PEGylated polyamidoamine dendrimers with bis-aryl hydrazone linkages for enhanced gene delivery.
PEGylated polyamidoamine dendrimers with bis-aryl hydrazone linkages for enhanced gene delivery.
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DOI：
10.1021/bm100589g
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发表时间：
2010-08-09
影响因子：
6.2
通讯作者：
Yang, Hu
中科院分区：
文献类型：
--
作者：
Yuan, Quan;Yeudall, W. Andrew;Yang, Hu
聚乙二醇化聚酰胺胺(PAMAM)树枝状大分子的表面修饰往往会导致其缓冲能力的降低，而缓冲能力是基因转移所必需的。在这项工作中，具有可质子化的吡啶和胺的双芳基腙键被探索为PAMAM树枝状大分子的聚乙二醇化反应的新键。聚乙二胺基聚酰胺(PAMAM)树状大分子G4.0与单官能团的甲氧基聚乙二醇胺(Mw=5000 Da)分别与丁二酰亚胺(SANH)和琥珀酰亚胺-4-甲酰基苯甲酸酯(SFB)反应，然后将SFB活化的聚乙二醇化聚乙二醇胺(G4.0-BAH-PEG)与SANH活化的G4.0偶联，合成了聚乙二胺基二芳肼(BAH)树枝状大分子G4.0。研究发现，即使在聚乙二醇化程度较高的情况下(每个树枝状大分子42个聚乙二醇链)，BAH键的引入也显著提高了载体的缓冲能力。G4.0-BAH-聚乙二醇偶联物能在较低的重量比下与DNA载体紧密结合，细胞相容性显著提高。在293T和HN12细胞中的基因转染研究表明，这种新的载体比亲本树枝状大分子能够转染更多的细胞并诱导更高的基因表达。这项工作表明，使用BAH键将聚乙二醇偶联到树枝状大分子上，有助于维持或增加功能化树枝状大分子的缓冲能力，并导致增强的转染率。
Surface modification of polyamidoamine (PAMAM) dendrimers with polyethylene glycol (PEG) often results in the decrease in their buffering capacity, which is essential for gene transfer. In this work, bis-aryl hydrazone bond, which possesses protonatable pyridine and amines, was explored as a new linkage for PEGylation of PAMAM dendrimers. PEGylated polyamidoamine (PAMAM) dendrimer G4.0 conjugates with bis-aryl hydrazone (BAH) linkages were synthesized following a two-step procedure: activation of PAMAM dendrimer G4.0 and monofunctional methoxypolyethylene glycol amine (MW=5000 Da) with succinimidyl 4-hydrazinonicotinate acetone hydrazone (SANH) and succinimidyl 4-formylbenzoate (SFB), respectively, and coupling of SFB-activated PEG to SANH-activated G4.0 to generate PEGylated G4.0 with bis-aryl hydrazone linkages (G4.0-BAH-PEG). It was found that the incorporation of BAH linkages into the vector significantly enhanced the buffering capacity of the vector even with a high degree of PEGylation (42 PEG chains per dendrimer). G4.0-BAH-PEG conjugates could complex with DNA plasmid tightly at low weight ratios and display dramatically improved cytocompatibility. According to gene transfection studies in 293T and HN12 cells, this new vector has been shown to be capable of both transfecting more cells and inducing higher gene expression than the parent dendrimer. This work demonstrates that the use of the BAH linkage in coupling of PEG to the dendrimer helps maintain or increase the buffering capacity of the functionalized dendrimer and results in enhanced transfection.
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