Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA.
Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA.
复制标题
肽和胺修饰的葡萄糖颗粒用于递送治疗性siRNA。
DOI：
10.1021/acs.molpharmaceut.5b00831
复制
发表时间：
2016-03-07
影响因子：
4.9
通讯作者：
Czech, Michael P.
中科院分区：
文献类型：
--
作者：
Cohen, Jessica L.;Shen, Yuefei;Aouadi, Myriam;Vangala, Pranitha;Tencerova, Michaela;Amano, Shinya U.;Nicoloro, Sarah M.;Yawe, Joseph C.;Czech, Michael P.
关键词：
由于需要针对特定细胞类型的改进的递送系统，siRNA技术在临床上的应用受到限制。巨噬细胞是RNAi治疗的特别有吸引力的靶点，因为它们在许多重要的人类疾病中促进致病性炎症反应。我们以前证明了β-1，3-D-葡聚糖包裹的小干扰RNA颗粒(GeRPs)的多组分配方可以特异性地和有效地沉默小鼠巨噬细胞中的基因。一项重大进步将是通过减少交付部件的数量来简化全球资源规划系统，从而使制造和未来的商业化变得更加便利。在这里，我们报道了一种简化的基于葡聚糖的颗粒(GP)的合成和评价，该颗粒能够在体内传递siRNA来选择性地沉默巨噬细胞的基因。小分子胺和含有弱碱基的短肽与GPs的共价结合促进了颗粒与siRNA的静电相互作用，并通过质子-海绵效应促进了siRNA的内体释放。修饰后的GPs无毒，体外能被巨噬细胞有效内化。当注射(Ip)时，几种新的多肽修饰的GP被发现能有效地将siRNA运送到瘦而健康的小鼠的腹膜巨噬细胞中。在肥胖引起炎症的动物模型中，ip。给予一种与siRNA结合的多肽修饰的GP(GP-Ep14)选择性地减少内脏脂肪组织巨噬细胞中靶向炎性细胞因子的表达。减少脂肪组织炎症导致这些代谢障碍动物的葡萄糖代谢得到改善。因此，修饰的GPs代表了一种有前景的新的简化系统，可以有效地将治疗性siRNAs特异性地输送到体内的吞噬细胞中，以调节炎症反应。
Translation of siRNA technology into the clinic is limited by the need for improved delivery systems that target specific cell types. Macrophages are particularly attractive targets for RNAi therapy because they promote pathogenic inflammatory responses in a number of important human diseases. We previously demonstrated that a multi-component formulation of β-1,3-D-glucan-encapsulated siRNA particles (GeRPs) can specifically and potently silence genes in mouse macrophages. A major advance would be to simplify the GeRP system by reducing the number of delivery components, thus enabling more facile manufacturing and future commercialization. Here we report the synthesis and evaluation of a simplified glucan-based particle (GP) capable of delivering siRNA in vivo to selectively silence macrophage genes. Covalent attachment of small-molecule amines and short peptides containing weak bases to GPs facilitated electrostatic interaction of the particles with siRNA and aided in the endosomal release of siRNA by the proton-sponge effect. Modified GPs were non-toxic and were efficiently internalized by macrophages in vitro. When injected intraperitoneally (i.p.), several of the new peptide-modified GPs were found to efficiently deliver siRNA to peritoneal macrophages in lean, healthy mice. In an animal model of obesity-induced inflammation, i.p. administration of one of the peptide-modified GPs (GP-EP14) bound to siRNA selectively reduced the expression of target inflammatory cytokines in the visceral adipose tissue macrophages. Decreasing adipose tissue inflammation resulted in an improvement of glucose metabolism in these metabolically challenged animals. Thus, modified GPs represent a promising new simplified system for the efficient delivery of therapeutic siRNAs specifically to phagocytic cells in vivo for modulation of inflammation responses.
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骨桥蛋白是高脂肪饮食诱导的小鼠胰岛素抵抗早期发生所必需的。
影响因子：
3.7
作者：
Chapman J;Miles PD;Ofrecio JM;Neels JG;Yu JG;Resnik JL;Wilkes J;Talukdar S;Thapar D;Johnson K;Sears DD
通讯作者：
Sears DD
影响因子：
4.1
作者：
Bartz, Rene;Fan, Haihong;Barnett, Stanley F.
通讯作者：
Barnett, Stanley F.
影响因子：
12.4
作者：
Abrams, Marc T.;Koser, Martin L.;Sepp-Lorenzino, Laura
通讯作者：
Sepp-Lorenzino, Laura
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1038/nri3071
发表时间：
2011-10-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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