Self-assembly pH-sensitive polyelectrolyte complex co-delivers niclosamide and colistin to overcome colistin resistance in bacterial infections.

Polyelectrolyte complexes (PECs) provided new opportunities for drug-controlled release systems and had the potential to address the challenges during the effective oral delivery of colistin and niclosamide. Here, an innovative pH-sensitive PEC for the oral co-delivery of colistin and niclosamide (CS/AL-PECs@COL/NIC) was developed, which was self-assembled through electrostatic interaction by an optimized double-emulsion method from two oppositely charged nanoparticles (chitosan-coated nanoparticles and alginate-coated nanoparticles). The CS/AL-PECs@COL/NIC exhibited pH sensitivity, formed a tight cross-linked structure in the gastric acid environment, effectively slowing down the release of the loaded drugs (colistin and niclosamide), and transformed into a loose structure in the neutral environment of the intestine, facilitating the stable release of the loaded drugs. Importantly, the CS/AL-PECs@COL/NIC had good in vivo antibacterial activity against E. coli infection and alleviated the inflammation and intestinal damage caused by bacterial infection in the mouse intestinal infection model. Both in vitro and in vivo studies indicated that the CS/AL-PECs@COL/NIC had good biocompatibility and good palatability. In particular, the oral administration of an effective dose of CS/AL-PECs@COL/NIC did not cause intestinal flora disorder, which had an advantage over colistin treatment. Thus, the prepared CS/AL-PECs@COL/NIC may contribute to treating colistin-resistant bacterial infections as a biocompatible oral administration.