Surface-Engineered Ethambutol-Loaded Nanoparticles: Design, Fabrication, and In Vitro-In Vivo Evaluation for...

Tuberculosis (TB) remains a major global health challenge, aggravated by limitations of current chemotherapeutic regimens, including poor oral bioavailability, systemic side effects, and patient noncompliance. This study aimed to develop and evaluate macrophage-targeted, mannose-conjugated solid lipid nanoparticles (Mn-ETB-SNs) for enhanced oral delivery of ethylbutol (ETB), a first-line anti-TB drug. The Mn-ETB SNs were fabricated using high-pressure homogenization followed by surface mannosylation through Schiff's base formation between mannose and amine-functionalized nanoparticles. The prepared formulations were characterized for particle size, ζ-potential, drug loading, entrapment efficiency, morphology, and stability. In vitro release, GI stability, cytotoxicity, and cellular uptake studies using J774A.1 macrophages were conducted. Further, in vivo pharmacokinetic and biodistribution studies were performed in Sprague-Dawley rats. The optimized Mn-ETB-SNs exhibited a uniform particle size of approximately 491 nm, a high entrapment efficiency of around 84%, and spherical morphology with stable physicochemical properties under varied storage and GI conditions. Mannosylation significantly enhanced macrophage uptake by 2.02-fold compared to unconjugated nanoparticles, as confirmed through fluorescence-activated cell sorting (FACS) and fluorescence microscopy. In vivo pharmacokinetic studies demonstrated an 8.5-fold increase in ETB bioavailability with Mn-ETB-SNs compared to the pure drug, accompanied by prolonged circulation and reduced hepatic metabolism. Biodistribution analysis revealed preferential and sustained lung accumulation, with Mn-ETB-SNs achieving 4.74-fold higher pulmonary concentrations at 48 h compared to free drug, owing to mannose receptor-mediated uptake by alveolar macrophages. Collectively, the findings highlight the potential of orally administered Mn-ETB-SNs as a promising nanocarrier system for targeted TB therapy. The developed formulation offers improved bioavailability, site-specific drug delivery, and enhanced pulmonary targeting, addressing key limitations of conventional TB treatment.