Bioreducible Zinc(II)-Dipicolylamine Functionalized Hyaluronic Acid Mediates Safe siRNA Delivery and Effective Glioblastoma RNAi Therapy.
Bioreducible Zinc(II)-Dipicolylamine Functionalized Hyaluronic Acid Mediates Safe siRNA Delivery and Effective Glioblastoma RNAi Therapy.
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DOI：
10.1021/acsabm.8b00622
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发表时间：
2018-12
影响因子：
4.7
通讯作者：
Meng Zheng;Zhipeng Yang;Shizhu Chen;Haigang Wu;Yang Liu;Amanda L. Wright;Jeng-Wei Lu;Xue Xia;Albert Lee;Jinchao Zhang;Huijun Yin;Yingze Wang;W. Ruan;Xing-jie Liang
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文献类型：
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作者：
Meng Zheng;Zhipeng Yang;Shizhu Chen;Haigang Wu;Yang Liu;Amanda L. Wright;Jeng-Wei Lu;Xue Xia;Albert Lee;Jinchao Zhang;Huijun Yin;Yingze Wang;W. Ruan;Xing-jie Liang
RNA干扰（RNAi）是一种新兴的肿瘤治疗方法。然而，缺乏安全有效的小干扰RNA（siRNA）递送系统限制了其临床应用。在这里，我们报告了一种生物可还原的和少阳离子的siRNA递送载体，其通过将Zn（II）-吡啶二甲基胺络合物（Zn-DPA）经由氧化还原敏感的二硫化物（-SS-）接头缀合到透明质酸（HA）上。这样的聚合物缀合物可以通过DPA的锌离子和siRNA的阴离子磷酸盐之间的配位来配制稳定的siRNA纳米药物。在缀合物被细胞吸收后，细胞内还原刺激随后触发siRNA的释放并阐明所需的RNAi效应。我们的研究表明，配制的siRNA纳米药物可以有效地递送到肿瘤细胞/组织中，并且在体外和体内介导较小的细胞毒性。更重要的是，当应用于异种移植胶质母细胞瘤肿瘤模型时，与裸siRNA相比，这种siRNA纳米药物显示出显著增强的抗肿瘤能力。这项工作表明，这种不使用阳离子材料作为siRNA载体的生物可还原的Zn-DPA-官能化的HA缀合物代表了基于RNAi的癌症治疗的有希望的方向。
RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)-dipicolylamine complexes (Zn-DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn-DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.