Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.
Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.
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DOI：
10.1038/nbt.3078
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发表时间：
2014-12
影响因子：
46.9
通讯作者：
Dowdy, Steven F.
中科院分区：
文献类型：
--
作者：
Meade, Bryan R.;Gogoi, Khirud;Hamil, Alexander S.;Palm-Apergi, Caroline;van den Berg, Arjen;Hagopian, Jonathan C.;Springer, Aaron D.;Eguchi, Akiko;Kacsinta, Apollo D.;Dowdy, Connor F.;Presente, Asaf;Loenn, Peter;Kaulich, Manuel;Yoshioka, Naohisa;Gros, Edwige;Cui, Xian-Shu;Dowdy, Steven F.
RNA干扰（RNAi）在治疗人类疾病方面具有巨大的潜力。然而，体内递送短干扰RNA（siRNA）（其是带负电荷的双链RNA大分子）仍然是一个主要障碍。目前的siRNA递送已经开始从大的脂质和合成纳米颗粒转移到更明确的分子缀合物。在这里，我们通过合成短干扰核糖核酸中性物（siRNN）来解决这个问题，其磷酸骨架含有中性磷酸三酯基团，允许递送到细胞中。一旦进入细胞内，siRNN被细胞质硫酯酶转化为天然的、带电荷的磷酸二酯骨架siRNA，其诱导稳健的RNAi反应。siRNN具有良好的药物样性质，包括高合成产率、血清稳定性和不存在先天免疫应答。与siRNA不同，siRNN强烈结合血清白蛋白以积极影响药代动力学特性。与肝细胞特异性靶向结构域缀合的siRNNs的全身递送在小鼠中诱导延长的剂量依赖性体内RNAi应答。我们相信siRNNs代表了一种技术，将为RNAi疗法的发展开辟新的途径。
RNA interference (RNAi) has great potential to treat human disease. However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle. Current siRNA delivery has begun to move away from large lipid and synthetic nanoparticles to more defined molecular conjugates. Here we address this issue by synthesis of short interfering ribonucleic neutrals (siRNNs) whose phosphate backbone contains neutral phosphotriester groups, allowing for delivery into cells. Once inside cells, siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses. siRNNs have favorable drug-like properties, including high synthetic yields, serum stability and absence of innate immune responses. Unlike siRNAs, siRNNs avidly bind serum albumin to positively influence pharmacokinetic properties. Systemic delivery of siRNNs conjugated to a hepatocyte-specific targeting domain induced extended dose-dependent in vivo RNAi responses in mice. We believe that siRNNs represent a technology that will open new avenues for development of RNAi therapeutics.
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DOI：
10.1038/mt.2011.263
发表时间：
2012-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.90.4.1201
发表时间：
1993-02-15
影响因子：
11.1
作者：
BRESLOW, R;XU, R
通讯作者：
XU, R
影响因子：
64.8
作者：
Castanotto, Daniela;Rossi, John J.
通讯作者：
Rossi, John J.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
7.2
作者：
Joshua-Tor, Leemor;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.