Inhalable oridonin-loaded poly(lactic-co-glycolic)acid large porous microparticles for in situ treatment of primary non-small cell lung cancer

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• 作者：Lifei Zhu^a ; ^b ; ^c ; ^&dagger ; ; Miao Li^a ; ^&dagger ; ; Xiaoyan Liu^a ; Lina Du^a ; Yiguang Jin^a ; ^b ; ^{jinyg@bmi.ac.cn}
• 关键词：BSA ; bovine serum albumin ; DAB ; 3 ; 3ʹ-diaminobenzidine ; DAPI ; 4ʹ ; 6-diamidino-2-phenylindole ; DPI ; dry powder inhalation ; EGFR ; epidermal growth factor receptor ; FPF ; fine particle fraction ; HPLC ; high performance liquid chromatography ; HRP ; horseradish peroxidase ; LPMP ; large porous microparticle ; NSCLC ; non-small cell lung cancer ; PLGA ; poly(lactic-co-glycolic)acid ; PVA ; polyvinyl alcohol ; qPCR ; quantitative polymerase chain reaction ; SEM ; scanning electron microscopy ; SLF ; simulated lung fluid
• 刊名：Acta Pharmaceutica Sinica B
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：7
• 期：1
• 页码：80-90
• 全文大小：14262 K
• 卷排序：7

文摘

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glycolic)acid (PLGA) large porous microparticle (LPMP) for in situ treatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of ~10 µm, the aerodynamic diameter of the spheres was only 2.72 µm, leading to highly efficient lung deposition. In vitro studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPs via airway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGA LPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations for in situ treatment of lung cancer.