Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes
Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes
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DOI：
10.1016/j.nano.2013.07.008
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发表时间：
2014-01-01
影响因子：
5.4
通讯作者：
Wagner, Ernst
中科院分区：
文献类型：
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作者：
Laechelt, Ulrich;Kos, Petra;Wagner, Ernst
“质子-海绵”转染剂的阳离子化性质在几个步骤中促进pDNA递送。质子化胺负责静电DNA结合和细胞摄取，缓冲胺介导复合物从酸化的胞内囊泡中逃逸。如用含有选择的寡聚乙氨基酸和组氨酸的寡聚（乙氨基）酰胺的序列定义的文库所证明的，总质子化能力以及内溶酶体范围内的阳离子化pH曲线对基因转移具有关键影响。具有偶数胺基团的结构单元（Gtt，Sph）表现出比奇数（Stp）类似物更高的总内溶酶体缓冲能力。在内溶酶体范围内，Gtt在pH 5左右具有最高缓冲能力，而Stp在pH 7左右具有最大缓冲能力。组氨酸增加了总的缓冲能力，导致更连续的阳离子化pH曲线，并大大提高了转基因表达在体外和体内。使用受体靶向和聚乙二醇屏蔽的聚合复合物，检测到更好的内体逃逸和>100倍的增强transfection.From the Clinical Editor：用于pDNA递送的质子海绵转染剂在本研究中表征，证明通过使用受体靶向和聚乙二醇屏蔽的聚合复合物，超过100倍的增强横断和更好的内体逃逸。(C)2014爱思唯尔公司All rights reserved.
The cationizable nature of 'proton-sponge' transfection agents facilitates pDNA delivery in several steps. Protonated amines account for electrostatic DNA binding and cellular uptake, buffering amines mediate polyplex escape from acidifying intracellular vesicles. As demonstrated with a sequence-defined library of oligo(ethanamino) amides containing selected oligoethanamino acids and histidines, the total protonation capacity as well as the cationization pH profile within the endolysosomal range have critical impact on gene transfer. Building blocks with even numbered amine groups (Gtt, Sph) exhibited higher total endolysosomal buffer capacity than odd number (Stp) analogs. Within the endolysosomal range, Gtt has the highest buffer capacity around pH 5, whereas Stp has its maximum around pH 7. Histidines increased the total buffer capacity, resulted in a more continuous cationization pH profile and greatly improved transgene expression in vitro and in vivo. Using receptor targeted and polyethylene glycol shielded polyplexes, better endosomal escape and >100-fold enhanced transfection was detected.From the Clinical Editor: Proton-sponge transfection agents for pDNA delivery are characterized in this study, demonstrating over 100-fold enhanced transection and better endosomal escape by using receptor targeted and polyethylene glycol shielded polyplexes. (C) 2014 Elsevier Inc. All rights reserved.