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Cyclodextrin polymer improves atherosclerosis therapy and reduces ototoxicity.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-13 , DOI: 10.1016/j.jconrel.2019.12.021
Heegon Kim 1 , Junhee Han 1 , Ji-Ho Park 1
Affiliation  

Recently, cyclodextrin (CD) has shown the potential for effective treatment of atherosclerotic plaques in mice by solubilizing plaque cholesterol. While promising as a new therapy for atherosclerosis, poor pharmacokinetics and ototoxicity of CD pose a therapeutic challenge. Thus far, however, there has been no attempts to overcome such limitations. Here, we showed that cyclodextrin polymer (CDP) with a diameter of ~ 10 nm exhibits outstanding pharmacokinetics and plaque targeting efficacy compared to a monomeric CD. Furthermore, we found out that CDP does not induce plasma membrane disruption as opposed to CD, which eliminated cytotoxicity and hemolytic activity of CD. In a mouse model of atherosclerosis, subcutaneous injections of beta-cyclodextrin polymer (βCDP) significantly inhibited plaque growth compared to monomeric hydroxypropyl-beta-cyclodextrin (HPβCD) at the same dose (1 g/kg). More importantly, βCDP did not induce significant ototoxicity at a high-dose (8 g/kg) where HPβCD reduced the outer hair cell content by 36%. These findings suggest that the polymerization of CD can overcome major limitations of CD therapy for treatment of atherosclerosis.

中文翻译:

环糊精聚合物可改善动脉粥样硬化治疗并降低耳毒性。

最近,环糊精(CD)已显示出通过溶解斑块胆固醇有效治疗小鼠动脉粥样硬化斑块的潜力。CD有望作为一种新的动脉粥样硬化疗法,但其不良的药代动力学和耳毒性提出了治疗挑战。然而,到目前为止,还没有尝试克服这些限制。在这里,我们表明,与单体CD相比,直径约10 nm的环糊精聚合物(CDP)表现出出色的药代动力学和噬菌斑靶向功效。此外,我们发现CDP与CD相比不会诱导质膜破坏,从而消除了CD的细胞毒性和溶血活性。在动脉粥样硬化的小鼠模型中,与相同剂量(1 g / kg)的单体羟丙基-β-环糊精(HPβCD)相比,皮下注射β-环糊精聚合物(βCDP)可显着抑制斑块的生长。更重要的是,在高剂量(8 g / kg)下,βCDP不会引起明显的耳毒性,其中HPβCD使外毛细胞含量减少了36%。这些发现表明,CD的聚合可以克服CD治疗动脉粥样硬化的主要限制。
更新日期:2019-12-17
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