Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Center for Medical Research, Medical University of Graz, Graz, Austria.
Center for Medical Research, Medical University of Graz, Graz, Austria.
Toxicol Appl Pharmacol. 2020 Jan 1;386:114833. doi: 10.1016/j.taap.2019.114833. Epub 2019 Nov 19.
One of the main problems for the development of pulmonary formulations is the low availability of approved excipients. Polyglycerol esters of fatty acids (PGFA) are promising molecules for acting as excipient for formulation development and drug delivery to the lung. However, their biocompatibility in the deep lung has not been studied so far. Main exposed cells include alveolar epithelial cells and alveolar macrophages. Due to the poor water-solubility of PGFAs, the exposure of alveolar macrophages is expected to be much higher than that of epithelial cells. In this study, two PGFAs and their mixture were tested regarding cytotoxicity to epithelial cells and cytotoxicity and functional impairment of macrophages. Cytotoxicity was assessed by dehydrogenase activity and lactate dehydrogenase release. Lysosome function, phospholipid accumulation, phagocytosis, nitric oxide production, and cytokine release were used to evaluate macrophage function. Cytotoxicity was increased with the increased polarity of PGFA molecules. At concentrations above 1 mg/ml accumulation in lysosomes, impairment of phagocytosis, secretion of nitric oxide, and increased release of cytokines were noted. The investigated PGFAs in concentrations up to 1 mg/ml can be considered as uncritical and are promising for advanced pulmonary delivery of high powder doses and drug targeting to alveolar macrophages.
开发肺部制剂的主要问题之一是批准的赋形剂的可用性低。脂肪酸聚甘油酯 (PGFA) 是一种很有前途的分子，可用作制剂开发和药物递送至肺部的赋形剂。然而，它们在深肺部的生物相容性尚未得到研究。主要暴露的细胞包括肺泡上皮细胞和肺泡巨噬细胞。由于 PGFAs 的水溶性差，预计肺泡巨噬细胞的暴露量要远高于上皮细胞。在这项研究中，测试了两种 PGFA 及其混合物对上皮细胞的细胞毒性以及对巨噬细胞的细胞毒性和功能障碍的影响。通过脱氢酶活性和乳酸脱氢酶释放评估细胞毒性。溶酶体功能、磷脂积累、吞噬作用、一氧化氮产生和细胞因子释放用于评估巨噬细胞功能。PGFA 分子的极性增加会导致细胞毒性增加。在浓度高于 1mg/ml 时，会注意到溶酶体积累、吞噬作用受损、一氧化氮分泌增加和细胞因子释放增加。在高达 1mg/ml 的浓度下研究的 PGFA 可被认为是非关键性的，并且对于高剂量粉末的先进肺部递药和靶向肺泡巨噬细胞具有很大的应用前景。
