Treatment of Bleomycin-induced Pulmonary Fibrosis by Intratracheal Instillation Administration of Ellagic Acid-Loaded Chitosan Nanoparticles

IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Zhilin Luo, Yao Sun, Shihao Cai, Hongting Liu, Conglu Zhao, Xiang Xu, Aiguo Xu, Honggang Zhou, Cheng Yang, Xiaoting Gu, Xiaoyu Ai
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引用次数: 0

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a rare and serious chronic interstitial lung disease that may endanger the lives of patients. The median survival time of patients with idiopathic pulmonary fibrosis is short, and the mortality rate is higher than that of many types of cancer. At present, pirfenidone (PFD) and nintedanib (NDNB) have been approved by FDA for IPF, but they can only delay the process of pulmonary fibrosis and cannot cure the disease. Therefore, it is urgent to develop other drugs with the effect of improving pulmonary fibrosis. Ellagic acid (EA) can inhibit the Wnt-signaling pathway and has an effect in treating pulmonary fibrosis induced by bleomycin (BLM) in mice. However, its solubility is poor, resulting in its low bioavailability and limited therapeutic benefits, so its clinical application has been limited. Herein, based on the characteristics of nano-drug lung delivery system, chitosan (CS) was selected as the carrier, and ellagic acid-loaded chitosan nanoparticles (EA-CS-NPs) were prepared by ionic gelation method. The EE% and DL% of prepared EA-CS-NPs was 73.73 ± 4.52% and 6.23 ± 1.09%, the particle size was 119.6 ± 5.51 nm (PDI = 0.234 ± 0.017), the zeta potential was 29.833 ± 0.503 mV. The morphology of the nanoparticles was observed by TEM microscope, which was round, uniform dispersion, indicating that the preparation process is stable and feasible. The toxicity experiment showed that EA-CS-NPs maintained 80% cell viability, significantly higher than that of the NDNB group, indicating lower toxicity and better inhibitory effects on TGF-β1-stimulated MLg and NIH-3T3 cells. Wound healing assay results showed that the inhibitory effect of EA-CS-NPs on cell migration was more pronounced than that of EA in the same amount of EA-containing drugs. Drug uptake experiments revealed that EA-CS-NPs significantly enhanced drug uptake in MLg and NIH-3T3 cells. In vivo, Cy7-CS-NPs exhibited higher fluorescence intensity in rat lungs compared to Cy7 solution, indicating better lung retention. The in vivo efficacy test showed that compared with the EA group, EA-CS-NPs could better reduce the area of pulmonary fibrosis and collagen deposition, improve lung function, and have a longer retention time in the lung. In summary, our results revealed that EA-CS-NPs may be a good choice for the treatment of pulmonary fibrosis.

Graphical Abstract

载鞣花酸壳聚糖纳米颗粒气管内灌注治疗博来霉素诱导的肺纤维化
特发性肺纤维化(Idiopathic Pulmonary Fibrosis, IPF)是一种罕见且严重的慢性肺间质性疾病,可危及患者的生命。特发性肺纤维化患者的中位生存时间短,死亡率高于许多类型的癌症。目前,吡非尼酮(PFD)和尼达尼布(NDNB)已被FDA批准用于IPF,但它们只能延缓肺纤维化的进程,不能治愈疾病。因此,迫切需要开发其他具有改善肺纤维化作用的药物。鞣花酸(EA)可抑制wnt信号通路,对博来霉素(BLM)所致小鼠肺纤维化有治疗作用。但其溶解度较差,导致其生物利用度低,治疗效果有限,因此其临床应用受到限制。本文根据纳米药物肺给药系统的特点,选择壳聚糖(CS)作为载体,采用离子凝胶法制备了载鞣花酸壳聚糖纳米颗粒(EA-CS-NPs)。所得EA-CS-NPs的EE%和DL%分别为73.73±4.52%和6.23±1.09%,粒径为119.6±5.51 nm (PDI = 0.234±0.017),zeta电位为29.833±0.503 mV。通过TEM显微镜观察纳米颗粒的形貌,纳米颗粒呈圆形,分散均匀,表明制备工艺稳定可行。毒性实验显示,EA-CS-NPs维持了80%的细胞活力,明显高于NDNB组,说明对TGF-β1刺激的MLg和NIH-3T3细胞的毒性更低,抑制作用更好。伤口愈合实验结果显示,EA- cs - nps对细胞迁移的抑制作用比相同剂量含EA药物的EA更明显。药物摄取实验显示,EA-CS-NPs显著增强MLg和NIH-3T3细胞的药物摄取。在体内,与Cy7溶液相比,Cy7- cs - nps在大鼠肺中表现出更高的荧光强度,表明肺潴留更好。体内药效试验显示,与EA组相比,EA- cs - nps能更好地缩小肺纤维化面积和胶原沉积,改善肺功能,在肺内滞留时间更长。总之,我们的研究结果表明,EA-CS-NPs可能是治疗肺纤维化的良好选择。图形抽象
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来源期刊
AAPS PharmSciTech
AAPS PharmSciTech 医学-药学
CiteScore
6.80
自引率
3.00%
发文量
264
审稿时长
2.4 months
期刊介绍: AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.
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