Multifunctional triblock copolymers for intracellular messenger RNA delivery.
Multifunctional triblock copolymers for intracellular messenger RNA delivery.
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DOI：
10.1016/j.biomaterials.2012.06.020
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发表时间：
2012-10
期刊：
影响因子：
14
通讯作者：
Bryers, James D.
中科院分区：
文献类型：
--
作者：
Cheng, Connie;Convertine, Anthony J.;Stayton, Patrick S.;Bryers, James D.
信使RNA（mRNA）是一种有前途的替代质粒DNA（pDNA）的基因疫苗接种应用，但安全和有效的输送系统是罕见的。采用可逆加成-断裂链转移（RAFT）聚合法合成了一系列三嵌段共聚物，旨在增强mRNA的细胞内递送。这些材料由介导mRNA缩合的阳离子甲基丙烯酸二甲氨基乙酯（DMAEMA）片段、增强稳定性和生物相容性的亲水性聚（乙二醇）甲基醚甲基丙烯酸酯（PEGMA）片段以及旨在促进细胞溶质进入的甲基丙烯酸二乙氨基乙酯（DEAEMA）和甲基丙烯酸丁酯（BMA）的pH响应性内体溶解共聚物组成。系统地改变阻断顺序和PEGMA片段长度以研究不同聚合物结构对mRNA递送功效的影响。这些聚合物是单分散的，表现出pH依赖性溶血活性，并将mRNA浓缩成86-216 nm的颗粒。由在聚合物链中心具有PEGMA片段的聚合物形成的mRNA聚合复合物显示出对肝素置换的最大稳定性，并且与两种免疫细胞系RAW 264.7巨噬细胞（77%）和DC 2.4树突状细胞（50%）中的最高转染效率相关。转染的DC2.4细胞被证明能够随后激活抗原特异性T细胞，证明了这些多功能三嵌段共聚物用于基于mRNA的疫苗接种策略的潜力。
Messenger RNA (mRNA) is a promising alternative to plasmid DNA (pDNA) for gene vaccination applications, but safe and effective delivery systems are rare. Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to synthesize a series of triblock copolymers designed to enhance the intracellular delivery of mRNA. These materials are composed of a cationic dimethylaminoethyl methacrylate (DMAEMA) segment to mediate mRNA condensation, a hydrophilic poly(ethylene glycol) methyl ether methacrylate (PEGMA) segment to enhance stability and biocompatibility, and a pH-responsive endosomolytic copolymer of diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) designed to facilitate cytosolic entry. The blocking order and PEGMA segment length were systematically varied to investigate the effect of different polymer architectures on mRNA delivery efficacy. These polymers were monodisperse, exhibited pH-dependent hemolytic activity, and condensed mRNA into 86–216 nm particles. mRNA polyplexes formed from polymers with the PEGMA segment in the center of the polymer chain displayed the greatest stability to heparin displacement and were associated with the highest transfection efficiencies in two immune cell lines, RAW 264.7 macrophages (77%) and DC2.4 dendritic cells (50%). Transfected DC2.4 cells were shown to be capable of subsequently activating antigen-specific T cells, demonstrating the potential of these multifunctional triblock copolymers for mRNA-based vaccination strategies.
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影响因子：
10.8
作者：
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发表时间：
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期刊：
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影响因子：
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