Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, Saarbrücken 66123, Germany.
Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, Saarbrücken 66123, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus E8 1, Saarbrücken 66123, Germany.
Eur J Pharm Sci. 2024 Nov 1;202:106891. doi: 10.1016/j.ejps.2024.106891. Epub 2024 Sep 2.
Pulmonary fibrosis, a disabling lung disease, results from the fibrotic transformation of lung tissue. This fibrotic transformation leads to a deterioration of lung capacity, resulting in significant respiratory distress and a reduction in overall quality of life. Currently, the frontline treatment of pulmonary fibrosis remains limited, focusing primarily on symptom relief and slowing disease progression. Bacterial infections with Pseudomonas aeruginosa are contributing to a severe progression of idiopathic pulmonary fibrosis. Phytic acid, a natural chelator of zinc, which is essential for the activation of metalloproteinase enzymes involved in pulmonary fibrosis, shows potential inhibition of LasB, a virulence factor in P. aeruginosa, and mammalian metalloproteases (MMPs). In addition, phytic acid has anti-inflammatory properties believed to result from its ability to capture free radicals, inhibit certain inflammatory enzymes and proteins, and reduce the production of inflammatory cytokines, key signaling molecules that promote inflammation. To achieve higher local concentrations in the deep lung, phytic acid was spray dried into an inhalable powder. Challenges due to its hygroscopic and low melting (25 °C) nature were mitigated by converting it to sodium phytate to improve crystallinity and powder characteristics. The addition of leucine improved aerodynamic properties and reduced agglomeration, while mannitol served as carrier matrix. Size variation was achieved by modifying process parameters and were evaluated by tools such as the Next Generation Impactor (NGI), light diffraction methods, and scanning electron microscopy (SEM). An inhibition assay for human MMP-1 (collagenase-1) and MMP-2 (gelatinase A) allowed estimation of the biological effect on tissue remodeling enzymes. The activity was also assessed with respect to inhibition of bacterial LasB. The formulated phytic acid demonstrated an IC50 of 109.7 µg/mL for LasB with viabilities > 80 % up to 188 µg/mL on A549 cells. Therefore, inhalation therapy with phytic acid-based powder shows promise as a treatment for early-stage Pseudomonas-induced pulmonary fibrosis.
肺纤维化是一种使人丧失能力的肺部疾病，源于肺部组织的纤维化转化。这种纤维化转化导致肺容量恶化，导致严重的呼吸窘迫和整体生活质量下降。目前，肺纤维化的一线治疗仍然有限，主要集中在缓解症状和减缓疾病进展。铜绿假单胞菌引起的细菌感染导致特发性肺纤维化的严重进展。植酸是一种天然的锌螯合剂，对于参与肺纤维化的金属蛋白酶的激活至关重要，它显示出对铜绿假单胞菌的 LasB 以及哺乳动物金属蛋白酶（MMPs）的潜在抑制作用。此外，植酸具有抗炎特性，据信这是由于其捕获自由基、抑制某些炎症酶和蛋白质以及减少炎症细胞因子产生的能力，炎症细胞因子是促进炎症的关键信号分子。为了在深部肺部达到更高的局部浓度，将植酸喷雾干燥成可吸入粉末。通过将其转化为植酸钠来提高结晶度和粉末特性，克服了其吸湿性和低熔点（25°C）的性质所带来的挑战。亮氨酸的添加改善了空气动力学特性并减少了团聚，甘露醇则作为载体基质。通过修改工艺参数来实现粒径变化，并使用下一代撞击器（NGI）、光衍射方法和扫描电子显微镜（SEM）等工具进行评估。人类 MMP-1（胶原酶-1）和 MMP-2（明胶酶 A）的抑制测定允许估计对组织重塑酶的生物学影响。还评估了 LasB 抑制方面的活性。该配方植酸对 LasB 的 IC50 为 109.7 µg/mL，在 A549 细胞上的活力> 80 %，直至 188 µg/mL。因此，基于植酸的粉末吸入疗法有望成为治疗早期铜绿假单胞菌诱导的肺纤维化的一种方法。
