Peptide-functionalized poly(ethylene glycol) star polymers: DNA delivery vehicles with multivalent molecular architecture
Peptide-functionalized poly(ethylene glycol) star polymers: DNA delivery vehicles with multivalent molecular architecture
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DOI：
10.1021/bc0701141
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Reineke, Theresa M.
中科院分区：
文献类型：
--
作者：
Fichter, Theresa M.;Zhang, Le;Reineke, Theresa M.
探索具有渐进的、特异性的和新颖的分子结构设计的非病毒核酸递送载体的发展是研究化学和物理结构方面如何影响转染过程的基本方法。在这项研究中，大分子组成的四臂星星聚（乙二醇）和末端修饰的五种不同的肝素结合肽的能力进行了研究，结合，紧凑。并在体外将DNA输送到哺乳动物细胞中。这些新的递送载体联合收割机将PEG衍生的稳定部分与肽结合，所述肽在允许阳离子肽的多价呈递的分子结构中表现出独特的细胞表面结合能力。研究了五种不同肝素结合亲和力的肽序列;发现每种肽序列都能充分结合肝素用于生物学应用。此外，大分子能够将DNA结合并压缩成适当大小的颗粒用于内吞作用。在生物学研究中，PEG-星形肽显示出依赖于肽身份的一系列毒性和转染效率。配备有最高肝素结合亲和力的肽的载体被发现紧密结合DNA，增加细胞内化的水平，并显示最有前途的转染质量。我们的研究结果表明，肝素结合肽与特定序列持有更多的潜力比非特异性阳离子聚合物，以优化转染效率，同时保持细胞活力。此外，这些大分子的内在多能性可以允许同时结合聚合复合物核心处的DNA和细胞表面上的硫酸乙酰肝素。该方案可以促进桥接转运机制，将DNA拴系到细胞表面并随后将治疗性核酸引入细胞中。因此，这种多价星星形状是一种有前途的结构特征，可以在未来的聚阳离子基因递送载体的设计中加以利用。
Exploring the development of nonviral nucleic acid delivery vectors with progressive, specific, and novel designs in molecular architecture is a fundamental way to investigate how aspects of chemical and physical structure impact the transfection process. In this study, macromolecules comprised of a four-arm star poly(ethylene glycol) and termini modified with one of five different heparin binding peptides have been investigated for their ability to bind, compact. and deliver DNA to mammalian cells in vitro. These new delivery vectors combine a PEG-derived stabilizing moiety with peptides that exhibit unique cell-surface binding ability in a molecular architecture that permits multivalent presentation of the cationic peptides. Five peptide sequences of varying heparin binding affinity were studied; each was found to sufficiently bind heparin for biological application. Additionally, the macromolecules were able to bind and compact DNA into particles of proper size for endocytosis. In biological studies, the PEG-star peptides displayed a range of toxicity and transfection efficiency dependent on the peptide identity. The vectors equipped with peptides of highest heparin binding affinity were found to bind DNA tightly, increase levels of cellular internalization, and display the most promising transfection qualities. Our results suggest heparin binding peptides with specific sequences hold more potential than nonspecific cationic polymers to optimize transfection efficiency while maintaining cell viability. Furthermore, the built-in multivatency of these macromolecules may allow simultaneous binding of both DNA at the core of the polyplex and heparan sulfate on the surface of the cell. This scheme may facilitate a bridging transport mechanism, tethering DNA to the surface of the cell and subsequently ushering therapeutic nucleic acids into the cell. This multivalent star shape is therefore a promising architectural feature that may be exploited in the design of future polycationic gene delivery vectors.