Polymeric nanocarriers for pulmonary co-delivery of anti-tuberculosis drugs
dirigée par Ruxandra Gref
Tuberculosis (TB) remains one of the world’s deadliest infectious diseases, and the emergence of drug-resistant strains continues to threaten global health, underscoring the urgent need for innovative therapeutic strategies. This interdisciplinary thesis presents a nanoparticle-based drug delivery platform designed to overcome major limitations of current TB treatments, including unfavorable drug physicochemical properties, limited pulmonary bioavailability, and systemic toxicity. Two complementary polymeric carrier systems were engineered and combined into a hybrid formulation capable of simultaneously delivering the complete BPaL regimen (bedaquiline, pretomanid, and linezolid) directly to the site of infection. A major finding of this work is the preferential accumulation of nanoparticles within infected cells, where uptake greatly exceeds that observed in non-infected cells, thereby enhancing drug delivery to the infectious niche. This phenomenon may represent a broader strategy for targeting intracellular pathogens and other intracellular diseases. In addition, we demonstrated that nanoparticles possessing specific physicochemical characteristics can exhibit intrinsic antibacterial activity, extending their role beyond that of passive drug carriers. The hybrid formulation, able of co-encapsulating three drugs with distinct physicochemical properties, was thoroughly evaluated through physicochemical characterization, stability studies, and pharmacokinetic assessment in mice. These findings establish a versatile and translational nanomedicine platform with the potential to improve the safety, efficacy, and treatment duration of therapies against one of humanity’s most persistent infectious diseases.