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Zinc(ii)-cyclen coordinative amphiphiles for enhanced gene delivery

机译：锌（II） - 环旋属协调两亲性，用于增强基因递送

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In this study, we developed coordinative amphiphiles for use as novel non-viral DNA vectors. As a modification of a conventional cationic lipid structure, we replaced the cationic head with a zinc( II )-1,4,7,10-tetraazacyclododecane (Zn-cyclen) complex as a phosphate-directing group, and used biocompatible skeletons (α-tocopherol or cholesterol) as hydrophobic tails. The structure-activity relationship (SAR) was systematically investigated to study the effect of Zn-coordination on the gene transfection between cyclen-based traditional head-tail lipids and Zn( II )-cyclen coordinative amphiphiles. The results reveal that both Zn-free lipids and Zn-containing amphiphiles could condense DNA into nano-sized particles with appropriate size and zeta-potentials. Agarose gel retardation assay and MTS-based cell viability assays demonstrated that the Zn( II )-cyclen complex exhibited slightly lower DNA binding ability and much lower cytotoxicity compared to liposome analogues, respectively. Most importantly, in vitro transfection studies showed that the coordination of zinc( II ) to cyclen may dramatically increase the transfection efficiency of the conventional cationic lipid, and α-tocopherol-containing coordinative amphiphile Zn-Cyc-Toc gives the best transfection efficiency, which was enhanced 24.4 times after coordination and was 6.1 times higher than commercial transfection reagent lipofectamine 2000. Mechanism studies confirmed that the DNA complex formed from Zn-Cyc-Toc might induce higher cellular uptake and better endosomal escape ability than the lipoplexes formed from Zn-free lipid Cyc-Toc . This study not only demonstrates that these coordinative amphiphiles might be promising non-viral gene vectors, but also presents a novel strategy to enhance the gene transfection efficiency and biocompatibility of cyclen-based cationic lipids.
机译：在这项研究中，我们开发了配合两用的双亲物，用作新型非病毒DNA载体。作为传统阳离子脂质结构的改性，我们用锌（II）-1,4,7,10-四氮谱十二烷（Zn-Cyclen）复合物作为磷酸盐引导基团的阳离子头，并使用生物相容性骨架（α -Tocopherol或胆固醇）作为疏水性尾巴。系统地研究了结构 - 活性关系（SAR）以研究Zn-协调对循环基传统头尾脂质和Zn（II） - 环丙烯协调两亲物之间基因转染的影响。结果表明，含有锌脂质和含Zn的两亲物可以用适当的尺寸和ζ电位凝集到纳米尺寸颗粒中的DNA。琼脂糖凝胶延迟测定和基于MTS的细胞活力测定证明，与脂质体类似物相比，Zn（II）-Cyclen复合物显着略低了DNA结合能力和更低的细胞毒性。最重要的是，体外转染研究表明，锌（II）至环旋转的协调可显着提高常规阳离子脂质的转染效率，含α-生育酚的协调两亲Zn-Cyc-TOC给出了最佳的转染效率协调后的24.4次增强，比商业转染试剂脂质截面2000高出6.1倍。机制研究证实，由Zn-Cyc-TOC形成的DNA复合物可能诱导比由Zn形成的脂质物诱导更高的细胞摄取和更好的内体逃逸能力。脂质cyc-toc。这项研究不仅证明这些协调两亲性可能是有前途的非病毒基因载体，而且提高了提高循环阳离子脂质的基因转染效率和生物相容性的新策略。

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