Albumin-Based LL37 Peptide Nanoparticles as a Sustained Release System against Pseudomonas aeruginosa Lung Infection

Abstract

Pseudomonas aeruginosa (PA) has emerged as a pressing challenge to pulmonary infection and lung damage. The LL37 peptide is an efficient antimicrobial agent against PA strains, but its application is limited because of fast clearance in vivo, biosafety concerns, and low bioavailability. Thus, an albumin-based nanodrug delivery system with reduction sensitivity was developed by forming intermolecular disulfide bonds to increase in vivo LL37 performance against PA. Cationic LL37 can be efficiently encapsulated via electrostatic interactions to exert improved antimicrobial effects. The LL37 peptide exhibits greater than 48 h of sustained released from LL37 peptide nanoparticles (LL37 PNP), and prolonged antimicrobial effects were noted as the incubation time increased. Levels of inflammatory cytokines secreted by peritoneal macrophages, including TNF-α and IL-6, were reduced significantly after LL37 PNP treatment following PA stimulation, indicating that LL37 PNP inhibits PA growth and exerts anti-inflammatory effects in vitro. In a murine model of acute PA lung infection, LL37 PNP significantly reduced TNF-α and IL-1β expression and alleviated lung damage. The accelerated clearance of PA indicates that LL37 PNP could improve PA lung infection and the subsequent inflammation response more efficiently compared with free LL37 peptide. In conclusion, this excellent biocompatible LL37 delivery strategy may serve as an alternative approach for the application of new types of clinical treatment in future.

Potential of Nanoparticles Integrated with Antibacterial Properties in Preventing Biofilm and Antibiotic Resistance

“…Bovine serum albumin nanoparticles (BSA NPs) have emerged as drug carriers for various diseases [ 99 ]. Yang and co-workers (2020) incorporated LL-37 with BSA NPs into the biopsy samples of mice infected with P. aeruginosa to observe the efficacy of this composite in preventing biofilm formed by P. aeruginosa , which is a causative agent of pulmonary infections [ 100 ]. LL-37 acts as an antibiofilm against S. aureus and P. aeruginosa .…”

“…Furthermore, they block the proliferation of bacterial cells, hence, significantly reducing the secretions of inflammatory cytokines by macrophages, gradually improving lung injury compared to LL-37 alone. These results indicate that BSA NPs are excellent nanocarriers, inhibiting bacterial biofilm, enhancing tolerance to an antibiotic and could become a novel therapy to treat other bacterial species causing pulmonary infections [ 100 ].…”

Survey of the Intermolecular Disulfide Bonds Observed in Protein Crystal Structures Deposited in the Protein Data Bank

“…It has been speculated that this is a general mechanism for short, helical antimicrobial peptides since they contain an odd number of cysteines, one of which is prone to form reversible intermolecular DBs [16]. The formation of intermolecular DBs between LL-37 and bovine serum albumin is believed to stabilize protein nanoparticles that might be used as promising vehicles to deliver therapeutics, otherwise unstable, for the treatments of lung infections from Pseudomonas aeruginosa [17]. Two cysteine residues of the Staphylococcus aureus catabolite control protein A (CcpA) have been shown to be important for resisting human innate immunity, too: they can be oxidized and form an intermolecular DB between two CcpA dimers, with the formation of a tetramer and CcpA dissociation from its cognate DNA promoter [18].…”

“…It has been speculated that this is a general mechanism for short, helical antimicrobial peptides since they contain an odd number of cysteines, one of which is prone to form reversible intermolecular DBs [ 16 ]. The formation of intermolecular DBs between LL-37 and bovine serum albumin is believed to stabilize protein nanoparticles that might be used as promising vehicles to deliver therapeutics, otherwise unstable, for the treatments of lung infections from Pseudomonas aeruginosa [ 17 ].…”

Special Issue: Nanomedicine Advances in Infectious Disease

“…Finally, Xu and colleagues 13 discuss a new approach to treating Pseudomonas aeruginosa (PA), the main pathogen involved in hospital-acquired and ventilator-associated pneumonia. The authors utilized albumin as a nanocarrier for the cationic peptide, LL37, which inhibits PA colony formation.…”