Zeng Zishan, Jiang Jingwen, Sun Yue, Li Wanzhen, Zheng Dong, Lin Huanxin, Zhao Chunshun
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
Biomaterials. 2025 Dec;323:123415. doi: 10.1016/j.biomaterials.2025.123415. Epub 2025 May 17.
Helicobacter pylori (H. pylori) is considered as the major pathogenic factor related to multiple digestive diseases. However, the efficacy of first-line treatment containing antibiotics gradually declined. It is urgent to develop treatment with antibiotic reduction/abandonment to combat H. pylori. Based on our previous discovery that Cu(DTC) exhibited stronger bactericidal effect than that of disulfiram or diethyldithiocarbamate (DTC), we constructed an antibiotic-free therapeutic strategy composed of DTC prodrug, Cu and shikonin (SK) to eliminate H. pylori. DTC was firstly modified with nitroaromatic moiety to acquire DTC prodrug (NTR-DTC), which was further encapsulated into Cu-SK@DOPA to construct nanoprodrug Cu-SK@NTR-DTC to achieve the triple masking of DTC, Cu and SK for the specificity therapeutics. Cu-SK@NTR-DTC could penetrate mucus layer and mainly detain in the bacteria infection area. In the presence of H. pylori, DTC was released from NTR-DTC to recover activity of copper chelation, and competitively bound Cu from Cu-SK to form Cu(DTC). The released SK possessed the bactericidal sensitization effect on Cu(DTC). The H. pylori-activable dissociation of Cu-SK@NTR-DTC, and the local release of Cu(DTC) and SK seriously destructed the bacterial membranes integrity and induce H. pylori death, which provided a feasible strategy to address the clinical limitations of H. pylori clearance.
幽门螺杆菌（H. pylori）被认为是与多种消化系统疾病相关的主要致病因素。然而，含抗生素的一线治疗效果逐渐下降。开发减少/摒弃抗生素的治疗方法来对抗幽门螺杆菌迫在眉睫。基于我们之前的发现，即Cu（DTC）比双硫仑或二乙基二硫代氨基甲酸盐（DTC）具有更强的杀菌作用，我们构建了一种由DTC前药、铜和紫草素（SK）组成的无抗生素治疗策略来消除幽门螺杆菌。首先用硝基芳基部分修饰DTC以获得DTC前药（NTR-DTC），然后将其进一步封装到Cu-SK@DOPA中构建纳米前药Cu-SK@NTR-DTC，以实现对DTC、铜和SK的三重掩蔽以进行特异性治疗。Cu-SK@NTR-DTC可以穿透黏液层并主要滞留在细菌感染区域。在幽门螺杆菌存在的情况下，DTC从NTR-DTC中释放出来以恢复铜螯合活性，并与Cu-SK中的铜竞争性结合形成Cu（DTC）。释放出的SK对Cu（DTC）具有杀菌致敏作用。Cu-SK@NTR-DTC的幽门螺杆菌激活解离以及Cu（DTC）和SK的局部释放严重破坏了细菌膜的完整性并导致幽门螺杆菌死亡，这为解决幽门螺杆菌清除的临床局限性提供了一种可行的策略。
