Delivery of Nucleic Acids through the Controlled Disassembly of Multifunctional Nanocomplexes
Delivery of Nucleic Acids through the Controlled Disassembly of Multifunctional Nanocomplexes
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DOI：
10.1002/adfm.200901139
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发表时间：
2009-12-23
影响因子：
19
通讯作者：
Leroux, Jean-Christophe
中科院分区：
文献类型：
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作者：
Elsabahy, Mahmoud;Wazen, Nada;Leroux, Jean-Christophe
本研究开发了一种新型的pH响应型聚离子复合物胶束（PICMs），用于核酸药物的高效递送，如反义寡核苷酸（AON）和短干扰RNA（siRNA）。PICMs由聚酰胺-胺（PAMAM）树状聚合物-核酸核和可分离的聚乙二醇-嵌段-聚（甲基丙烯酸丙酯-co-甲基丙烯酸）（PEG-b-P（PrMA-co-MAA））壳组成。胶束的平均流体动力学直径范围为50至70 nm，窄的尺寸分布，和近中性的表面电荷。它们可以在没有任何添加剂的情况下冻干并以干燥形式储存。在水中再分散后，没有观察到络合效率或胶体性质的变化。胶束进入癌细胞由位于PEG片段末端的单克隆抗体片段通过二硫键介导。在酸性内体环境中MAA单元的细胞摄取和质子化后，胶束失去了它们的冠，从而暴露了它们带正电荷的内体溶解PAMAM/核酸核心。当这些pH响应性靶向PICM负载有靶向癌蛋白1362的AON或siRNA时，它们表现出比非靶向PICM或商业PAMAM树枝状聚合物更大的转染活性。而且，它们的非特异性细胞毒性低于PAMAM。本文报道的pH响应性PICMs是一种很有前途的核酸传递载体。
In this study, novel pH-responsive polyion complex micelles (PICMs) were developed for the efficient delivery of nucleic acid drugs, such as antisense oligonucleotide (AON) and short interfering RNA (siRNA). The PICMs consisted of a poly(amidoamine) (PAMAM) dendrimer-nucleic acid core and a detachable poly(ethylene glycol)-block-poly(propyl methacrylate-co-methacrylic acid) (PEG-b-P(PrMA-co-MAA)) shell. The micelles displayed a mean hydrodynamic diameter ranging from 50 to 70 nm, a narrow size distribution, and a nearly neutral surface charge. They could be lyophilized without any additives and stored in dried form. Upon redispersion in water, no change in complexation efficiency or colloidal properties was observed. Entry of the micelles into cancers cells was mediated by a monoclonal antibody fragment positioned at the extremity of the PEG segment via a disulfide linkage. Upon cellular uptake and protonation of the MAA units in the acidic endosomal environment, the micelles lost their corona, thereby exposing their positively charged endosomolytic PAMAM/nucleic acid core. When these pH-responsive targeted PICMs were loaded with AON or siRNAs that targeted the oncoprotein 1362, they exhibited a greater transfection activity than nontargeted PICMs or commercial PAMAM dendrimers. Moreover, their nonspecific cytotoxicity was lower than that of PAMAM. The pH-responsive PICMs reported here appear as promising carriers for the delivery of nucleic acids.