Abstract：
β-Cyclodextrins (β-CDs) and β-CD-containing polymers have attracted considerable attention as potential candidates for the treatment of cholesterol-related metabolic and intractable diseases. We have advocated the use of β-CD-threaded acid-degradable polyrotaxanes (PRXs) as intracellular delivery carriers for β-CDs. As unmodified PRXs are insoluble in aqueous solutions, chemical modification of PRXs is an essential process to improve their solubility and impart novel functionalities. In this study, we investigated the effect of the modification of zwitterionic sulfobetaines on PRXs due to their excellent solubility, biocompatibility, and bioinert properties. Sulfobetaine-modified PRXs were synthesized by converting the tertiary amino groups of precursor 2-(N,N-dimethylamino)ethyl carbamate-modified PRXs (DMAE-PRXs) using 1,3-propanesultone. The resulting sulfobetaine-modified PRXs showed high solubility in aqueous solutions and no cytotoxicity, while their intracellular uptake levels were low. To further improve this system, we designed PRXs cografted with zwitterionic sulfobetaine and cationic DMAE groups via partial betainization of the DMAE groups. Consequently, the interaction with proteins, intracellular uptake levels, and liver accumulation of partly betainized PRXs were found to be higher than those of completely betainized PRXs. Additionally, partly betainized PRXs showed no toxicity in vitro or in vivo despite the presence of residual cationic DMAE groups. Furthermore, partly betainized PRXs ameliorated the abnormal free cholesterol accumulation in Niemann-Pick type C disease patient-derived cells at lower concentrations than β-CD derivatives and previously designed PRXs. Overall, the cografting of sulfobetaines and amines on PRXs is a promising chemical modification for therapeutic applications due to the high cholesterol-reducing ability and biocompatibility of such modified PRXs. In addition, modification with both zwitterionic and cationic groups can be used for the design of various polymeric materials exhibiting both bioinert and bioactive characteristics.
摘要：
β-环糊精（β-CD）和含β-CD的聚合物作为治疗胆固醇相关的代谢和难治性疾病的潜在候选物引起了极大的关注。我们提倡使用β-CD-螺纹酸可降解聚轮烷（PRX）作为β-CD的细胞内递送载体。由于未修饰的PRX不溶于水溶液，PRX的化学修饰是提高其溶解度和赋予新功能的重要方法。在这项研究中,我们研究了两性离子磺基甜菜碱修饰对PRX的影响，因为它们具有优异的溶解性，生物相容性，和生物惰性特性。通过转化前体2-（N，使用1,3-丙磺酸内酯的N-二甲基氨基)乙基氨基甲酸酯改性的PRX(DMAE-PRX)。所得磺基甜菜碱修饰的PRX在水溶液中显示出高溶解度，无细胞毒性，而它们的细胞内摄取水平较低。为了进一步完善这一制度，我们通过DMAE基团的部分甜菜碱化设计了与两性离子磺基甜菜碱和阳离子DMAE基团共接枝的PRXs。因此,与蛋白质的相互作用，细胞内摄取水平，发现部分甜菜碱化PRX的肝脏积累高于完全甜菜碱化PRX的肝脏积累。此外,尽管存在残留的阳离子DMAE基团，但部分甜菜碱化的PRX在体外或体内均无毒性。此外，部分甜菜碱化的PRX在低于β-CD衍生物和先前设计的PRX的浓度下改善了Niemann-PickC型疾病患者来源的细胞中异常的游离胆固醇积累。总的来说,磺基甜菜碱和胺在PRX上的共接枝是用于治疗应用的有前途的化学修饰,这归因于此类修饰的PRX的高胆固醇降低能力和生物相容性。此外,具有两性离子和阳离子基团的改性可用于设计具有生物惰性和生物活性特性的各种聚合物材料。
