Despite the potent clinical efficacy of linezolid (LNZ) against drug-resistant tuberculosis, its safety and tolerability remain of major concern. Our objective is to develop antitubercular inhalable LNZ nano-embedded microparticles. In this context, LNZ incorporated in non-structured lipid carriers (NLCs) was characterized in terms of colloidal, morphological, thermal, and release profiles. The potential of LNZ-NLCs to cross mucosal barriers and invade alveolar macrophages (AM, MH-S cells) was appraised. In vivo proof of concept was accomplished via orotracheal administration to mice. Respirable microparticles prepared by spray drying NLCs with diluents were assessed for their size, shape, flowability, aerosolization performance, and lung deposition pattern. NLCs (809-827 nm in size, zeta potential - 37.4 to - 58.9 mV) ensued 19% LNZ loading and pH-independent sustained release. Penetration studies revealed 73% LNZ crossing mucus within 1 h. Meanwhile, viability assay on A549 cells ensured an IC50 of 1.2 and 0.32 mg/mL for plain and LNZ-NLCs, respectively. CLSM confirmed phagocytosis of NLCs by MH-S macrophages, while H&E staining demonstrated NLC accumulation in murine AM in vivo with no signs of histopathological/biochemical changes. Bronchoalveolar lavage showed significantly low levels of LDH and total proteins (TP) for LNZ-NLCs highlighting their superior safety. Respirable microparticles embedding LNZ-NLCs ensured excellent aerosolization (MMAD 2 μm, FPF 93%) denoting perfect alveolar deposition. The developed inhalation therapy provided sustained LNZ release, mucus penetrability, potential safety in therapeutic doses, in vitro and in vivo macrophage targetability, and preferential deposition in the deep lung. Overall positive outcomes rely on reduced dose, dosing frequency, and per se superior safety circumventing systemic-associated life-threatening side effects. Graphical abstract.
Keywords: Inhalable microparticles; Linezolid; Macrophage-targeted drug delivery; Non-structured lipid carriers; Spray drying.