Toward Drug Release Using Polymer Mechanochemical Disulfide Scission,Journal of the American Chemical Society

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Toward Drug Release Using Polymer Mechanochemical Disulfide Scission
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-08-17 , DOI: 10.1021/jacs.0c07077
Zhiyuan Shi _{1,

2} , Jingnan Wu _{1,

2} , Qingchuan Song _{1,

2} , Robert Göstl ₁ , Andreas Herrmann _{1,

2,

3}

Affiliation

Traditional pharmacotherapy suffers from multiple drawbacks that hamper patient treatment, such as the buildup of antibiotic resistances or low drug selectivity and toxicity during systemic application. To overcome these challenges, drug activity can be controlled by employing delivery, targeting, or release solutions that mostly rely on the response to external physicochemical stimuli. Due to various technical limitations, mechanical force as a stimulus in the context of polymer mechanochemistry has so far not been used for this purpose, yet it has been proven to be a convenient and robust method to site-selectively rearrange or cleave bonds with submolecular precision in the realm of materials chemistry. Here, we present an unprecedented mechanochemically responsive system capable of successively releasing small furan-containing molecules, including the furylated fluorophore dansyl and the drugs furosemide as well as furylated doxorubicin, by ultrasound-induced selective scission of disulfide-centered polymers in solution. We show that mechanochemically generated thiol-terminated polymers undergo a Michael-type addition to Diels-Alder (DA) adducts of furylated drugs and acetylenedicarboxylate derivatives, initiating the downstream release of the small molecule drug by a retro DA reaction. We believe that this method can serve as a blueprint for the activation of many other small molecules.

中文翻译：

使用聚合物机械化学二硫化物断裂实现药物释放

传统药物疗法存在多种阻碍患者治疗的缺点，例如抗生素耐药性的积累或全身应用过程中药物选择性和毒性低。为了克服这些挑战，可以通过采用主要依赖于对外部物理化学刺激的反应的递送、靶向或释放解决方案来控制药物活性。由于各种技术限制，机械力作为聚合物机械化学背景下的刺激迄今为止尚未用于此目的，但它已被证明是一种方便且可靠的方法，可以以亚分子精度进行位点选择性重排或裂解键在材料化学领域。在这里，我们提出了一种前所未有的机械化学响应系统，能够连续释放含呋喃的小分子，通过超声诱导溶液中以二硫化物为中心的聚合物的选择性断裂，包括呋喃基荧光团丹磺酰和药物呋塞米以及呋喃基多柔比星。我们表明，机械化学生成的硫醇封端聚合物对呋喃基药物和乙炔二羧酸衍生物的狄尔斯-阿尔德 (DA) 加合物进行迈克尔型加成，通过逆向 DA 反应启动小分子药物的下游释放。我们相信这种方法可以作为激活许多其他小分子的蓝图。我们表明，机械化学生成的硫醇封端聚合物对呋喃基药物和乙炔二羧酸衍生物的狄尔斯-阿尔德 (DA) 加合物进行迈克尔型加成，通过逆向 DA 反应启动小分子药物的下游释放。我们相信这种方法可以作为激活许多其他小分子的蓝图。我们表明，机械化学生成的硫醇封端聚合物对呋喃基药物和乙炔二羧酸衍生物的狄尔斯-阿尔德 (DA) 加合物进行迈克尔型加成，通过逆向 DA 反应启动小分子药物的下游释放。我们相信这种方法可以作为激活许多其他小分子的蓝图。

更新日期：2020-08-17

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