药学学报, 2021, 56(10): 2650-2657
引用本文:
张国立, 肖志美, 王秀, 于翔, 方荣震, 杜丽娜, 金义光. 治疗原发性肺癌的共轭亚油酸粉雾剂研究[J]. 药学学报, 2021, 56(10): 2650-2657.
ZHANG Guo-li, XIAO Zhi-mei, WANG Xiu, YU Xiang, FANG Rong-zhen, DU Li-na, JIN Yi-guang. Dry powder inhalers of conjugated linoleic acid for the treatment of primary lung cancer[J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2650-2657.

治疗原发性肺癌的共轭亚油酸粉雾剂研究
张国立1,2,3, 肖志美1,2, 王秀3, 于翔1, 方荣震1, 杜丽娜1*, 金义光1,3*
1. 军事科学院军事医学研究院辐射医学研究所, 北京 100850;
2. 深圳善康医疗健康产业有限公司, 广东 深圳 518118;
3. 蚌埠医学院药学院, 安徽 蚌埠 233030
摘要:
共轭亚油酸(conjugated linoleic acid,CLA)是存在于人和动物体内的营养物质,具有抗肿瘤、抗动脉粥样硬化和调节免疫等功能,但其口服生物利用度低。本文制备了CLA粉雾剂(conjugated linoleic acid dry powder inhalers,CDPIs),经大鼠气管给药后治疗大鼠原发性肺癌。首先,制备CLA纳米乳,加入10%甘露醇冻干后得到CDPIs疏松白色粉末,其空气动力学粒径(aerodynamic median diameter,Da)为3.10 μm,适合肺吸入给药。用3-甲基胆蒽及NN-二甲基亚硝胺经气管喷入大鼠肺中,45天后得到原发性肺癌模型。所有动物实验经军事科学院军事医学研究院伦理委员会批准且实验均按照相关指导原则和规定进行。分别将CDPIs、吉非替尼混悬液和空白粉雾剂经气管喷入肺癌大鼠肺中。与模型组比较,吉非替尼混悬液组和CDPIs组的肿瘤结节和炎性细胞数量均明显减少,其中CDPIs组的药效优于吉非替尼混悬液组。CDPIs组CD31和NF-κB p65表达明显减少,优于吉非替尼混悬液组;CDPIs组血管内皮生长因子(vascular endothelial growth factor,VEGF)水平明显降低,与吉非替尼组治疗效果相当;CDPIs组Tunel检测表明细胞凋亡明显增多,明显优于吉非替尼混悬液组。CDPIs能直接将具有优良药理活性的药物递送至肺部肿瘤,是一种具有前景的用于肺癌治疗的肺吸入给药剂型。
关键词:    共轭亚油酸      纳米乳      粉雾剂      肺癌      吉非替尼     
Dry powder inhalers of conjugated linoleic acid for the treatment of primary lung cancer
ZHANG Guo-li1,2,3, XIAO Zhi-mei1,2, WANG Xiu3, YU Xiang1, FANG Rong-zhen1, DU Li-na1*, JIN Yi-guang1,3*
1. Institute of Radiation Medicine, Academy of Military Medicine Sciences, Academy of Military Sciences, Beijing 100850, China;
2. Shenzhen Sciencare Medical Industries Co., Ltd., Shenzhen 518118, China;
3. College of Pharmacy, Bengbu Medical University, Bengbu 233030, China
Abstract:
Conjugated linoleic acid (CLA) is a nutrient substance that exists in humans and animals. It has anti-tumor, anti-atherosclerosis, and immune-regulating functions, but its oral bioavailability is low. Conjugated linoleic acid dry powder inhalers (CDPIs) were prepared and intratracheally administered to the rats that suffered from primary lung cancer. Conjugated linoleic acid nanoemulsions were prepared first and CDPIs were with 10% mannitol after lyophilization. CDPIs are loose white powders with the aerodynamic median diameter (Da) of 3.10 μm, which were suitable for pulmonary delivery. Rats lung cancer models were established after 45 days by instilling 3-methylcholanthrene (MCA) and N,N-dimethylnitrosamine (DEN) into the rats lung once. The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and conducted in accordance with the relevant guidelines and regulations. The CDPIs, gefitinib suspension and blank DPIs were sprayed into the lungs of rats with lung cancer through the trachea. Compared with the model group, both the gefitinib suspension group and the CDPIs group showed significantly fewer tumor nodules and inflammatory cells, and the CDPIs group was better than the gefitinib suspension group. The inhibition efficiency of CDPIs on CD31 and NF-κB p65 was better than that of the gefitinib suspension group. The vascular endothelial growth factor (VEGF) level in the CDPIs group was significantly reduced, which was equivalent to that of the gefitinib suspension group. The apoptosis in the CDPIs group by Tunel tests showed a significant increase, which was significantly better than the gefitinib suspension group. Therefore, CDPIs had excellent pharmacological activity on lung cancer, which provided a model for the efficient delivery of oil therapeutic agents.
