Institute of Polymers Chemistry and Technology, CNR, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
J Biomed Mater Res A. 2010 Aug;94(2):619-30. doi: 10.1002/jbm.a.32752.
The major aim of nonviral delivery systems for gene therapy is to mediate high levels of gene expression with low toxicity. Nowadays, one of the most successful synthetic polycations used in gene delivery research is poly(ethylenimine) (PEI) in its high-molecular weight (HMW) branched form. However, PEI is not the ideal transfection agent in vivo because of its overwhelming cytotoxicity. To overcome its toxic effects with a minimal impact on transfection efficiency, PEI has been conjugated with several nonionic biocompatible polymers. Here, we describe the synthesis of nanosized particles consisting of HMW PEI (25 kDa) crosslinked with poly(epsilon-caprolactone) (PCL, 50-60 kDa), a biodegradable aliphatic polyester. PCL was modified by the insertion of glycidyl groups able to condense with the amines of PEI to chemically bind PEI onto PCL. The nanoparticles obtained have been characterized in relation to their physicochemical and biological properties, and the results are extremely promising in terms of low cell toxicity and high transfection efficiency. These biological effects might be related to the peculiar DNA binding to covalently connected polymeric nanoparticles, without the formation of entangled DNA/polymer-soluble aggregates.
基因治疗中非病毒传递系统的主要目的是实现高表达水平和低毒性。目前，在基因传递研究中使用的最成功的合成多阳离子之一是高分子量（HMW）支化形式的聚（亚乙基亚胺）（PEI）。然而，由于其强烈的细胞毒性，PEI 并不是体内理想的转染剂。为了克服其毒性作用，同时对转染效率的影响最小，PEI 已与几种非离子型生物相容性聚合物结合。在这里，我们描述了由 HMW PEI（25 kDa）与可生物降解的脂肪族聚酯聚己内酯（PCL，50-60 kDa）交联而成的纳米颗粒的合成。PCL 通过插入缩水甘油基进行修饰，能够与 PEI 的胺缩合，将 PEI 化学结合到 PCL 上。已经对获得的纳米颗粒进行了物理化学和生物学特性的表征，结果在低细胞毒性和高转染效率方面非常有前景。这些生物学效应可能与 DNA 与共价连接的聚合物纳米颗粒的特殊结合有关，而不会形成缠结的 DNA/聚合物可溶性聚集体。
