Development of novel synthetic gene delivery systems with an ability to fuse with cells

在这项研究中，我们试图开发新型的基因传递系统，通过与细胞融合来有效地转染细胞。我们先前发现琥珀酸化的缩水甘油在弱酸性条件下表现出融合活性。因此，为了提高其融合活性，引入了疏水基团。疏水性的引入并没有提高其融合活性，但琥珀酸基含量较高的聚合物表现出更强的促进膜融合的活性。制备了结构优化的琥珀酰聚缩水甘油修饰的脂质体。聚合物修饰的脂质体具有很强的融合能力。接下来，我们制备了融合脂质体与脂复合物(阳离子脂-DNA复合体)或多聚体(阳离子聚合物-DNA复合体)之间形成的复合体，作为具有融合活性的新型基因递送系统。我们发现，与传统的非病毒载体，如DC-CHOL相比，融合脂质体-脂质体复合体更有效地实现了对各种细胞的转染。此外，与传统载体相比，这些复合体对细胞的毒性较小。我们还开发了一种新的合成载体树枝状大分子脂类，它通过膜融合和质子海绵效应的协同作用展示了一种有效的转导。结论：膜融合是实现细胞高效转导的有效策略。

In this study, we attempted to develop novel gene delivery systems that transfect cells efficiently by fusing with cells. We have previously found that succinylated oly(glycidol) exhibits fusogenic activity under weakly acidic conditions. Thus, to improve its fusogenic activity, hydrophobic groups were introduced. While the introduction of hydrophobic did not enhance its fusogenic activity, the polymer with higher succinylated unit content showed stronger activity to promote membrane fusion. We prepared liposomes modified with the succinylated poly(glycidol) with the optimized structure. The polymer-modified liposomes exhibited strong fusion ability. We next prepared complexes formed between the fusogenic liposomes and lipoplexes (cationic lipid-DNA complexes) or polyplexes (cationic polymer-DNA complexes) as new types of gene delivery systems with fusogenic activity. We found that the fusogenic liposome-lipoplex complexes achieved more efficient transfection of various cells than conventional non-viral vectors, such as DC-chol. In addition, these complexes were less toxic to cells than these conventional vectors. We also developed a new synthetic vector, dendrimer lipids, which exhibited an efficient transfection through a synergy of membrane fusion and the proton sponge effect. It is concluded that membrane fusion is an efficient strategy to achieve an efficient transfection of cells.