Chronic lung infection caused by bacterial biofilms is an extremely serious clinical problem, which can lead to the failure of antibiotic therapy. Although nanoparticles have shown great potential in the treatment of biofilms, the efficient penetration and retention of nanoparticles in biofilms is still a big challenge. To address this issue, we herein fabricate size and charge adaptive azithromycin (AZM)-conjugated clustered nanoparticles (denoted as AZM-DA NPs) as therapeutic agents for treating biofilms. The AZM-DA NPs are prepared by electrostatic complexation between AZM conjugated amino-ended poly(amidoamine) dendrimer (PAMAM) and 2,3-dimethyl maleic anhydride (DA) modified poly(ethylene glycol)-block-polylysine (PEG-b-PLys). It is noteworthy that the AZM-DA NPs can disassemble in an acidic biofilm microenvironment (pH 6.0), leading to the release of secondary AZM-conjugated PAMAM nanoparticles (PAMAM-AZM NPs). PAMAM-AZM NPs with small size and positive charge are beneficial for improved penetration and retention inside biofilms, enhanced permeabilization of the bacterial membrane, and increased internalization of AZM, thus exhibiting excellent antibiofilm activities. AZM-DA NPs are also favorable as long-term antibacterial agents due to the reduced occurrence of drug resistance. In vivo therapeutic performance is confirmed by the reduced bacterial burden and the alleviated inflammation in the chronic lung infection model. This research not only develops an innovative strategy for antibiotic delivery in vivo but also provides an effective way for the management of biofilm-associated infections, including chronic lung infection.
Keywords: antibiotic resistance; azithromycin; biofilm penetration; nanoparticle; permeability.