Key words:    conjugated linoleic acid    nanoemulsion    dry powder inhaler    lung cancer    gefitinib   
收稿日期: 2021-04-06
DOI: 10.16438/j.0513-4870.2021-0492
基金项目: 十三五国家科技重大专项军特药专项(2018ZX09J18104-001);蚌埠医学院联合科技攻关项目(BYLK201823).
通讯作者: 杜丽娜,Tel:86-10-66930216,E-mail:dulina@188.com;金义光,Tel:86-10-66931220,E-mail:jinyg@sina.com
Email: dulina@188.com;jinyg@sina.com
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参考文献:
[1] Liu R, Wei S, Chen J, et al. Mesenchymal stem cells in lung cancer tumor microenvironment:their biological properties, influence on tumor growth and therapeutic implications[J]. Cancer Lett, 2014, 353:145-152.
[2] Chen Y, Li J, Chen S, et al. Nab-paclitaxel in combination with cisplatin versus docetaxel plus cisplatin as first-line therapy in non-small cell lung cancer[J]. Sci Rep, 2017, 7:10760-10767.
[3] Zhang T, Wang R, Li M, et al. Comparative study of intratracheal and oral gefitinib for the treatment of primary lung cance[J]. Eur J Pharm Sci, 2020, 18:105352-105361.
[4] Hunt WT, Kamboj A, Anderson HD, et al. Protection of cortical neurons from excitotoxicity by conjugated linoleic acid[J]. J Neurochem, 2010, 115:123-130.
[5] Yuan G, Chen X, Li D. Conjugated linolenic acids and their bioactivities:a review[J]. Food Funct, 2014, 5:1360-1368.
[6] Fuke G, Nornberg JL. Systematic evaluation on the effectiveness of conjugated linoleic acid in human health[J]. Crit Rev Food Sci Nutr, 2017, 57:1-7.
[7] Dubey KKD, Sharma G, Kumar A. Conjugated linolenic acids:implication in cancer[J]. J Agric Food Chem, 2019, 67:6091-6101.
[8] Bruen R, Fitzsimons S, Belton O. Atheroprotective effects of conjugated linoleic acid[J]. Br J Clin Pharmacol, 2017, 83:46-53.
[9] Wang W, Li Q, Pan J. Inhibitory effect of conjugated linoleic acid on obesity of mice[J]. Food Sci (食品科学), 2016, 37:211-216.
[10] Villacorta L, Minarrieta L, Salvatore SR, et al. In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation[J]. Redox Biol, 2018, 15:522-531.
[11] Liu L, Miao J, Zheng Z. Review on the physiological function of conjugated linoleic acid[J]. J Food Safe Qual (食品安全质量检测学报), 2020, 11:2552-2556.
[12] Yang MY, Chan JGY, Chan HK. Pulmonary drug delivery by powder aerosols[J]. J Control Release, 2014, 193:228-240.
[13] Li M, Zhu L, Liu B, et al. Tea tree oil nanoemulsions for inhalation therapies of bacterial and fungal pneumonia[J]. Colloids Surf B Biointerf, 2016, 141:408-416.
[14] Kuzmov A, Minko T. Nanotechnology approaches for inhalation treatment of lung diseases[J]. J Control Release, 2015, 219:500-518.
[15] Zhang G, Xiao Z, Yu X, et al. Comparative study of zedoary turmeric oil and curcumol dry powder inhalers for treatment of acute lung injury[J]. Acta Pharm Sin (药学学报), 2020, 55:1312-1319.
