Short biodegradable polyamines for gene delivery and transfection of brain capillary endothelial cells.
Short biodegradable polyamines for gene delivery and transfection of brain capillary endothelial cells.
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DOI：
10.1016/j.jconrel.2010.01.020
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发表时间：
2010-05-10
影响因子：
10.8
通讯作者：
Vinogradov, Serguei V.
中科院分区：
文献类型：
--
作者：
Zhang, Hongwei;Vinogradov, Serguei V.
关键词：
为了合理设计系统基因传递系统和有效转染形成血脑屏障（BBB）的毛细血管内皮细胞，我们合成了几种具有可还原二硫骨架的短多胺，用于pDNA的包装、内化和随后从内体腔室释放。由短线性PEI (pLPEI)，三乙基四胺（pTETA）和精胺（pSPE）制备的合成阳离子聚合物具有非常低的毒性，良好的缩合能力和高水平的pDNA保护，可以产生小颗粒纳米配方。二硫化物主链的轻度还原允许pDNA从这些多聚体中完全释放。小鼠脑毛细血管内皮细胞的体外转染。在血清存在的情况下，与不可降解的LPEI 22kDa试剂（ExGen500）相比，具有pSPE、pTETA和pLPEI复合物的3细胞的有效性提高了2.3-4.9倍。细胞还原性谷胱甘肽（GSH）抑制后，转染能力明显下降。在细胞摄取可生物降解的复合物后，与ExGen500相比，转染细胞的细胞质中观察到标记的pDNA的分散分布。在这些多胺的基础上，通过nls肽和peg修饰的插层偶联物的共同应用，开发出了新的多功能多聚物，用于pDNA的高效核递送。观察到核积累显著增加，转染bEnd。与ExGen500相比，3个细胞的pLPEI、pTETA和pSPE水平分别提高了8.5倍、6.3倍和3.7倍，增加了近2倍。在脑特异性靶向之后，这些安全有效的复合物可能转化为系统性纳米载体，用于基因传递和血脑屏障的转染。
With the goal of rational design of systemic gene delivery system and efficient transfection of capillary endothelial cells forming the blood-brain barrier (BBB), we synthesized several short polyamines with reducible disulfide backbones for pDNA packaging, internalization and consequent release from endosomal compartments. The synthetic cationic polymers prepared from short linear PEI (pLPEI), triethylenetetramine (pTETA), and spermine (pSPE), demonstrated very low toxicity, good condensation capacity, and high levels of pDNA protection, producing small particulate nanoformulations. Mild reduction of the disulfide backbone allowed complete release of pDNA from these polyplexes. In vitro transfection of murine brain capillary endothelial bEnd.3 cells with pSPE, pTETA, and pLPEI polyplexes was 2.3–4.9 times more effective compared with the non-degradable LPEI 22kDa reagent (ExGen500) in the presence of serum. Their transfection ability was noticeably decreased following inhibition of the cellular reduced glutathione (GSH). After cellular uptake of biodegradable polyplexes, a disperse distribution of labeled pDNA in the cytoplasm of transfected cells was observed in contrast to ExGen500. Based on these polyamines, novel multifunctional polyplexes have been developed for efficient nuclear delivery of pDNA by co-application of NLS-peptide and PEG-modified intercalating conjugates. Significant increase of nuclear accumulation was observed, and the transfection of bEnd.3 cells was additionally enhanced nearly 2-fold, demonstrating 8.5-, 6.3- and 3.7-fold better levels for pLPEI, pTETA, and pSPE, respectively, compared to ExGen500. Following brain-specific targeting, these safe and effective polyplexes may be converted into systemic nanocarriers for gene delivery and transfection of the BBB.
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影响因子：
14.9
作者：
Read ML;Singh S;Ahmed Z;Stevenson M;Briggs SS;Oupicky D;Barrett LB;Spice R;Kendall M;Berry M;Preece JA;Logan A;Seymour LW
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