未观察到急性毒性和诱发炎症。最后，该递送系统构成了用于靶向递送的有前途的非病毒载体，并且可以进一步开发以提供基于RNAi的针对癌症的个性化药物。我们的研究还为在各种生物医学应用中使用基于自组装树枝状大分子的纳米技术提供了新的视角。

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A dual targeting dendrimer-mediated siRNA delivery system for effective gene silencing in cancer therapy

Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.

更新日期：2018-10-22

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