Transferrin-Appended Nanocaplet for Transcellular siRNA Delivery into Deep Tissues
Transferrin-Appended Nanocaplet for Transcellular siRNA Delivery into Deep Tissues
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DOI：
10.1021/jacs.8b12501
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发表时间：
2019-02-20
影响因子：
15
通讯作者：
Aida, Takuzo
中科院分区：
文献类型：
--
作者：
Kohata, Ai;Hashim, P. K.;Aida, Takuzo
转铁蛋白(Tf)可引起转胞作用，这是一种连续的胞吞/胞吐作用。我们开发了一种添加了Tf的纳米集合体((NC)-N-Tf siRNA超集)，以实现siRNA进入深层组织和随后的RNA干扰(RNAi)。为了获得(Tf)NCDsiRNA，新设计了一种大分子单体((Az)Gu)，在主链、侧链和末端分别含有多个胍离子单元、叠氮(N-3)基团和三丁基(TRT)保护的硫醇基团。由于多价肠道磷酸盐桥相互作用，(Az)Gu可以沿其链与siRNA黏附。当12加入预先孵育的AzGu和siRNA混合物中时，(Az)Gu沿着siRNA链发生氧化聚合，得到C-siRNA超集，这是迄今报道的最小的含有反应性纳米胶束的siRNA。通过与肠道附着的生物黏附树突(Glue)和二苯甲酮衍生物(BP)的点击反应，该偶联物被转化为Glue/BPN siRNA超集。然后，通过肠道介导的黏附和与BP的光化学反应，将Tf共价固定在Clue/spNc D_siRNA上。在Tf诱导的跨细胞作用的帮助下，TfNCDsiRNA史无前例地深入到癌症球体--3D组织模型--的深度，达到近70个堵塞。
Transferrin (Tf) is known to induce transcytosis, which is a consecutive endocytosis/exocytosis event. We developed a Tf-appended nanocaplet ((NC)-N-Tf superset of siRNA) for the purpose of realizing siRNA delivery into deep tissues and RNA interference (RNAi) subsequently. For obtaining (Tf)NCDsiRNA, a macro monomer ((Az)Gu) bearing multiple guanidinium (Gut) ion units, azide (N-3) groups, and trityl (Trt)-protected thiol groups in the main chain, side chains, and termini, respectively, was newly designed. Because of a multivalent Gut phosphate salt-bridge interaction, (Az)Gu can adhere to siRNA along its strand. When 12 was added to a preincubated mixture of AzGu and siRNA, oxidative polymerization of (Az)Gu took place along the siRNA strand, affording C-AN superset of siRNA, the smallest siRNAcontaining reactive nanocaplet so far reported. This conjugate was converted into Glue/BPN superset of siRNA by the click reaction with a Gut-appended bioadhesive dendron (Glue) followed by a benzophenone derivative (BP). Then, Tf was covalently immobilized onto clue/spNc D_ siRNA by Gut-mediated adhesion followed by photochemical reaction with BP. With the help of Tf-induced transcytosis, TfNCDsiRNA permeated deeply into a cancer spheroid, a 3D tissue model, at a depth of up to nearly 70 jAm, unprecedentedly.