Targeted delivery of antitubercular drugs using glucan lipid particles
ABSTRACT Simpler, safer, and faster chemotherapeutic regimens for tuberculosis and other respiratory mycobacterial infections are an urgent need. Many current therapies suffer from suboptimal drug exposure and dose-limiting systemic adverse effects, challenges that could be addressed via controlled...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2025-03-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02744-24 |
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| Summary: | ABSTRACT Simpler, safer, and faster chemotherapeutic regimens for tuberculosis and other respiratory mycobacterial infections are an urgent need. Many current therapies suffer from suboptimal drug exposure and dose-limiting systemic adverse effects, challenges that could be addressed via controlled delivery of drugs to the primary site of infection. We sought to address this need by designing a flexible formulation platform that targets drugs to the lung macrophages that concentrate at infectious foci. Our approach is based on an encapsulation strategy in which drugs or specifically designed prodrugs are captured in the hydrophobic core of a glucan-lipid particle (GLP). We show chemically diverse antimycobacterial drugs can be efficiently and stably encapsulated within GLP and that these microparticles can be engineered to release drugs upon low pH or reducing conditions that occur upon phagocytosis by macrophages. Encapsulated formulations of clofazimine, isoniazid, and linezolid retain activity against intracellular Mycobacterium tuberculosis (Mtb) in an ex vivo model, demonstrating efficient drug delivery and release. Intranasal administration of GLP-clofazimine to Mtb-infected mice effectively concentrates the drug in the lung and reduces bacterial burden, whereas GLP-delivered linezolid was systemically distributed and failed to inhibit bacterial growth in the lung. This work establishes GLPs as a promising platform for targeted antibiotic delivery to the lung and also illustrates pharmacokinetic parameters that must be considered in future development.IMPORTANCETuberculosis (TB) causes an estimated 10.8 million cases each year and remains one of the leading causes of infectious death. Effective treatment is complicated due to the lengthy drug regimen required to prevent relapse and treatment failure. A primary challenge is delivering drugs effectively to lung granulomas, where TB bacteria can persist. Here, we developed yeast-derived glucan lipid microparticles (GLPs) as a novel delivery system to efficiently encapsulate and deliver TB drugs directly to lung tissue via intranasal administration. Of the formulations evaluated, GLP-encapsulated clofazimine achieved increased lung drug levels and reduced bacterial burden in TB-infected mice. The use of GLPs offers a promising approach to improve TB treatment by enabling targeted drug delivery to infection sites within the lungs. |
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| ISSN: | 2165-0497 |