Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles

Joana Costa-Gouveia (1) , Elisabetta Pancani (2) , Samuel J Jouny (1) , Arnaud Machelart (1) , Vincent Delorme (1) , Giuseppina Salzano (2) , Raffaella Iantomasi (1) , Catherine Piveteau (3) , Christophe J Queval (1) , Ok-Ryul Song (1) , Marion Flipo (3) , Benoit Déprez (3) , Jean-Paul Saint-Andre (4) , José Hureaux (4) , Laleh Majlessi (5) , Nicolas Willand (3) , Alain Baulard (1) , Priscille Brodin (1) , Ruxandra Gref (2)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 ISMO - Institut des Sciences Moléculaires d'Orsay
3 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
4 CHU Angers - Centre Hospitalier Universitaire d'Angers
5 Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics

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.

Domaines: Chimie; Matériaux

Joana Costa-Gouveia, Elisabetta Pancani, Samuel J Jouny, Arnaud Machelart, Vincent Delorme, et al.. Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. Scientific Reports, 2017, 7 (1), ⟨10.1038/s41598-017-05453-3⟩. ⟨hal-02367442⟩