Infected microenvironment responsive nanoprodrug for the specific therapeutics of Helicobacter pylori clearance.

Abstract

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)₂ exhibited stronger bactericidal effect than that of disulfiram or diethyldithiocarbamate (DTC), we constructed an antibiotic-free therapeutic strategy composed of DTC prodrug, Cu²⁺ 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, Cu²⁺ 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 Cu²⁺ from Cu-SK to form Cu(DTC)₂. The released SK possessed the bactericidal sensitization effect on Cu(DTC)₂. The H. pylori-activable dissociation of Cu-SK@NTR-DTC, and the local release of Cu(DTC)₂ 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.