SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles
SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles
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DOI：
10.1016/j.jconrel.2016.12.006
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发表时间：
2017-02-28
影响因子：
10.8
通讯作者：
Schuppan, Detlef
中科院分区：
文献类型：
--
作者：
Leber, Nadine;Kaps, Leonard;Schuppan, Detlef
阳离子纳米水凝胶颗粒已成为系统性siRNA递送的一种有吸引力的工具，但改善其体内耐受性是可取的，特别是为了防止组织和细胞积累的潜在长期副作用。在这里，我们设计了新型的酮交联阳离子纳米水凝胶颗粒，在体外和体内评估其减少组织积累和强大的siRNA递送。摘要合成了一种核部带有金属键的低聚胺交联剂，并将其应用于DMSO中自组装反应性酯嵌段共聚物的纳米水凝胶交联。所得到的酸敏感阳离子纳米颗粒在酸性环境中随着时间的推移自发分解，通过动态光散射进行了研究。荧光相关光谱显示与siRNA的有效络合以及其在内体ph下颗粒降解时的释放。这些特性导致与不可降解的精胺类似物相比，酸可降解阳离子纳米颗粒的体外基因敲除增强。在小鼠肝纤维化模型中，纤维化组织中载体和载荷积累的增强促进了序列特异性基因的敲除并阻止了纤维化的进展。对体内载体的长期监测显示，即使在多次给药后，对酸降解载体的清除也有所增强。因此，这些酸降解的阳离子纳米水凝胶颗粒可以被认为是有前途的siRNA载体，在体内用于治疗应用。(C) 2016 Elsevier B.V.版权所有
Cationic nanohydrogel particles have become an attractive tool for systemic siRNA delivery, but improvement of their in vivo tolerance is desirable, especially to prevent potential long term side effects by tissue and cellular accumulation. Here, we designed novel ketal cross-linked cationic nanohydrogel particles that were assessed for reduced tissue accumulation and robust siRNA delivery in vitro and in vivo. An oligo-amine cross-linker equipped with a ketal moiety in its core was synthesized and applied to nanohydrogel cross-linking of self-assembled reactive ester block copolymers in DMSO. The resulting acid-sensitive cationic nanoparticles spontaneously disassembled over time in acidic milieu, as investigated by dynamic light scattering. Fluorescent correlation spectroscopy showed effective complexation with siRNA as well as its release upon particle degradation at endosomal pH. These properties resulted in an enhanced in vitro gene knockdown for the acid-degradable cationic nanoparticles compared to their non-degradable spermine analogues. In a murine liver fibrosis model enhanced carrier and payload accumulation in the fibrotic tissue facilitated sequence-specific gene knockdown and prevented fibrosis progression. Long-term monitoring of the carrier in the body showed an enhanced clearance for the aciddegradable carrier, even after multiple dosing. Therefore, these acid-degradable cationic nanohydrogel particles can be considered as promising siRNA carriers for in vivo purposes towards therapeutic applications. (C) 2016 Elsevier B.V. All rights reserved.