Tang Jing, Li Jianming, Li Guo, Zhang Haitao, Wang Ling, Li Dai, Ding Jinsong
School of Pharmaceutical Sciences, Changsha Medical University.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha.
Int J Nanomedicine. 2017 Sep 8;12:6687-6704. doi: 10.2147/IJN.S140569. eCollection 2017.
Idiopathic pulmonary fibrosis is a progressive, fatal lung disease with poor survival. The advances made in deciphering this disease have led to the approval of different antifibrotic molecules, such as pirfenidone and nintedanib. An increasing number of studies with particles (liposomes, nanoparticles [NPs], microspheres, nanopolymersomes, and nanoliposomes) modified with different functional groups have demonstrated improvement in lung-targeted drug delivery. In the present study, we prepared, characterized, and evaluated spermidine (Spd)-modified poly(lactic--glycolic acid) (PLGA) NPs as carriers for fluorofenidone (AKF) to improve the antifibrotic efficacy of this drug in the lung. Spd-AKF-PLGA NPs were prepared and functionalized by modified solvent evaporation with Spd and polyethylene glycol (PEG)-PLGA groups. The size of Spd-AKF-PLGA NPs was 172.5±4.3 nm. AKF release from NPs was shown to fit the Higuchi model. A549 cellular uptake of an Spd-coumarin (Cou)-6-PLGA NP group was found to be almost twice as high as that of the Cou-6-PLGA NP group. Free Spd and difluoromethylornithine (DFMO) were preincubated in A549 cells to prove uptake of Spd-Cou-6-PLGA NPs via a polyamine-transport system. As a result, the uptake of Spd-Cou-6-PLGA NPs significantly decreased with increased Spd concentrations in incubation. At higher Spd concentrations of 50 and 500 µM, uptake of Spd-Cou-6-PLGA NPs reduced 0.34- and 0.49-fold from that without Spd pretreatment. After pretreatment with DFMO for 36 hours, cellular uptake of Spd-Cou-6-PLGA NPs reached 1.26-fold compared to the untreated DFMO group. In a biodistribution study, the drug-targeting index of Spd-AKF-PLGA NPs in the lung was 3.62- and 4.66-fold that of AKF-PLGA NPs and AKF solution, respectively. This suggested that Spd-AKF-PLGA NPs accumulated effectively in the lung. Lung-histopathology changes and collagen deposition were observed by H&E staining and Masson staining in an efficacy study. In the Spd-AKF-PLGA NP group, damage was further improved compared to the AKF-PLGA NP group and AKF-solution group. The results indicated that Spd-AKF-PLGA NPs are able to be effective nanocarriers for anti-pulmonary fibrosis therapy.
特发性肺纤维化是一种进行性、致命的肺部疾病，生存率低。在对这种疾病的解读方面取得的进展已促使不同的抗纤维化分子获批，如吡非尼酮和尼达尼布。越来越多关于用不同官能团修饰的颗粒（脂质体、纳米颗粒 [NPs]、微球、纳米聚合物囊泡和纳米脂质体）的研究表明，肺靶向给药得到了改善。在本研究中，我们制备、表征并评估了用亚精胺（Spd）修饰的聚乳酸 - 乙醇酸共聚物（PLGA）纳米颗粒作为氟非尼酮（AKF）的载体，以提高该药物在肺部的抗纤维化疗效。通过用 Spd 和聚乙二醇（PEG）-PLGA 基团进行改良溶剂蒸发来制备并功能化 Spd-AKF-PLGA 纳米颗粒。Spd-AKF-PLGA 纳米颗粒的尺寸为 172.5±4.3 纳米。纳米颗粒中 AKF 的释放显示符合 Higuchi 模型。发现 Spd-香豆素（Cou）-6-PLGA 纳米颗粒组在 A549 细胞中的摄取量几乎是 Cou-6-PLGA 纳米颗粒组的两倍。将游离 Spd 和二氟甲基鸟氨酸（DFMO）在 A549 细胞中预孵育，以证明 Spd-Cou-6-PLGA 纳米颗粒通过多胺转运系统被摄取。结果，随着孵育中 Spd 浓度的增加，Spd-Cou-6-PLGA 纳米颗粒的摄取量显著降低。在 Spd 浓度为 50 和 500 μM 时，Spd-Cou-6-PLGA 纳米颗粒的摄取量分别比未进行 Spd 预处理时降低了 0.34 倍和 0.49 倍。在用 DFMO 预处理 36 小时后，Spd-Cou-6-PLGA 纳米颗粒的细胞摄取量相对于未处理的 DFMO 组达到了 1.26 倍。在生物分布研究中，Spd-AKF-PLGA 纳米颗粒在肺部的药物靶向指数分别是 AKF-PLGA 纳米颗粒和 AKF 溶液的 3.62 倍和 4.66 倍。这表明 Spd-AKF-PLGA 纳米颗粒在肺部有效蓄积。在一项疗效研究中，通过苏木精 - 伊红（H&E）染色和 Masson 染色观察肺组织病理学变化和胶原沉积。在 Spd-AKF-PLGA 纳米颗粒组中，与 AKF-PLGA 纳米颗粒组和 AKF 溶液组相比，损伤进一步得到改善。结果表明，Spd-AKF-PLGA 纳米颗粒能够成为抗肺纤维化治疗的有效纳米载体。
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