Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
Drug Deliv Transl Res. 2021 Jun;11(3):1037-1055. doi: 10.1007/s13346-020-00815-3.
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.
尽管利奈唑胺（LNZ）对耐药结核病具有强大的临床疗效，但它的安全性和耐受性仍是主要关注点。我们的目标是开发抗结核可吸入 LNZ 纳米嵌入微球。在这种情况下，对包含在非结构化脂质载体（NLC）中的 LNZ 进行了胶体、形态、热和释放特性的表征。评估了 LNZ-NLC 穿透黏膜屏障并侵袭肺泡巨噬细胞（AM，MH-S 细胞）的潜力。通过口腔气管给药途径在小鼠体内进行了概念验证。通过喷雾干燥 NLC 与稀释剂制备可吸入微球，并对其粒径、形状、流动性、雾化性能和肺部沉积模式进行了评估。NLC（大小为 809-827nm，Zeta 电位为-37.4 至-58.9mV）可负载 19%的 LNZ，并实现 pH 无关的持续释放。穿透研究显示，1 小时内有 73%的 LNZ 穿过黏液。同时，A549 细胞的活力测定确保普通 LNZ 和 LNZ-NLC 的 IC50 分别为 1.2 和 0.32mg/mL。CLSM 证实了 MH-S 巨噬细胞对 NLC 的吞噬作用，而 H&E 染色显示 NLC 在体内的 AM 中积累，且无组织病理学/生化变化的迹象。支气管肺泡灌洗显示 LNZ-NLC 的 LDH 和总蛋白（TP）水平显著降低，突出了其优异的安全性。嵌入 LNZ-NLC 的可吸入微球确保了出色的雾化效果（MMAD 为 2μm，FPF 为 93%），表示可实现完美的肺泡沉积。所开发的吸入疗法提供了持续的 LNZ 释放、黏液穿透性、治疗剂量下的潜在安全性、体外和体内巨噬细胞靶向性以及在深肺中的优先沉积。总体上积极的结果依赖于减少剂量、给药频率和本身优越的安全性，避免了与全身相关的危及生命的副作用。图表摘要。
