Improvement of DNA Vector Delivery of DOTAP Lipoplexes by Short-Chain Aminolipids.
Improvement of DNA Vector Delivery of DOTAP Lipoplexes by Short-Chain Aminolipids.
复制标题
DOI：
10.1021/acsomega.0c03303
复制
发表时间：
2020-09-29
期刊：
影响因子：
4.1
通讯作者：
Witzigmann D
中科院分区：
文献类型：
--
作者：
Buck J;Mueller D;Mettal U;Ackermann M;Grisch-Chan HM;Thöny B;Zumbuehl A;Huwyler J;Witzigmann D
用于表达治疗性蛋白质的 DNA 载体的细胞递送是治疗单基因疾病或癌症的一种有前景的方法。在临床前和临床环境中已经做出了巨大的努力来开发基于由永久阳离子脂质组成的脂质复合物的有效非病毒基因递送系统。然而，此类系统的转染效率和耐受性在大多数情况下并不令人满意。在这里，我们提出了一种基于双还原胺化的一锅组合方法来合成短链氨基脂质。当与阳离子脂质 1,2-二油酰基-3-三甲基丙烷铵 (DOTAP) 结合时，这些脂质可用于最大化 DNA 载体递送。我们将各种氨基脂质掺入此类脂质复合物中以复合小环DNA，并在人肝源性细胞系（HuH7）中筛选这些系统的基因表达和细胞毒性。与天然 DOTAP：胆固醇脂质复合物相比，先导氨基脂质 AL-A12 显示出双倍增强的基因传递和降低的毒性。此外，含有 AL-A12 的脂质复合物能够增强斑马鱼胚胎模型中的体内转基因表达。
Cellular delivery of DNA vectors for the expression of therapeutic proteins is a promising approach to treat monogenic disorders or cancer. Significant efforts in a preclinical and clinical setting have been made to develop potent nonviral gene delivery systems based on lipoplexes composed of permanently cationic lipids. However, transfection efficiency and tolerability of such systems are in most cases not satisfactory. Here, we present a one-pot combinatorial method based on double-reductive amination for the synthesis of short-chain aminolipids. These lipids can be used to maximize the DNA vector delivery when combined with the cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). We incorporated various aminolipids into such lipoplexes to complex minicircle DNA and screened these systems in a human liver-derived cell line (HuH7) for gene expression and cytotoxicity. The lead aminolipid AL-A12 showed twofold enhanced gene delivery and reduced toxicity compared to the native DOTAP:cholesterol lipoplexes. Moreover, AL-A12-containing lipoplexes enabled enhanced transgene expression in vivo in the zebrafish embryo model.
登录
查看更多内容
影响因子：
3.6
作者：
Jansen, PLM
通讯作者：
Jansen, PLM
影响因子：
10.2
作者：
Durán MC;Willenbrock S;Barchanski A;Müller JM;Maiolini A;Soller JT;Barcikowski S;Nolte I;Feige K;Murua Escobar H
通讯作者：
Murua Escobar H
影响因子：
12.4
作者：
Chen, Zhi-Ying;Riu, Efren;Kay, Mark A.
通讯作者：
Kay, Mark A.
影响因子：
3.9
作者：
Ilies, MA;Johnson, BH;Balaban, AT
通讯作者：
Balaban, AT
DOI：
10.1053/siny.2001.0086
发表时间：
2002-02-01
期刊：
Seminars in neonatology : SN
影响因子：
--
作者：
Clayton, Peter T
通讯作者：
Clayton, Peter T