[16] Xu C, Wang Y, Guo Z, et al. Pulmonary delivery by exploiting doxorubicin and cisplatin coloaded nanoparticles for metastatic lung cancer therapy[J]. J Control Release, 2019, 10:153-163.
[17] Cheng S, Kourmatzis A, Mekonnen T, et al. Does upper airway deformation affect drug deposition?[J]. Int J Pharm, 2019, 572:118773-118782.
[18] Jin Y, Li M. Pulmonary drugs delivery systems and progress in their applications to lung disease treatment[J]. J Int Pharm Res (国际药学研究杂志), 2015, 42:289-322.
[19] Zhang T, Chen Y, Ge Y, et al. Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers[J]. Acta Pharm Sin B, 2018, 8:440-448.
[20] Huang C, Wu Y, Huang B, et al. Formulation design, absorption mechanism and bioavailability of nanoemulsions for enhancing oral absorption of raloxifene[J]. Acta Pharm Sin (药学学报), 2018, 53:1726-1735.
[21] Zeng Y, Liu P, Yang X, et al. The dietary c9,t11-conjugated linoleic acid enriched from butter reduces breast cancer progression in vivo[J]. J Food Biochem, 2020, 44:13163-13173.
[22] Zhang M, Li M, Ge Y, et al. Liposomal melatonin dry powder inhalers for the treatment of primary lung cancer[J]. Acta Pharm Sin (药学学报), 2019, 54:555-564.
[23] Kadirareddy RH, GhantaVemuri S, Palempalli UMD. Probiotic conjugated linoleic acid mediated apoptosis in breast cancer cells by downregulation of NF-κB[J]. Asian Pac J Cancer Prev, 2016, 17:3395-3403.
[24] Ricci M, Miola M, Multari C, et al. PPARs are mediators of anti-cancer properties of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with conjugated linoleic acid[J]. Chem Biol Interact, 2018, 25:9-14.
[25] Ma N, Chang G, Huang J, et al. cis-9, trans-11-Conjugated linoleic acid exerts an anti-inflammatory effect in bovine mammary epithelial cells after Escherichia. coli stimulation through NF-κB signaling pathway[J]. J Agric Food Chem, 2018, 67:193-200.
[26] Queiroz MP, Lima MDS, Barbosa MQ, et al. Effect of conjugated linoleic acid on memory and reflex maturation in rats treated during early life[J]. Front Neurosci, 2019, 13:1-12.
[27] Haghighatdoost F, Gh BFNM. Effect of conjugated linoleic acid on blood inflammatory markers:a systematic review and meta-analysis on randomized controlled trials[J]. Eur J Clin Nutr, 2018, 72:1071-1082.
[28] Moon HS. Biological effects of conjugated linoleic acid on obesity-related cancers[J]. Chem Biol Interact, 2014, 5:189-195.
[29] Hartigh LJD. Conjugated linoleic acid effects on cancer, obesity, and atherosclerosis:a review of pre-clinical and human trials with current perspectives[J]. Nutrients, 2019, 11:370-398.
[30] Li Q, Xue F, Qu J, et al. Nano-in-micro delivery system prepared by co-axial air flow for oral delivery of conjugated linoleic acid[J]. Mar Drugs, 2018, 17:15-25.
[31] Li M, Zhang T, Zhu L, et al. Liposomal andrographolide dry powder inhalers for treatment of bacterial pneumonia via anti-inflammatory pathway[J]. Int J Pharm, 2017, 528:163-171.
[32] Hu Y, Li M, Zhang M, et al. Inhalation treatment of idiopathic pulmonary fibrosis with curcumin large porous microparticles[J]. Int J Pharm, 2018, 551:212-222.
[33] Chen H, Qi H, Shi Y. Research process on analytical methods of conjugated linoleic acids[J]. Chin J Pharm Anal (药物分析杂志), 2014, 34:1519-1523.
[34] Tan J, Wan L, Chen X, et al. Conjugated linoleic acid ameliorates high fructose-induced hyperuricemia and renal inflammation in rats via NLRP3 inflammasome and TLR4 signaling pathway[J]. Mol Nutr Food Res, 2019, 63:e1801402.
[35] Olson JM, Haas AW, Lor J, et al. A comparison of the anti-inflammatory effects of cis-9, trans-11 conjugated linoleic acid to celecoxib in the collagen-induced arthritis model[J]. Lipids, 2017, 52:151-159.
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