Synthesis of poly(β-amino ester)s optimized for highly effective gene delivery
Synthesis of poly(β-amino ester)s optimized for highly effective gene delivery
复制标题
DOI：
10.1021/bc034067y
复制
发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Langer, R
中科院分区：
文献类型：
--
作者：
Akinc, A;Anderson, DG;Langer, R
包括可降解的聚（β-氨基酯）在内的几种合成聚合物家族先前已被证明可有效地介导基因转移。然而，潜在的重要因素，如聚合物的分子量，聚合物链末端基团，和聚合物/DNA的比例对不同的基因转移性能的综合影响还有待系统地研究。这些关系的阐明可能有助于设计具有极大增强的转染特性的非病毒载体。为了检查这些因素，通过将1，4-丁二醇二丙烯酸酯和1，6-己二醇二丙烯酸酯分别加入到I-氨基丁醇中，产生两种不同的聚（β-氨基酯）结构，Poly-1和Poly-2。通过改变胺/二丙烯酸酯的化学计量比合成了每个结构的12个独特版本，从而产生具有胺或丙烯酸酯端基的聚合物，分子量范围为3350至18000。使用高通量方法，以10：lw/w至150：lw/w的九种不同的聚合物/DNA比率对所有聚合物进行四次重复测试。通过优化分子量、聚合物链末端基团和聚合物/DNA比率，这些聚合物在体外成功地以超过PEI和Lipofectamine 2000的水平介导基因转移。
Several families of synthetic polymers, including degradable poly(beta-amino ester)s, have been previously shown to effectively mediate gene transfer. However, the combined impact of potentially significant factors-such as polymer molecular weight, polymer chain end-group, and polymer/DNA ratio-on different gene transfer properties has yet to be systematically investigated. The elucidation of these relationships may aid in the design of nonviral vectors with greatly enhanced transfection properties. To examine these factors, two distinct poly(beta-amino ester) structures, Poly-1 and Poly-2, were generated by adding 1,4-butanediol diacrylate and 1,6-hexanediol diacrylate, respectively, to I-aminobutanol. Twelve unique versions of each structure were synthesized by varying amine/diacrylate stoichiometric ratios, resulting in polymers with either amine or acrylate end-groups and with molecular weights ranging from 3350 to 18 000. Using high throughput methods, all polymers were tested in quadruplicate at nine different polymer/DNA ratios ranging from 10:1 w/w to 150:1 w/w. Through the optimization of molecular weight, polymer chain end-group, and polymer/DNA ratio, these polymers successfully mediated gene transfer at levels that surpassed both PEI and Lipofectamine 2000 in vitro.