Abstract
Tuberculosis (TB) remains one of the most pressing global infectious diseases, with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains presenting significant challenges to current therapeutic strategies. Existing treatment regimens are prolonged, systemically toxic, and poorly targeted, often resulting in poor patient compliance and limited drug penetration into granulomatous lesions in the lungs. To address these limitations, this study aimed to develop a pulmonary theranostic platform composed of poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) coated superparamagnetic iron oxide nanoparticles (SPIONs), capable of delivering antitubercular agents directly to the site of infection while providing T2-weighted magnetic resonance imaging (MRI) contrast for diagnostic tracking.SPIONs were synthesized via the chemical co-precipitation method and surface-stabilized with oleic acid to ensure colloidal stability. These SPIONs were subsequently encapsulated within PLGA-PEG matrices using an emulsion solvent evaporation method, with Ethambutol and a novel MmpL3 inhibitor, N-(adamantyl)-1H-indole-2-carboxamide (N2), incorporated as model therapeutic agents. The resulting nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA).
Optimized nanoparticles showed uniform spherical morphology with a hydrodynamic diameter of ~250 nm and high colloidal stability. LC-MS/MS confirmed efficient drug loading and encapsulation. T2 relaxivity studies demonstrated strong MRI contrast potential (r₂ = 73.709 s⁻¹·mM⁻¹; r₂/r₁ = 76.3), and magnetic analysis indicated superparamagnetic behavior with a blocking temperature near 50 K. Freeze-drying with cryoprotectants produced inhalable dry powders with MMADs of 2–4 µm, suitable for alveolar delivery. Cytotoxicity assays in A549 and BEAS-2B cells confirmed biocompatibility over 72 hours. The nanoparticles' extracellular antibacterial activity, coupled with their efficient uptake by macrophages, confirms that nanotechnology-enabled delivery can simultaneously enhance the safety, efficacy, and targeting of anti-tubercular therapies.
This study successfully developed a multifunctional, aerosolizable nanoparticle system for targeted pulmonary delivery of antitubercular drugs. The integration of SPIONs enables simultaneous therapeutic and diagnostic capabilities, supporting real-time treatment monitoring via MRI. The PLGA-PEG-coated SPIONs demonstrated high stability, a high drug loading capacity, efficient lung deposition, and strong antibacterial and imaging potential. This platform holds significant promise for improving TB therapy through enhanced lung-targeting, reduced systemic toxicity, and non-invasive monitoring of treatment efficacy.