Preferential liver gene expression with polypropylenimine dendrimers
Preferential liver gene expression with polypropylenimine dendrimers
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DOI：
10.1016/j.jconrel.2004.08.024
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发表时间：
2005-01-03
影响因子：
10.8
通讯作者：
Uchegbu, IF
中科院分区：
文献类型：
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作者：
Schatzlein, AG;Zinselmeyer, BH;Uchegbu, IF
前情提要较低代（DAB 8-第2代和DAB 16-第3代）聚丙烯亚胺树枝状聚合物已被证明是有效的体外基因递送系统。在本工作中，我们试图：（a）测试载体强度、DNA静电相互作用对基因转移的影响;（B）研究这些低分子量（< 1687 Da）非两亲性平原和季铵基因载体的体内基因转移活性。为此，合成了DAB 4（第1代）、DAB 8、DAB 16和DAB 32（第4代）的甲基季铵衍生物，分别得到Q4、Q8、Q16和Q32。DAB 8的三甲基化被证明在改善DNA结合中是关键的，如来自溴化乙锭排除测定的数据和树枝状聚合物-DNA胶体稳定性数据所证明的。这种改进的胶体稳定性对载体耐受性产生了重大影响，因为Q8-DNA制剂在静脉注射时耐受性良好，而类似的DAB 8-DNA剂量通过相同途径具有致命毒性。三甲基化还使DAB 16-DNA和DAB 32-DNA树状聚合物复合物的体外细胞生物相容性提高了约4倍，但不是较低代DAB 4-DNA和DAB 8-DNA制剂的体外细胞生物相容性。静脉注射DAB 16-DNA和Q8-与对照聚合物-Exgen 500 [线性聚（乙烯亚胺）]获得的肺靶向基因表达相反，DNA制剂导致肝靶向基因表达，并假设肺回避假说。我们的结论是，聚丙烯亚胺树枝状聚合物是有前途的基因递送系统，可用于靶向肝脏，避免肺，并赋予胶体稳定性的基因递送制剂的分子修饰有深远的影响，其耐受性静脉给药。(c)2004 Elsevier B. V.保留所有权利。
Previously. the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (< 1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations.In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is Postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration. (c) 2004 Elsevier B.V. All rights reserved.