Experimental, inhaled nanoparticles that incorporate antimicrobial peptides (AMPs) and encapsulate an antibiotic were demonstrated to penetrate mucus and biofilm barriers to quell infection and related inflammation, in a mouse model of exacerbated chronic obstructive pulmonary disease (COPD).

Junliang Zhu, Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, China and colleagues sought to deliver antimicrobials directly to the lung via nebulization to reduce systemic exposure and diminish potential side effects.The dosage form would have to overcome multiple pathophysiologic barriers, however, including hypersecretion of mucus in the upper airway and bronchi characteristic of COPD, and the biofilms formed by bacteria colonizing the lungs.

“Effective mucus and biofilm penetration are critically imperative for inhaled antimicrobials,” Zhu and colleagues declared.

Their approach exploited particular obstructive mechanisms that they encountered within those barriers:the viscous mucus layer lining above the bronchial epithelium trapped antimicrobials through electrostatic attraction with mucin; and the extracellular polymeric substance (EPS) matrix of the biofilms captured positively charged antimicrobial compounds.

They posited that a negatively charged nanoparticle shell, which they constructed from porous silica, would penetrate mucus and biofilm through electrostatic repulsion with glycoproteins and polysaccharides; the incorporated polypeptides would be “conditionally activated” inside the mildly acidic biofilm; and the encapsulated antibiotic (ceftazidime) would be released as the acidity changed the shell charge from negative to positive.

The chemical mechanism for activation of the polypeptides, Zhu and colleagues explain, is the acid-triggered removal of their carboxyl groups.This change transforms them from negatively charged, flexible random coil with low affinity for bacterial membranes, to a positively charged, rigid α-helix “with a potent capacity to disrupt bacterial membranes.”

The investigators reported that the penetration of the barriers and release of active agents was measurable in both in vitro and in vivo settings, as was the eradication of microbes.In addition to the antibacterial action of ceftazidime, the investigators found that the positively charged polypeptides effectively scavenged bacterial e- and g-DNA, to inhibit the infiltration and activation of immune cells, and mitigate the infection-associated inflammation.

“With these unique properties, the IMAMs (immunoantimicrobials) demonstrated potent therapeutic efficacy in mice with COPD exacerbations, effectively eradicating lung-colonizing bacteria and inhibiting TLR9 (toll-like receptor 9) activation to alleviate pulmonary inflammation,” Zhu and colleagues reported.

The investigators acknowledge that among the questions remaining after this animal model study is whether the nanoparticles are cleared from the lungs.

“The repeated nebulization of silica-based nanomaterials may raise concerns about pulmonary fibrosis, and thus, the long-term safety of IMAMs alongside the degradation profiles of silica nanomaterials should by systematically studied,” Zhu and colleagues indicated.

In addition, the investigators point out the challenge of developing complex manufacturing practices to manage batch-to-batch variance of the nanoparticle antimicrobial delivery systems.

“Nevertheless, our study clearly demonstrates that the vast therapeutic potential of IMAMs is poised to shift the paradigm in COPD management,” Zhu and colleagues claim.

Reference

1Zhu J, Li X, Zhou Y, et al. Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease. Sci Adv 2024; 10: eabd7904.https://www.science.org/doi/10.1126/sciadv.abd7904.Accessed Feb 7, 2024.