Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation
Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation
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DOI：
10.1006/mthe.2002.0568
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发表时间：
2002-04-01
影响因子：
12.4
通讯作者：
Seymour, LW
中科院分区：
文献类型：
--
作者：
Oupicky, D;Ogris, M;Seymour, LW
系统性疾病的基因治疗需要静脉给药，但现有的载体不适合全身递送，通常会从血液中迅速消除，将潜在的转染点限制在“第一次通过”的器官。为了开发长循环载体，我们比较了用单价聚乙二醇改性或多价N-(2-羟丙基)甲基丙烯酰胺共聚物修饰的含有脱氧核糖核酸的多聚L赖氨酸或聚乙烯亚胺的聚合物，以及它们的生物物理性质与静脉注射后的分布的关系。这两种涂层之间的一个关键区别是，除了这两种类型的聚合物提供的空间稳定性外，还引入了通过表面附着多价PHPMA来实现横向稳定。使用多价PHPMA涂层可以将聚阳离子/DNA多聚体的血流清除半衰期(在小鼠中通常为5分钟)延长至90分钟。我们发现，给药剂量以及涂层PHPMA的量和相对分子质量对循环性能有重要影响。多价PHPMA涂层首次允许使用复合系统显著延长循环时间--这是系统性基因传递的先决条件。
Gene therapy for systemic diseases requires intravenous administration, but existing vectors are not suitable for systemic delivery, often showing rapid elimination from the bloodstream that restricts potential transfection sites to "first-pass" organs. To develop long-circulating vectors, here we have compared polyplexes containing DNA and poly-L-lysine (PLL) or polyethylenimine (PEI), surface-modified with either monovalent polyethylene glycol (PEG) or multivalent copolymers of N-(2-hydroxypropyl)methacrylamide (PHPMA), correlating their biophysical properties with their distribution following intravenous injection. A key difference between the two types of coating is the introduction of lateral stabilization by surface attachment of multivalent PHPMA, in addition to the steric stabilization provided by both types of polymers. The a-half-life for bloodstream clearance of polycation/DNA polyplexes (typically < 5 minutes in mice) could be extended using multivalent PHPMA coating to > 90 minutes. We found that the dose administered, as well as the amount and molecular weight of the coating PHPMA, had important effects on circulation properties. Multivalent PHPMA coating allows, for the first time, considerably extended circulation time using polyplex systems-a prerequisite for systemic gene delivery.