纳米复合材料介导肝细胞生长因子基因治疗博来霉素诱导的大鼠肺纤维化。

Hepatocyte Growth Factor Delivered by Nanocomposites for Gene Therapy of Bleomycin-Induced Pulmonary Fibrosis in Rats.

机构信息

Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China.

The Second Affiliated Hospital of Xuzhou Medical University, 32 Meijian Road, Xuzhou, Jiangsu, 221006, China.

出版信息

Curr Drug Deliv. 2023;20(9):1368-1379. doi: 10.2174/1567201819666220613145417.

DOI:10.2174/1567201819666220613145417

PMID:35702802

Abstract

BACKGROUND

Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. There is no effective treatment for PF. Hepatocyte growth factor (HGF) has anti-inflammatory and antifibrotic effects but has limited potential owing to its short half-life.

METHODS

To increase the transfection efficiency of pVAX-HGF, we prepared polyethyleneiminepolyethylene glycol: polyethyleneimine/pVAX-HGF (PEG-PEI: PEI/pVAX-HGF) nanocomposite loaded with a plasmid encoding the HGF gene. The PEG-PEI:PEI/pVAX-HGF characteristics, including morphology, particle size, zeta-potential, and DNA entrapment efficiency, were investigated. The pVAX-HGF nanocomposites with low toxicity and high transfection efficiency were screened by cell viability assay and cell transfection. The antifibrotic effect of pVAX-HGF nanocomposite on PF rats induced by bleomycin (BLM) was evaluated by pulmonary function measurement, pathological examination and collagen content assay.

RESULTS

Different nanocomposites were prepared to deliver pVAX-HGF, in which mix1 (PEGPEI: PEI/pVAX-HGF) has lower potential and better entrapment ability.

PEG-PEI: PEI/pVAX-HGF (N/P=25) nanocomposite with low toxicity and high transfection efficiency was administered to PF rats. After treatment with mix 1/pVAX-HGF, the index of lung function(including EF50, MV, TV, PEF and PIF) in mix 1/pVAX-HGF group was higher than that of the PF group. The number of cells in BALF of the mix 1/pVAX-HGF group was significantly lower than that of the PF groups, and the content of hydroxyproline(HYP) and collagen Type I (Col-I) in the lung of the mix 1/pVAX-HGF group was much lower than that of the PF groups in the early stage. The result of pathological examination showed that rats in the mix1/pVAX-HGF group showed obviously reduced alveolar septal thickening, fewer infiltrated inflammatory cells and less collagen deposition.

CONCLUSION

The PEG-PEI:PEI/pVAX-HGF nanocomposite can ameliorate PF induced by BLM. The pVAX-HGF nanocomposite is a latent therapeutic strategy for PF.

摘要

背景

肺纤维化（PF）是一种慢性进行性间质性肺疾病。目前尚无有效的 PF 治疗方法。肝细胞生长因子（HGF）具有抗炎和抗纤维化作用，但由于半衰期短，其应用潜力有限。

方法

为了提高 pVAX-HGF 的转染效率，我们制备了聚乙烯亚胺-聚乙二醇：聚乙烯亚胺/pVAX-HGF（PEG-PEI：PEI/pVAX-HGF）纳米复合物，其中负载了一个编码 HGF 基因的质粒。研究了 PEG-PEI：PEI/pVAX-HGF 的特征，包括形态、粒径、Zeta 电位和 DNA 包封效率。通过细胞活力测定和细胞转染筛选出毒性低、转染效率高的 pVAX-HGF 纳米复合物。通过肺功能测定、病理检查和胶原含量测定评估 pVAX-HGF 纳米复合物对博来霉素（BLM）诱导的 PF 大鼠的抗纤维化作用。

结果

制备了不同的纳米复合物来递送 pVAX-HGF，其中 mix1（PEG-PEI：PEI/pVAX-HGF）具有较低的电位和更好的包封能力。毒性低、转染效率高的 PEG-PEI：PEI/pVAX-HGF（N/P=25）纳米复合物用于 PF 大鼠。与 mix1/pVAX-HGF 治疗后，mix1/pVAX-HGF 组的肺功能指标（包括 EF50、MV、TV、PEF 和 PIF）均高于 PF 组。mix1/pVAX-HGF 组 BALF 中的细胞数明显低于 PF 组，早期 mix1/pVAX-HGF 组肺中的羟脯氨酸（HYP）和胶原 I 型（Col-I）含量明显低于 PF 组。病理检查结果表明，mix1/pVAX-HGF 组大鼠肺泡间隔增厚明显减轻，浸润的炎性细胞减少，胶原沉积减少。