Pulmonary delivery of clofoctol-loaded nanoparticles inhibits SARS-CoV-2 replication and reduces pneumonia
Tom Bourguignon1, Jesus Alfredo Godinez-Leon1, Amine Pochet2
1Université Paris-Saclay, CNRS, Institut des Sciences Moléculaires d'Orsay 91405 Orsay, France.
Abstract:
Despite the progress made through vaccination campaigns and the use of antivirals, the need for more effective therapeutics to combat respiratory viral infections remains critical. A recent screening of over 2000 repurposed molecules has identified the antibiotic clofoctol (CFT) as a promising candidate for treating COVID-19. However, administering CFT systemically poses challenges due to its low solubility and potential toxicity. In this study, we engineered poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) designed to encapsulate high payloads of CFT, allowing for a controlled drug release in the pulmonary environment. Pharmacokinetic studies demonstrated high CFT bioavailability 8 h after intranasal (i.n.) administration. In preclinical models (mouse and hamster) of COVID-19, i.n. administration of CFT-loaded NPs significantly reduced pulmonary viral loads. Remarkably, vectorized CFT also decreased inflammation and improved pathological scores in the lungs. These results pave the way for a groundbreaking CFT formulation designed to tackle the challenges posed by acute respiratory infections. This study marks the first demonstration of a stable, effective and well-tolerated CFT formulation for the treatment of lung diseases.
Insights
This study developed novel nanoparticles to deliver the antibiotic clofoctol (CFT) directly to the lungs for treating respiratory viral infections like COVID-19. The new formulation improved drug delivery and significantly reduced viral load and lung inflammation in preclinical models.
Area of Science:
- Nanomedicine
- Pharmacology
- Virology
Background:
- Respiratory viral infections, including COVID-19, necessitate improved therapeutic strategies beyond vaccines and antivirals.
- Clofoctol (CFT), an antibiotic, shows promise for COVID-19 treatment but faces bioavailability and toxicity challenges with systemic administration.
- Effective drug delivery to the pulmonary system is crucial for treating lung-specific viral diseases.
Purpose of the Study:
- To engineer poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) for efficient encapsulation and controlled pulmonary release of clofoctol (CFT).
- To evaluate the pharmacokinetic profile and therapeutic efficacy of intranasally administered CFT-loaded NPs in preclinical models of COVID-19.
- To establish a stable, well-tolerated CFT formulation for treating lung diseases.
Main Methods:
- Development of PLGA nanoparticles for high-payload CFT encapsulation.
- Intranasal administration of CFT-loaded NPs in mouse and hamster models of COVID-19.
- Pharmacokinetic studies to assess CFT bioavailability after intranasal delivery.
- Evaluation of viral load, lung inflammation, and pathological scores.
Main Results:
- High CFT bioavailability was achieved 8 hours post-intranasal administration.
- Intranasal CFT-loaded NPs significantly reduced pulmonary viral loads in preclinical models.
- Vectorized CFT treatment decreased lung inflammation and improved pathological outcomes.
- The formulation demonstrated stability, efficacy, and good tolerability.
Conclusions:
- PLGA nanoparticles provide an effective platform for pulmonary delivery of clofoctol (CFT), overcoming its systemic administration challenges.
- Intranasal vectorized CFT offers a promising therapeutic approach for acute respiratory viral infections, including COVID-19.
- This study presents the first successful development of a CFT formulation for treating lung diseases.
