Oligo(ethylene glycol)-modified β-cyclodextrin-based polyrotaxanes for simultaneously modulating solubility and cellular internalization efficiency
Oligo(ethylene glycol)-modified β-cyclodextrin-based polyrotaxanes for simultaneously modulating solubility and cellular internalization efficiency
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DOI：
10.1080/09205063.2017.1304173
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发表时间：
2017-01-01
影响因子：
3.6
通讯作者：
Yui, Nobuhiko
中科院分区：
文献类型：
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作者：
Tamura, Atsushi;Ohashi, Moe;Yui, Nobuhiko
我们开发了由β-环糊精（β-CD）、Pluronic作为轴聚合物和可酸裂解的N-三苯基甲基作为大终止分子组成的刺激不稳定的聚轮烷（PRX），并发现PRX是治疗尼曼-匹克C型疾病的有效药物，因为PRX可以通过细胞内释放螺纹β-CD来有效降低细胞内胆固醇。一般来说，PRX 需要用亲水性官能团进行化学修饰，因为 PRX 不溶于水介质。在此，将具有不同乙二醇重复单元（2或3）和OEG末端化学结构（羟基或甲氧基）的四个系列的低聚乙二醇（OEG）修饰到PRX中的螺纹β-CD上。研究了OEG的结构对OEG修饰的PRX的水溶性、毒性和细胞内化效率的影响，以优化OEG的化学结构。羟基封端的 OEG 修饰的 PRX 在水性介质中表现出优异的溶解度，并且无论乙二醇重复单元的数量如何，都没有毒性。就甲氧基封端的OEG修饰的PRX而言，当乙二醇重复单元的数量为3时，在水介质中观察到足够的溶解度和可忽略的毒性，而当乙二醇重复单元的数量为2时，观察到低溶解度和毒性。此外，甲氧基封端的OEG修饰的PRX在RAW264.7细胞中的细胞摄取水平高于羟基封端的OEG修饰的PRX。因此，OEG的化学结构强烈影响PRX的化学和生物学性质，并且具有3个乙二醇重复单元的甲氧基封端的OEG是PRX最优选的修饰，因为所得的PRX在水介质中充分溶解，无毒，并且具有高细胞内化效率。
We developed stimuli-labile polyrotaxanes (PRXs) composed of beta-cyclodextrin (beta-CD), Pluronic as an axle polymer, and acid-cleavable N- triphenylmethyl groups as bulky stopper molecules, and found that the PRXs are potent therapeutics for Niemann-Pick type C disease, because the PRX can effectively reduce intracellular cholesterol through the intracellular release of threaded beta-CDs. In general, the PRXs need to be chemically modified with hydrophilic functional groups because PRXs are not soluble in aqueous media. Herein, four series of oligo(ethylene glycol) s (OEGs) with different ethylene glycol repeating unit (2 or 3) and chemical structure of OEG terminal (hydroxy or methoxy) were modified onto the threaded beta-CDs in PRX. The effects of the structure of OEG on the aqueous solubility, toxicity, and cellular internalization efficiency of OEG-modified PRXs were investigated to optimize the chemical structure of OEG. The hydroxy-terminated OEG-modified PRXs showed excellent solubility in aqueous media and no toxicity, regardless of the number of ethylene glycol repeating units. In the case of the methoxy-terminated OEG-modified PRXs, sufficient solubility in aqueous media and negligible toxicity were observed when the number of ethylene glycol repeating units was 3, while low solubility and toxicity were observed when the ethylene glycol repeating unit was 2. Additionally, cellular uptake levels of methoxy-terminated OEG-modified PRXs in RAW264.7 cells were higher than those of hydroxy-terminated OEG-modified PRXs. Consequently, the chemical structure of the OEG strongly affects the chemical and biological properties of the PRXs, and that a methoxy-terminated OEG with 3 ethylene glycol repeating units is the most preferable modification of PRXs, since the resultant PRX is sufficiently soluble in aqueous media, non-toxic, and possesses high cellular internalization efficiency.