Schellinger Joan G, Pahang Joshuel A, Shi Julie, Pun Suzie H
Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, 3720 15 Ave NE, Box 355061, Seattle, Washington 98195, United States.
ACS Macro Lett. 2013 Aug 20;2(8):725-730. doi: 10.1021/mz400331w.
Endosomal release peptides have been incorporated in synthetic gene delivery formulations to increase transfection efficiencies. In this work, cationic copolymers containing sHGP, a membrane-lytic peptide derived from HIV gp41, were synthesized and evaluated. Diblock, with sHGP displayed on one block, and statistical, with sHGP randomly displayed, copolymers were prepared via RAFT polymerization. While the statistical copolymer existed as unimers in solution, amphiphilic diblock copolymers self-assembled into cationic micelles in aqueous solution as evidenced by TEM and dynamic light scattering analyses. This self-assembly sequestered the lytic domain and significantly reduced the cytotoxicity of the materials. However, when complexed with plasmid DNA, both the diblock and statistical copolymers of sHGP showed higher gene delivery efficacy compared to the copolymers without the membrane lytic motif. The ability of amphiphilic, diblock copolymers containing endosomal release motifs to self-assemble and sequester lytic domains is a promising feature for the nucleic acid delivery.
内体释放肽已被纳入合成基因递送制剂中以提高转染效率。在这项工作中，合成并评估了含有sHGP（一种源自HIV gp41的膜裂解肽）的阳离子共聚物。通过可逆加成-断裂链转移（RAFT）聚合制备了一种嵌段共聚物（其中sHGP显示在一个嵌段上）和一种统计共聚物（其中sHGP随机显示）。透射电子显微镜（TEM）和动态光散射分析表明，统计共聚物在溶液中以单聚体形式存在，而两亲性嵌段共聚物在水溶液中自组装成阳离子胶束。这种自组装隔离了裂解结构域并显著降低了材料的细胞毒性。然而，当与质粒DNA复合时，与没有膜裂解基序的共聚物相比，sHGP的嵌段共聚物和统计共聚物均显示出更高的基因递送效率。含有内体释放基序的两亲性嵌段共聚物自组装和隔离裂解结构域的能力是核酸递送的一个有前景的特性。
