Targeted delivery of antibiotics to the infected pulmonary tissues using ROS-responsive nanoparticles

Abstract

Background Immunocompromised individuals and those with lung dysfunction readily acquire pulmonary bacterial infections, which may cause serious diseases and carry a heavy economic burden. Maintaining adequate antibiotic concentrations in the infected tissues is necessary to eradicate resident bacteria. To specifically deliver therapeutics to the infected pulmonary tissues and enable controlled release of payloads at the infection site, a ROS-responsive material, i.e. 4-(hydroxymethyl) phenylboronic acid pinacol ester-modified α-cyclodextrin (Oxi-αCD), was employed to encapsulate moxifloxacin (MXF), generating ROS-responsive MXF-containing nanoparticles (MXF/Oxi-αCD NPs). Results MXF/Oxi-αCD NPs were coated with DSPE-PEG and DSPE-PEG-folic acid, facilitating penetration of the sputum secreted by the infected lung and enabling the active targeting of macrophages in the inflammatory tissues. In vitro drug release experiments indicated that MXF release from Oxi-αCD NPs was accelerated in the presence of 0.5 mM H2O2. In vitro assay with Pseudomonas aeruginosa demonstrated that MXF/Oxi-αCD NPs exhibited higher antibacterial activity than MXF. In vitro cellular study also indicated that folic acid-modified MXF/Oxi-αCD NPs could be effectively internalized by bacteria-infected macrophages, thereby significantly eradicating resident bacteria in macrophages compared to non-targeted MXF/Oxi-αCD NPs. In a mouse model of pulmonary P. aeruginosa infection, folic acid-modified MXF/Oxi-αCD NPs showed better antibacterial efficacy than MXF and non-targeted MXF/Oxi-αCD NPs. Meanwhile, the survival time of mice was prolonged by treatment with targeting MXF/Oxi-αCD NPs. Conclusions Our work provides a strategy to overcome the mucus barrier, control drug release, and improve the targeting capability of NPs for the treatment of pulmonary bacterial infections.

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

“…This ester link is cleaved in the presence of a low H 2 O 2 concentration, which is produced by neutrophils at the site of infection. This original controlled-release formulation is thus able to deliver moxifloxacin specifically to infected tissue [114]. With the increasing bacterial resistance to antibiotics and the lack of new antibiotics, the development of these new strategies is increasingly necessary.…”

Nano-Based Drug Delivery or Targeting to Eradicate Bacteria for Infection Mitigation: A Review of Recent Advances

“…The micelle treatment in P. aeruginosainfected mice reduced the bacterial load and alveolar injury in the lung compared to free ciprofloxacin. To deliver moxifloxacin to the infected lung tissue and enable sustained drug release, a ROS-responsive 4-(hydroxymethyl) phenylboronic acid pinacol ester-modified α-cyclodextrin was coated with phospholipids to form a lipidcoated nanoparticles for lung infection management (Wang et al, 2019). The coating with 1,2-distearoyl-sn-glycero-3phosphoethanolamine (DSPE)-PEG-folic acid on nanocarriers helped to promote sputum penetration and targeting to the macrophages with overexpressed ROS in the inflammatory region.…”

The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials

“…Nowadays, the drug delivery systems (DDS) that respond to the ALI microenvironment have attracted much concern [ 275 ]. Wang et al used 4-(hydroxymethyl) phenylboronic acid pinacol ester-modified alpha-cyclodextrin (Oxi-alpha CD) as a carrier to obtain a kind of ROS-responsive moxifloxacin- (MXF-) loaded nanoparticles, which release MXF triggered by H 2 O 2 and are effective in a mouse model of pulmonary P. aeruginosa infection [ 276 ]. Zhang and his coworkers developed an acid-sensitive nanoparticle to target inflamed lungs.…”