Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages.
Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages.
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基于微粒的 INH 肺部递送可降低 INH 代谢并靶向肺泡巨噬细胞。
DOI：
10.1016/j.jconrel.2005.06.009
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Ng,Ka-yun
中科院分区：
文献类型：
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作者：
Zhou,Huiyu;Zhang,Yanling;Biggs,DanielleL;Manning,MarkC;Randolph,TheodoreW;Christians,Uwe;Hybertson,BrooksM;Ng,Ka-yun
通过用压缩抗溶剂（PCA）方法沉淀制备的微粒被评估其靶向异烟肼（INH）的可电离前药、异烟肼甲磺酸盐（INHMS）用于持续递送INH至肺泡巨噬细胞（AM）的潜力。将带电荷的前药与两种不同的疏水阳离子（溴化四戊基铵（TPA）和溴化四庚基铵（THA））离子配对，并分别加载到聚（1-丙交酯）（PLA）微粒中。药物/聚合物颗粒为球形，直径在1 - 3 μm之间。疏水阳离子的选择不影响药物掺入效率或INH从微粒的释放动力学。使用灵敏的液相色谱串联质谱（LC-MS/MS）测定INH，高水平的INH检测NR 8383，大鼠AM细胞系，这些细胞暴露于载药微粒。为了证实微粒可以在体内靶向AM，我们通过LC-MS/MS比较了在Sprague-Dawley大鼠通过气管内滴注给予PLA微粒中的INHMS或通过管饲或气管内滴注给予INH溶液后灌洗的支气管肺泡巨噬细胞中的INH水平。正如预期的那样，只有微粒提供持续和靶向递送INH到AM。最重要的是，这种递送方法导致乙酰异噻嗪（AcINH）的血液水平显著降低，AcINH是INH的主要和潜在的毒性代谢物。
Microparticles prepared by the precipitation with a compressed antisolvent (PCA) process were evaluated for their potential in targeting an ionizable prodrug of isoniazid (INH), isoniazid methanesulfonate (INHMS), for sustained delivery of INH to alveolar macrophages (AMs). The charged prodrug was ion-paired with two different hydrophobic cations (tetrapentylammonium (TPA)— and tetraheptylammonium (THA)—bromide), and loaded separately into the poly(l-lactide) (PLA) microparticles. The drug/polymer particles were spherical in shape and between 1 and 3 μm in diameter. The choice of hydrophobic cations did not affect drug incorporation efficiencies or the release kinetics of INH from the microparticles. Using a sensitive liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay developed for INH, high level of INH was detected in NR8383, a rat AM cell line, following exposure of these cells to drug-loaded microparticles. To confirm the microparticles can target AMs in vivo, we compared the INH levels in lavaged bronchoalveolar macrophages by LC-MS/MS after the Sprague–Dawley rats were administered either INHMS in PLA microparticles by intra-tracheal instillation or INH solution by gavage or intra-tracheal instillation. As expected, only microparticles provided sustained and targeted delivery of INH to AMs. Most importantly, this method of delivery led to substantial reduction in the blood levels of acetylisoniazid (AcINH), a major and potential toxic metabolite of INH.