Reductively responsive siRNA-conjugated hydrogel nanoparticles for gene silencing.
Reductively responsive siRNA-conjugated hydrogel nanoparticles for gene silencing.
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DOI：
10.1021/ja300174v
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发表时间：
2012-05-02
影响因子：
15
通讯作者：
DeSimone, Joseph M.
中科院分区：
文献类型：
--
作者：
Dunn, Stuart S.;Tian, Shaomin;Blake, Steven;Wang, Jin;Galloway, Ashley L.;Murphy, Andrew;Pohlhaus, Patrick D.;Rolland, Jason P.;Napier, Mary E.;DeSimone, Joseph M.
仍然迫切需要将RNA干扰（RNAi）治疗剂有效递送至靶组织和细胞。自组装的脂质和聚合物为基础的系统已被最广泛的探索与小干扰RNA（siRNA）在肝脏和癌症治疗的转染。必须确保输送系统中使用的材料的安全性和相容性，以最大限度地提高治疗指数。在这些研究中探索了通过颗粒成型工艺制备的具有限定尺寸和组成的水凝胶纳米颗粒作为递送载体，所述颗粒成型工艺是称为PRINT（非润湿模板中的颗粒复制）的软光刻的独特分支。最初，siRNA通过静电缔合和物理截留被封装在颗粒中。聚乙二醇化水凝胶在低siRNA剂量下引起剂量依赖性基因沉默，而无细胞毒性。为了防止在全身施用后或在用于表面官能化的制造后处理期间货物从颗粒解离，制备具有可降解的二硫键的可聚合siRNA前药缀合物。在还原环境下观察到siRNA从前药水凝胶的触发释放，同时在生理条件下保持货物保留和完整性。通过筛选颗粒的胺含量来优化基因沉默效率和细胞相容性。当将适当的对照siRNA货物加载到水凝胶中时，仅在含有可释放的靶特异性siRNA的水凝胶中遇到基因敲低，伴随着最小的细胞死亡。对siRNA缀合的水凝胶的形状、大小和表面装饰的进一步研究应该能够实现有效的靶向体内RNAi疗法。
A critical need still remains for effective delivery of RNA interference (RNAi) therapeutics to target tissues and cells. Self-assembled lipid- and polymer-based systems have been most extensively explored for transfection with small interfering RNA (siRNA) in liver and cancer therapies. Safety and compatibility of materials implemented in delivery systems must be ensured to maximize therapeutic indices. Hydrogel nanoparticles of defined dimensions and compositions, prepared via a particle molding process that is a unique off-shoot of soft lithography known as PRINT (Particle Replication in Non-wetting Templates), were explored in these studies as delivery vectors. Initially, siRNA was encapsulated in particles through electrostatic association and physical entrapment. Dose-dependent gene silencing was elicited by PEGylated hydrogels at low siRNA doses without cytotoxicity. To prevent disassociation of cargo from particles after systemic administration or during post-fabrication processing for surface functionalization, a polymerizable siRNA pro-drug conjugate with a degradable, disulfide linkage was prepared. Triggered release of siRNA from the prodrug hydrogels was observed under a reducing environment while cargo retention and integrity were maintained under physiological conditions. Gene silencing efficiency and cytocompatibility were optimized by screening the amine content of the particles. When appropriate control siRNA cargos were loaded into hydrogels, gene knockdown was only encountered for hydrogels containing releasable, target-specific siRNAs, accompanied by minimal cell death. Further investigation into shape, size, and surface decoration of siRNA-conjugated hydrogels should enable efficacious targeted in vivo RNAi therapies.
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由于异常高的化学治疗载荷，有效的工程PLGA纳米颗粒。
影响因子：
10.8
作者：
Enlow EM;Luft JC;Napier ME;DeSimone JM
通讯作者：
DeSimone JM
DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
DOI：
10.1002/wnan.40
发表时间：
2009-07
影响因子：
8.6
作者：
Canelas, Dorian A.;Herlihy, Kevin P.;DeSimone, Joseph M.
通讯作者：
DeSimone, Joseph M.
影响因子：
4.9
作者：
Beaudette TT;Bachelder EM;Cohen JA;Obermeyer AC;Broaders KE;Fréchet JM;Kang ES;Mende I;Tseng WW;Davidson MG;Engleman EG
通讯作者：
Engleman EG
影响因子：
41.2
作者：
通讯作者：
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