Self-assembled supramolecular nano vesicles for safe and highly efficient gene delivery to solid tumors.
Self-assembled supramolecular nano vesicles for safe and highly efficient gene delivery to solid tumors.
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DOI：
10.2147/ijn.s34675
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发表时间：
2012
影响因子：
8
通讯作者：
Guo Y
中科院分区：
文献类型：
--
作者：
Li W;Li H;Li J;Wang H;Zhao H;Zhang L;Xia Y;Ye Z;Gao J;Dai J;Wang H;Guo Y
阳离子复合物在基因递送中的主要障碍是体内不稳定性和低的实体肿瘤积累。因此，具有高转染效率和体内肿瘤累积的安全载体是非常需要的。采用可逆加成断裂链转移（RAFT）自由基聚合法合成了两亲性嵌段共聚物聚甲基丙烯酸正丁酯-b-聚N-丙烯酰吗啉。通过调节共聚物的堆积参数（β）（1/2 < β < 1），可得到尺寸分布较窄的囊泡。与传统的“金标准”聚阳离子（聚乙烯亚胺，25 kDa）相比，超分子纳米囊泡提高了质粒DNA的凝聚效率、DNase I降解保护和细胞摄取。此外，在10%胎牛血清培养基中质粒DNA的转移效率是聚乙烯亚胺在肾小管上皮细胞和人肝癌细胞系中的5倍。这种改进的体外转染主要归因于密集堆积的双层。这种隐形复合物通过熵排斥显示出高的血清稳定性，这进一步保护了复合物在灭菌过程中不被破坏。如IVIS® Lumina II成像系统（Caliper Life Sciences，Hopkinton，MA）在静脉内施用后24小时所指示的，隐形复合物的肿瘤内积累被明显促进。这项研究成功地规避了传统的困境，有效的基因转染在一个高氮从聚乙烯亚胺磷酸从DNA的比例，是伴随着网站的细胞毒性和低稳定性。因此，这些简单定制的非细胞毒性纳米囊泡显示出在实际基因治疗中使用的显着潜力。
The main obstacles for cationic polyplexes in gene delivery are in vivo instability and low solid-tumor accumulation. Safe vectors with high transfection efficiency and in vivo tumor accumulation are therefore highly desirable. In this study, the amphiphilic block copolymer poly(n-butyl methacrylate)-b-poly(N-acryloylmorpholine) was synthesized by reversible addition–fragmentation chain-transfer (RAFT) radical polymerization. The corresponding well-defined vesicles with narrow size distribution were tailored by finely regulating the packing parameter (β) of copolymer (1/2 < β < 1). Compared with traditional “gold-standard” polycation (polyethylenimine, 25 kDa), plasmid DNA condensing efficiency, DNase I degradation protection, and cellular uptake were improved by the supramolecular nano vesicles. In addition, the plasmid DNA transferring efficiency in 10% fetal bovine serum medium was enlarged five times to that of polyethylenimine in renal tubular epithelial and human hepatocellular carcinoma cell lines. This improved in vitro transfection was mainly attributed to the densely packed bilayer. This stealth polyplex showed high serum stability via entropic repulsion, which further protected the polyplex from being destroyed during sterilization. As indicated by the IVIS® Lumina II Imaging System (Caliper Life Sciences, Hopkinton, MA) 24 hours post-intravenous administration, intra-tumor accumulation of the stealth polyplex was clearly promoted. This study successfully circumvented the traditional dilemma of efficient gene transfection at a high nitrogen-from-polyethylenimine to phosphate-from-DNA ratio that is accompanied with site cytotoxicity and low stability. As such, these simply tailored noncytotoxic nano vesicles show significant potential for use in practical gene therapy.