Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization.
Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization.
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DOI：
10.1021/acs.biomac.6b00900
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发表时间：
2016-10-10
影响因子：
6.2
通讯作者：
Tew, Gregory N.
中科院分区：
文献类型：
--
作者：
Caffrey, Leah M.;deRonde, Brittany M.;Minter, Lisa M.;Tew, Gregory N.
聚合物结构如何影响生物学相关货物（特别是siRNA）的内化和递送能力的基本理解对于成功设计改进的递送试剂至关重要。在本文中，我们报告了使用开环易位聚合（ROMP）方法来合成两个系列的富含胍的蛋白转导结构域模拟物（PTDM）：一个基于酰亚胺支架，每个重复单元包含一个胍部分，另一个基于二酯支架，每个重复单元包含两个胍部分。通过改变聚合度和实际上每个PTDM中阳离子电荷的相对数量，评估和比较两种ROMP主链用于siRNA内化的性能。将荧光标记的siRNA内化到Jurkat T细胞中证明FITC-siRNA内化具有电荷含量依赖性，其中含有约40至60个阳离子电荷的PTDM促进最多的内化。尽管存在这种电荷含量依赖性，但酰亚胺支架在Jurkat T细胞中产生的活力比具有类似阳离子电荷数的相应二酯PTDM低得多，表明二酯支架优选用于siRNA内化和递送应用。这些发展不仅提高了我们对最佳siRNA内化所需的结构因素的理解，而且还将指导未来开发用于siRNA内化和递送的优化PTDM。
A fundamental understanding of how polymer structure impacts internalization and delivery abilities of biologically relevant cargoes, particularly siRNA, is of critical importance to the successful design of improved delivery reagents. Herein we report the use of ring-opening metathesis polymerization (ROMP) methods to synthesize two series of guanidinium-rich protein transduction domain mimics (PTDMs): one based on an imide scaffold that contains one guanidinium moiety per repeat unit and another based on a diester scaffold that contains two guanidinium moieties per repeat unit. By varying both the degree of polymerization and, in effect, the relative number of cationic charges in each PTDM, the performances of the two ROMP backbones for siRNA internalization were evaluated and compared. Internalization of fluorescently labeled siRNA into Jurkat T cells demonstrated that FITC-siRNA internalization had a charge content dependence, with PTDMs containing approximately 40 to 60 cationic charges facilitating the most internalization. Despite this charge content dependence, the imide scaffold yielded much lower viabilities in Jurkat T cells than the corresponding diester PTDMs with similar numbers of cationic charges, suggesting that the diester scaffold is preferred for siRNA internalization and delivery applications. These developments not only improve our understanding of the structural factors necessary for optimal siRNA internalization, but will also guide the future development of optimized PTDMs for siRNA internalization and delivery.
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DOI：
10.1073/pnas.1211361109
发表时间：
2012-08-14
影响因子：
11.1
作者：
Geihe, Erika I.;Cooley, Christina B.;Wender, Paul A.
通讯作者：
Wender, Paul A.
影响因子：
6.2
作者：
Gabriel GJ;Madkour AE;Dabkowski JM;Nelson CF;Nüsslein K;Tew GN
通讯作者：
Tew GN
影响因子：
7.3
作者：
Heitz F;Morris MC;Divita G
通讯作者：
Divita G
影响因子：
2.9
作者：
deRonde BM;Tew GN
通讯作者：
Tew GN
影响因子：
15
作者：
Bang EK;Gasparini G;Molinard G;Roux A;Sakai N;Matile S
通讯作者：
Matile S