Paeonol loaded cyclodextrin metal-organic framework particles for treatment of acute lung injury via inhalation
Paeonol loaded cyclodextrin metal-organic framework particles for treatment of acute lung injury via inhalation
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DOI：
10.1016/j.ijpharm.2020.119649
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发表时间：
2020-09-25
影响因子：
5.8
通讯作者：
Zhang, Jiwen
中科院分区：
文献类型：
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作者：
Li, Haiyan;Zhu, Jie;Zhang, Jiwen
通过吸入给药可以克服与口服给药相关的水溶性差、吸收低或生物利用度低的问题。在目前的研究中，我们使用具有立方体形态和良好的空气动力学特性的可吸入颗粒大小的伽马-环糊精金属有机骨架(CD-MOF)通过干粉吸入器实现肺部靶向给药。活性天然化合物丹皮酚(PAE)被选为治疗急性肺损伤(ALI)的模型药物。将PAE负载到可吸入大小的CD-MOF颗粒中后，PAE在磷酸盐缓冲液(pH=7.4；30min内释放90%)和体内实验中迅速释放。丹皮酚与粗乳糖和细乳糖(INHALAC(R)230：INHALAC(R)400：PAE-CD-MOF=40：10：50，w/w/w)混合后，具有较高的细粒分数(FPF)(28.59%)。原子力显微镜用于评估表面粗糙度和粘附力。大鼠吸入PAE-CD-MOF干粉吸入剂后，PAE的吸收迅速(Tmax为4.0min)，绝对生物利用度高(71%)，与口服相比(C-max和绝对生物利用度分别提高6.5倍和9.3倍)，PAE的吸收和生物利用度显著提高。体内实验结果与细胞通透性研究结果一致(负载CD-MOF后，PAE的通透性较纯PAE提高约5倍)。最后，通过组织病理学检查和降低大鼠血浆中炎症因子的水平来验证吸入PAE对ALI的疗效。总体而言，吸入PAE-CD-MOF颗粒的丹皮酚肺靶向给药似乎是治疗ALI的一种有前途的给药方法。
Administration of drugs via inhalation can overcome issues related to poor water solubility, low absorption or bioavailability associated with oral administration. In the current study we used gamma-cyclodextrin metal organic frameworks (CD-MOFs) of inhalable particle sizes, with cubic morphologies and favorable aerodynamic properties to achieve targeted pulmonary drug delivery via dry powder inhalers. The active natural compound, paeonol (PAE), was chosen as a model drug for treatment of acute lung injury (ALI). After loading of PAE into CD-MOF particles of inhalable sizes, PAE was rapidly released in phosphate buffer (pH = 7.4; 90% within 30 min) and in vivo experiments. After mixing with coarse and fine lactose (Inhalac (R) 230: Inhalac (R) 400: PAE-CD-MOF = 40:10:50, w/w/w), paeonol had a high fine particle fraction (FPF) (28.59%). Atom force microscopy was used to assess surface roughness and adhesive force. In vivo inhalation of PAE-CD-MOF dry powder inhaler by rat demonstrated rapid absorption (tmax of 4.0 min) and high absolute bioavailability (71%) of PAE, highlighting significant improvements in absorption and bioavailability of PAE when compared with oral administration (C-max and absolute bioavailability increased 6.5 and 9.3 folds, respectively). Results of in vivo experiments were consistent with cellular permeability studies (after loading into CD-MOF, the permeability of PAE improved about 5 folds in comparison to the pure PAE). Finally, the efficacy of inhaled PAE for ALI was validated by histopathological examination and via reduced levels of inflammatory factors observed in rat plasma. Overall, targeted pulmonary delivery of paeonol by inhaled PAE-CD-MOF particles appears to be promising method of delivery for treatment of ALI.