载锰单原子纳米酶和驱蛔素的壳聚糖水凝胶制备及其抗幽门螺杆菌活性  

Preparation and anti-Helicobacter pylori activity of Mn single-atom nanozyme and ascaridole co-loaded chitosan hydrogel

作　　者：张丁丁 郭荣[1] 赵松峰[1] 段飞[2] 丁波[3] 韩冰洁 荆自伟 ZHANG Dingding;GUO Rong;ZHAO Songfeng;DUAN Fei;DING Bo;HAN Bingjie;JING Ziwei(Department of Pharmacy,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Department of Gastroenterology,The First Affiliated Hospital of Henan University of Chinese Medicine,Zhengzhou 450099,China;Department of Pharmacy,The First Affiliated Hospital of Henan University of Chinese Medicine,Zhengzhou 450099,China;Translational Medicine Center,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]郑州大学第一附属医院药学部,河南郑州450052 [2]河南中医药大学第一附属医院消化科,河南郑州450099 [3]河南中医药大学第一附属医院药学部,河南郑州450099 [4]郑州大学第一附属医院转化医学中心,河南郑州450052

出　　处：《中草药》2024年第6期1925-1934,共10页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学基金资助项目(82003956);国家自然科学基金资助项目(22007085);河南省青年人才托举工程项目(2023HYTP032);河南省卫生健康委国家中医临床研究基地科研专项(2022JDZX092);河南省中医药科学研究专项课题(2023ZY2001)。

摘　　要：目的设计一类共载锰单原子纳米酶(manganese single-atom nanozyme,MnSAE)和驱蛔素(ascaridole,Asc)的壳聚糖靶向水凝胶,为幽门螺杆菌Helicobacter pylori的根除治疗提供一种新思路。方法首先以NH2-PEG-COOH为连接臂,将脲基(urea-)修饰到壳聚糖的C6-羟基上,制备壳聚糖靶向材料脲基PEG壳聚糖(Urea-PEG-Cs,UPCs),然后以中空的沸石咪唑酯骨架材料-8(zeolitic imidazolate frameworks-8,ZIF-8)为模板吸附锰离子(Mn2+),并通过高温热解法构建MnSAE,最后将MnSAE和土荆芥Chenopodium ambrosioides的药效成分驱蛔素加入到UPCs溶液中,构建共递送MnSAE和驱蛔素的壳聚糖靶向水凝胶(Asc/MnSAE@UPCs);利用核磁共振氢谱(1H-NMR)、傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FTIR)对UPCs结构进行鉴定,扫描电子显微镜和透射电子显微镜观察水凝胶的形态和元素分布。并对水凝胶的释药、溶胀率、黏附性、类酶催化活性和体外安全性进行评价;最后考察其体外抗幽门螺杆菌活性和胞内产生活性氧能力。结果1H-NMR、FTIR结果表明,脲基修饰到壳聚糖骨架上。Asc/MnSAE@UPCs水凝胶为片状多孔结构,具有良好的溶胀性、黏附强度和体外安全性;该水凝胶具有过氧化物酶和氧化物酶活性,能够产生羟基自由基和超氧阴离子,与驱蛔素联用发挥优异的抗幽门螺杆菌活性。结论Asc/MnSAE@UPCs水凝胶能够整合MnSAE和土荆芥的中药单体成分驱蛔素的优势,发挥优异的化学动力、化学治疗的协同靶向抗菌作用,具有重要的研究价值和临床意义。Objective A kind of targeted chitosan hydrogel co-loaded with manganese single-atom nanozyme(MnSAE)and ascaridole(Asc),has been designed to provide a new idea for the eradication of Helicobacter pylori.Methods Firstly,using NH2-PEG-COOH as link arm,the urea-group was modified on the C6 hydroxyl group of chitosan to prepare chitosan targeting materials Urea-PEG-Cs(UPCs).Then the hollow zeolitic imidazolate frameworks-8(ZIF-8)was used as template to adsorb manganese ions(Mn2+),and MnSAE was constructed by high temperature pyrolysis.Finally,the MnSAE and effective ingredients ascaridole of Chenopodium ambrosioides were added to the UPCs solutions to construct MnSAE and Asc co-loaded UPCs targeted hydrogels(Asc/MnSAE@UPCs).The structures of UPCs were identified by 1H-NMR and Fourier transform infrared spectroscopy(FTIR),and the morphology and elements distribution of hydrogel were observed by scanning electron microscopy and transmission electron microscopy.The drug release behaviors,swelling ratio,adhesion strengths,multienzyme-like catalytic activities,and in vitro biocompatibility of hydrogel were evaluated.Finally,the in vitro anti-H.pylori activity and the levels of intracellular reactive oxygen species were investigated.Results The results of 1H-NMR and FTIR showed that urea groups were modified onto chitosan skeleton.The prepared Asc/MnSAE@UPCs hydrogel had multilayer porous structure with good swelling ratio,adhesion strengths and in vitro biocompatibility.More importantly,the hydrogel had peroxidase and oxidase-like activities,which could produce hydroxyl radical and superoxide anion,and exhibit excellent anti-H.pylori activity when combined with ascaridole.Conclusion The Asc/MnSAE@UPCs hydrogel could integrate the advantages of MnSAE and the traditional Chinese medicine effective component ascaridole of Chenopodium ambrosioides to exhibit synergistic targeted anti-H.pylori effects by chemodynamic therapy/chemotherapy,which has important research value and clinical significance.

关 键 词：幽门螺杆菌 纳米酶 驱蛔素 壳聚糖 水凝胶 土荆芥 靶向 沸石咪唑酯骨架材料-8 过氧化物酶 

分 类 号：R283.6[医药卫生—中药学]