Abstract
Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered “booster” molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, “green” β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.
Highlights
Tuberculosis (TB) is a leading infectious cause of death worldwide
The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs
To address the challenges related to the co-encapsulation of ETH with the booster BDM4190616, we considered investigating NPs made of biodegradable PLGA and poly(lactic acid) (PLA) copolymers and NPs of polymeric β-cyclodextrins
Summary
The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy. About one-third of the world’s population is infected with Mycobacterium tuberculosis, the bacterium that causes TB. Lungs are the primary site for M. tuberculosis infection. If first-line drugs are misused or mismanaged, the onset of multidrug-resistant TB (MDR-TB) can occur. MDR-TB is defined as TB caused by strains that are resistant to at least isoniazid (INH) and rifampicin (RIF), two powerful first-line anti-TB drugs. MDR-TB takes up to two years of chemotherapy with second-line drugs such as ethionamide.
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