Abstract
Background: The drugs used for treating multi drug resistant tuberculosis (MDR-TB) are extremely toxic, expensive and less potent with limited sterilizing activity. With the emergence of several drug resistant strains of tuberculosis there is a pressing need for new drug development. In the current study, clinically used anti-infective antibiotics such as moxifloxacin (MOX), econazole (ECZ) and ethionamide (ETH) were encapsulated in poly-(lactide-co-glycolide) nanoaprticles and evaluated for their therapeutic efficacy in a MDR-TB infected mouse model. It is envisaged that such formulations would improve patient compliance and reduction in the number of dosages.
Methods: Moxifloxacin and ethionamide nanoparticles were prepared by multiple emulsion and solvent evaporation method while econazole nanoparticles were prepared by nanopreciptitation method. Mice were aerosol infected with MDR-TB JAL11050 and treated with free drugs and drugs encapsulated in PLGA nanoparticles. The lungs and spleen were evaluated for reduction in bacterial load (colony forming units, CFU) and histopathological studies.
Results: Moxifloxacin, econazole and ethionamide were encapsulated with high efficiency in PLGA nanoparticles. Eight weeks of oral administration of individual nanoformulations (PLGA-NP-ECZ / PLGA-NP-MOX / PLGA-NP-ETH) showed limited reduction of CFUs in lungs and spleen while with 8 doses of a combination of the three nanoformulations (PLGA- NP- ECZ+PLGA-NPMOX+PLGA-NP-ETH) there was a significant reduction in CFUs in lungs as well as in spleen. Corroborating the results with histopathology revealed that the combination of 3-drugs loaded nanoparticles decreased the congestion in the lungs to 50%.
Conclusion: Chemotherapy of MDR-TB infected mice with weekly doses of 3-drugs nanoformulations (PLGA-NPECZ+ PLGA-NP-MOX+PLGA-NP-ETH) led to the clearance of bacilli from lungs and the spleen. This is a first report on the potential efficacy of a combination of ECZ, MOX and ETH nanoparticles against MDR-TB.
Keywords: Azoles, colony forming units, econazole, ethioanmide, fluoroquinolones, moxifloxacin, multi drug resistant tuberculosis, poly-(lactide-co-glycolide).
Graphical Abstract
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