Missing pieces in understanding the intracellular trafficking of polycation/DNA complexes.
Missing pieces in understanding the intracellular trafficking of polycation/DNA complexes.
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DOI：
10.1016/j.jconrel.2009.06.031
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发表时间：
2009-10-15
影响因子：
10.8
通讯作者：
Konieczny, Stephen F.
中科院分区：
文献类型：
--
作者：
Won, You-Yeon;Sharma, Rahul;Konieczny, Stephen F.
迄今为止，在全球范围内进行的 1,400 多项基因治疗临床试验中，约 70% 的试验都采用转基因病毒作为治疗性遗传物质的首选载体 [1]。虽然病毒有望实现高转移效率和对治疗基因的良好保护 [2]，但这种方法也存在引起不良（炎症或免疫）反应 [3, 4] 甚至癌症 [5] 的风险。非病毒系统，例如阳离子脂质和合成聚合物（特别是聚阳离子），作为更安全的替代品吸引了大量研究人员的兴趣[6]。特别是，聚阳离子已成为非病毒基因载体的流行成分，因为其化学和物理特性可以相对容易地针对特定应用进行改造。然而，基于聚阳离子的方法在临床应用中受到限制，很大程度上是由于合成聚合物在细胞和系统水平上的生物活性较差。一个主要问题是与体内遗传物质的靶细胞特异性递送相关的困难[6, 7]。然而，即使是在跨各种细胞内屏障运输治疗基因时实现足够效率的基本问题也仍然是开发基于聚阳离子的优质基因递送系统的主要挑战之一。在这方面，即使是最有效的聚阳离子基因载体（例如，线性聚乙烯亚胺或简称PEI）的效率也比其病毒对应物[9]低105倍[8]。自1987年首次展示聚阳离子药物基因转染以来[10]，许多聚阳离子材料（包括新的和现成的）已经被探索用于基因传递应用，其中研究最深入的例子是PEI聚阳离子（参考文献[11-16]中综述）。 PEI 受到极大关注的一个明显原因是这种聚阳离子可提供最高水平的体外基因转染。人们认为，PEI 所观察到的高基因转染效率归因于其独特的能力，可以同时克服 DNA 颗粒细胞内运输的几个关键障碍（例如，从核内体中逃逸 [17, 18]、保护 DNA 免受内切核酸酶降解 [19]、进入核 [17,19,20]、DNA 释放和转录 [20]）。然而，目前，PEI如何协调在宿主细胞中有效表达转基因所需的细胞内过程序列的确切机制，以及PEI负责每个事件的特定化学/分子属性，在很大程度上仍不清楚，使得难以进一步提高基于PEI的载体在递送过程的其他方面的性能。最近改进基于 PEI 的递送系统的一个例子是在 PEI 分子的主链结构中掺入细胞内可降解的二硫键 [21-24]，以减少聚阳离子固有的细胞（和全身）毒性 [25-27]。
In about 70% of over 1,400 gene therapy clinical trials that have been conducted to date worldwide, genetically-modified viruses have been the carrier of choice for delivery of therapeutic genetic material [1]. While the viruses promise both high efficiency of transfer and great protection of the therapeutic genes [2], this approach also carries a risk of causing adverse (inflammatory or immune) reactions [3, 4] or even cancer [5]. Non-viral systems, such as cationic lipids and synthetic polymers (in particular, polycations), have attracted the interest of a large number of researchers as safer alternatives [6]. In particular, polycations have become popular components of non-viral gene carriers because of the relative ease with which their chemical and physical properties can be engineered for specific applications. However, the polycation-based approach has been limited in its clinical application in large part due to the poor biological activities of synthetic polymers on both cellular and systemic levels. A major issue is the difficulty associated with target-cellspecific delivery of genetic materials in vivo [6, 7]. However, even the basic problem of achieving a sufficient efficiency in the transportation of therapeutic genes across various intracellular barriers also remains one of the leading challenges in the development of superior polycation-based gene delivery systems. In this regard, even the most effective polycation gene carrier (eg, linear polyethylenimine or PEI for short) remains 105 times less efficient [8] than its viral counterpart [9]. Since the first demonstration of polycationmedicated gene transfection in 1987 [10], many polycation materials (both new and off-theshelf) have been explored for gene delivery applications with the most intensively studied example being the PEI polycation (reviewed in Refs.[11–16]). An obvious reason for the great attention devoted to PEI is that this polycation affords the highest levels of in vitro gene transfection. It is believed that the high gene transfection efficiency observed with PEI is attributable to its unique ability to simultaneously overcome several key barriers to intracellular trafficking of the DNA particles (eg, escape from endosomes [17, 18], protection of DNA from degradation by endonulceases [19], nuclear entry [17, 19, 20], DNA release and transcription [20]). Currently, however, the exact mechanisms of how PEI orchestrates the sequence of the intracellular processes required for effective expression of the transgene in the host cell, and the particular chemical/molecular attributes of PEI responsible for each event, remain largely unexplained, making it difficult to further improve the performances of the PEI-based carriers in other aspects of the delivery process. One recent example to improve the PEI-based delivery system is the incorporation of intracellularly degradable disulfide bonds in the backbone structure of the PEI molecule [21–24] to reduce the inherent cellular (and systemic) toxicity of the polycation [25–27].
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