Preparation of efficient gene vectors with multi functions

高效多功能基因载体的制备

• 批准号: 16300159
• 负责人: KONO Kenji
• 金额: $ 9.34万
• 依托单位: Osaka Prefecture University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300159/
• 关键词: gene therapy; non-viral vector; gene delivery; nano-bio; lipoplex; liposome; drug delivery system; nano-medicine; ナノ医薬; ドラッグデリバリーシステム; ベクタ

In this study, we attempted to develop highly efficient nonviral vectors with multi-functions according to two different approaches, namely liposome-based systems with fusogenic polymers and dendrimer-based systems. First, we prepared complexes of lipoplexes and liposomes modified with pH-sensitive fusogenic polymer, succinylated poly(glycidol) with transferrin, which is a cancer cell-specific ligand. We found that the complexation of the fusogenic polymer-modified liposomes enhanced ability of the lipoplexes as gene vectors. We also examined the influence of the complex size on its transfection activity and found that decrease in the size resulted in increase in transfection activity. The obtained complexes with small size exhibited high transfection activity in the presence of serum proteins, which often decreases transfection activity of gene vectors. We further attempted to improve transfection activity of the lipoplexes-fusogenic liposomes complexes by increasing fusogenic ability … More of the liposomes. For this purpose, we synthesized several fusogenic polymers with hydrophobic side groups. We found that fusogenic activity of the polymers increased with increasing hydrophobicity of the polymers. In addition, transfection activity of the complexes of the lipoplexes and polymer-modified liposomes exhibited extremely high transfection activity when the polymer with the highest fusogenic activity was used for the liposome modification. It was noteworthy that the obtained complexes achieved efficient transfection of DC 2.4, which is derived from dendritic cell. On the other hand, we also attempted to develop a new type of synthetic vector by using dendritic molecules, which achieve efficient transfection through so-called proton sponge effect. We prepared a new family of cationic lipids, which consist of a polyamidoamine dendron moiety and two long alkyl groups. These molecules formed complexes with DNA. The obtained complexes achieved efficient transfection of cells through a synergetic action of the proton sponge effect and membrane fusion. In addition, we attached polyethylene glycol chains to all chain ends of the dendron moiety. The obtained polyethylene glycol-modified dendron-bearing lipids were found to be useful for preparation of vectors with colloidal stability and high transfection activity. We believe that information obtained through this study will contribute for establishment of safe and efficient gene therapy. Less

在这项研究中，我们试图通过两种不同的方法来开发高效的多功能非病毒载体，即基于融合聚合物的脂质体系统和基于树枝状大分子的系统。首先，我们制备了pH敏感的融合聚合物修饰的脂合物和脂质体的络合物，琥珀酰化聚缩水甘油与转铁蛋白，这是一种癌细胞特异性配体。我们发现，融合聚合物修饰的脂质体的络合作用增强了脂合物作为基因载体的能力。我们还考察了复合体大小对其转染性的影响，发现尺寸的减小会导致转染性的增加。得到的小分子复合体在血清蛋白存在的情况下表现出较高的转染率，这往往会降低基因载体的转染率。我们进一步尝试通过增加融合能力…来提高脂合物-融合脂质体复合体的转染活性。更多的脂质体。为此，我们合成了几种带有疏水侧基的融合性聚合物。我们发现，聚合物的融合活性随着聚合物疏水性的增加而增加。此外，当融合活性最高的聚合物用于脂质体修饰时，脂合物与聚合物修饰脂质体的复合体具有极高的转染活性。值得注意的是，所获得的复合体能够有效地转染树突状细胞来源的DC 2.4。另一方面，我们还试图利用树枝状分子来开发一种新型的合成载体，通过所谓的质子海绵效应来实现高效的转染。我们制备了一个新的阳离子脂类家族，它由一个聚酰胺-胺树枝状部分和两个长的烷基组成。这些分子与DNA形成络合物。得到的复合体通过质子海绵效应和膜融合的协同作用实现了对细胞的高效转染。此外，我们还将聚乙二醇链连接到树枝状部分的所有链端。所得聚乙二醇化树枝状脂类可用于制备具有胶体稳定性和高转染率的载体。我们相信，通过这项研究获得的信息将有助于建立安全有效的基因治疗。较少

项目成果

Synthesis of biocompatible dendrimers with a peripheral network formed by linking of polymerizable groups

• DOI: 10.1016/j.polymer.2005.01.004
• 发表时间: 2005-02-24
• 期刊: POLYMER
• 影响因子: 4.6
• 作者: Haba, Y;Harada, A;Kono, K
• 通讯作者: Kono, K

Preparation of efficient gene carriers using a polyamidoamine dendron-bearing lipid: Improvement of serum resistance

• DOI: 10.1021/bc050012f
• 发表时间: 2005-09-01
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 作者: Takahashi, T;Harada, A;Kono, K
• 通讯作者: Kono, K

Temperature sensitization of liposomes by use of N-isopropylacrylamide copolymers with varying transition endotherms.

• DOI: 10.1021/bc034205j
• 发表时间: 2004-08
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Keisuke Yoshino;A. Kadowaki;T. Takagishi;K. Kono

薬物担体

药物载体

• 发表时间: 2006

Synthesis and characterization of head-tail head-tail type polycation block copolymer non-viral gene vector

头尾头尾型聚阳离子嵌段共聚物非病毒基因载体的合成及表征

• 发表时间: 2006
• 期刊: Bioconjugate Chemistry 17
• 作者: A.Harada;M.Kawamura;T.Matsuo;T.Takahashi;K.Kono
• 通讯作者: K.Kono