Institut für Pharmazeutische Technologie, TU Braunschweig, Braunschweig, Germany.
Inhal Toxicol. 2013 Aug;25(9):536-43. doi: 10.3109/08958378.2013.810315.
The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid:triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180 nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0-5000 µg/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD50) values for A549 cells and PCLS were found to be in the range of 1200-1900 µg/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800 µg/ml. PCHS showed slightly higher LD50 values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.
本研究旨在探究载有西地那非的固体脂质纳米粒（SLN）的潜在细胞毒性。这些 SLN 被测试为一种新的药物传递系统（DDS），用于治疗人类肺部的肺动脉高压。测定了西地那非在 SLN 脂质基质（30:70 磷脂：甘油三酯）中的溶解度，分别为 1%西地那非碱和 0.1%西地那非柠檬酸盐。采用新型微通道匀化法成功制备了粒径约为 180nm、单模态粒径分布的载有西地那非的 SLN，且在 3 个月内保持稳定。随后，将载有西地那非的 SLN 用于代表肺和心脏组织的体外和离体模型。体外模型采用人肺泡上皮细胞系（A459）和小鼠心脏内皮细胞系（MHEC5-T）。离体模型采用大鼠精密切割肺切片（PCLS）和大鼠心脏切片（PCHS）。所有模型均以脂质基质浓度为 0-5000μg/ml 的普通 SLN 和载有西地那非的 SLN 进行处理。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定法在体外和离体模型中评价毒性。A549 细胞和 PCLS 的半数致死剂量 50%（LD50）值为 1200-1900μg/ml，而 MHEC5-T 细胞和精密切割心脏切片的 LD50 值在 1500-2800μg/ml 之间。与 PCLS 相比，PCHS 的 LD50 值略高。考虑到毒理学方面，载有西地那非的 SLN 有可能通过吸入途径治疗肺动脉高压。
