Ciprofloxacin–polymer conjugates targeted with iron(iii) for effective treatment of intracellular bacterial infections

Abstract

The increasing prevalence of multidrug-resistant bacteria necessitates innovative antibiotic strategies beyond the discovery of new active compounds. Here, we report N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer–ciprofloxacin conjugates combining controlled drug release with siderophore-mediated targeting via a deferoxamine–Fe³⁺ (DFX–Fe) complex. The conjugates differed in linker type (non-cleavable amide vs. reductively cleavable disulfide) and in the presence of the DFX–Fe targeting unit. Non-cleavable conjugates showed strongly reduced antibacterial activity, whereas disulfide-linked systems enabled the release of chemically intact and biologically active ciprofloxacin under reducing conditions. DFX–Fe targeting significantly enhanced the efficacy of non-cleavable conjugates, while modulating drug release kinetics in cleavable systems due to the redox activity of Fe³⁺. Antibacterial activity against Escherichia coli and Staphylococcus aureus strongly depended on the conjugate structure and bacterial species. Importantly, in a macrophage intracellular infection model, stimuli-responsive conjugates exhibited high bactericidal activity, reducing intracellular bacteria to below 1% at a 2× MIC concentration. This observation indicates the great potential of these nanotherapeutics in the treatment of challenging bacterial infections. All systems showed good biocompatibility toward human fibroblasts. Overall, this study highlights the critical roles of linker cleavability and siderophore-mediated targeting in the design of polymeric antibiotics for intracellular bacterial infections.