Odd-Even Effect of Repeating Aminoethylene Units in the Side Chain of N-Substituted Polyaspartamides on Gene Transfection Profiles

被引:178
作者
Uchida, Hirokuni [1 ]
Miyata, Kanjiro [3 ]
Oba, Makoto [4 ]
Ishii, Takehiko [1 ]
Suma, Tomoya [1 ]
Itaka, Keiji [3 ]
Nishiyama, Nobuhiro [3 ]
Kataoka, Kazunori [1 ,2 ,3 ]
机构
[1] Univ Tokyo, Dept Bioengn, Grad Sch Engn, Bunkyo Ku, Tokyo 1138656, Japan
[2] Univ Tokyo, Dept Mat Engn, Grad Sch Engn, Bunkyo Ku, Tokyo 1138656, Japan
[3] Univ Tokyo, Ctr Dis Biol & Integrat Med, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan
[4] Univ Tokyo, Dept Clin Vasc Regenerat, Grad Sch Med, Bunkyo Ku, Tokyo 1138655, Japan
基金
日本科学技术振兴机构; 日本学术振兴会;
关键词
IN-VIVO; LINEAR POLYETHYLENIMINE; POLYPLEX NANOMICELLES; DNA COMPLEXES; PLASMID DNA; DELIVERY; CELLS; CYTOTOXICITY; POLYMERS; DESIGN;
D O I
10.1021/ja204466y
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A series of the N-substituted polyaspartamides possessing repeating aminoethylene units in the side chain was prepared in this study to identify polyplexes with effective endosomal escape and low cytotoxicity. All cationic N-substituted polyaspartamides showed appreciably lower cytotoxicity than that of commercial transfection reagents. Interestingly, a distinctive odd even effect of the repeating aminoethylene units in the polymer side chain on the efficiencies of endosomal escape and transfection to several cell lines was observed. The polyplexes from the polymers with an even number of repeating aminoethylene units (PA-Es) achieved an order of magnitude higher transfection efficiency, without marked cytotoxicity, than those of the polymers with an odd number of repeating aminoethylene units (PA-Os). This odd even effect agreed well with the buffering capacity of these polymers as well as their capability to disrupt membrane integrity selectively at endosomal pH, leading to highly effective endosomal escape of the PA-E polyplexes. Furthermore, the formation of a polyvalent charged array with precise spacing between protonated amino groups in the polymer side chain was shown to be essential for effective disruption of the endosomal membrane, thus facilitating transport of the polyplex into the cytoplasm. These data provide useful knowledge for designing polycations to construct safe and efficient nonviral gene carriers.
引用
收藏
页码:15524 / 15532
页数:9
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