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首页> 外文期刊>Acta biomaterialia >Characterization of a multifunctional PEG-based gene delivery system containing nuclear localization signals and endosomal escape peptides.
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Characterization of a multifunctional PEG-based gene delivery system containing nuclear localization signals and endosomal escape peptides.

机译：包含核定位信号和内体逃逸肽的多功能PEG基基因传递系统的表征。

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摘要

Endosomal escape and nuclear localization are two barriers to gene delivery that need to be addressed in the design of new nonviral gene delivery vehicles. We have previously synthesized low-toxicity polyethylene glycol (PEG)-based vehicles with endosomal escape functionalities, but it was determined that the transfection efficiency of PEG-based vehicles that escaped the endosome was still limited by poor nuclear localization. Two different nuclear localization signal (NLS) peptides, SV40 and TAT, were coupled to PEG-based vehicles with DNA-binding peptides (DBPs) to determine the effect of NLS peptides on the transfection efficiency of PEG-based gene delivery vehicles. Coupling one SV40 peptide, a classical NLS, or two TAT peptides, a nonclassical NLS, to PEG-DBP vehicles increased the transfection efficiency of PEG-DBP/DNA particles 15-fold and resulted in similar efficiency to that of a common cationic polymer vehicle, polyethylenimine (PEI). The transfection efficiency of both types of PEG-DBP-NLS particles was further increased 7-fold in the presence of chloroquine, suggesting that the transfection efficiency of PEG-DBP-NLS particles is limited by their ability to escape the endosome. To develop particles that could escape the endosome and target the nucleus, a mixture of PEG-DBP-NLS vehicles and PEG-based vehicles with DBPs and endosomal escape peptides were complexed with plasmid DNA to form multifunctional particles that had a transfection efficiency 2-3 times higher than that of PEI. Additionally, the PEG-based vehicles were less toxic and more resistant to nonspecific protein adsorption than PEI, making them an attractive alternative for nonviral gene delivery.
机译：内体逃逸和核定位是基因传递的两个障碍，在设计新的非病毒基因传递载体时需要解决这些障碍。我们以前已经合成了具有内体逃逸功能的基于低毒性聚乙二醇（PEG）的载体，但是已确定，逃离内体的PEG载体的转染效率仍然受到不良核定位的限制。将两种不同的核定位信号（NLS）肽SV40和TAT与带有DNA结合肽（DBP）的基于PEG的载体偶联，以确定NLS肽对基于PEG的基因传递载体的转染效率的影响。将一种SV40肽（一种经典的NLS或两种TAT肽，一种非经典的NLS）与PEG-DBP媒介物偶联，可使PEG-DBP / DNA颗粒的转染效率提高15倍，并产生与普通阳离子聚合物媒介物相似的效率，聚乙烯亚胺（PEI）。在存在氯喹的情况下，两种类型的PEG-DBP-NLS颗粒的转染效率进一步提高了7倍，这表明PEG-DBP-NLS颗粒的转染效率受到其逃脱内体的能力的限制。为了产生可以逃逸核内体并靶向核的颗粒，将带有DBP和内体逃逸肽的PEG-DBP-NLS载体和PEG基载体的混合物与质粒DNA结合形成具有转染效率的多功能颗粒2-3比PEI高出三倍此外，与PEI相比，基于PEG的媒介物毒性更小，对非特异性蛋白质吸附的抵抗力更强，这使其成为非病毒基因递送的有吸引力的选择。

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