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

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, Cu 2+ 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 2+ 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 2+ 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.