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Lung-Targeting Drug Delivery System of Baicalin- Loaded

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Lung-Targeting Drug Delivery System of Baicalin- Loaded Journal name: International Journal of Nanomedicine Article Designation: Original Research Year: 2017 Volume: 12 International Journal of Nanomedicine Dovepress Running head verso: Wei et al Running head recto: Lung-targeting drug delivery system of baicalin-loaded nanoliposomes open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IJN.S119895 Open Access Full Text Article ORIGINAL RESEARCH Lung-targeting drug delivery system of baicalin- loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer Yumeng Wei1 Abstract: The present study aims to develop a kind of novel nanoliposomes for the lung-targeting Jing Liang1 delivery system of baicalin as a Chinese medicine monomer. Baicalin-loaded nanoliposomes Xiaoli Zheng2 were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded Chao Pi1 nanoliposomes had an average particle size of 131.7±11.7 nm with 0.19±0.02 polydispersity Hao Liu1 index, 82.8%±1.24% entrapment efficiency and 90.47%±0.93% of yield and sustaining drug Hongru Yang3 release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of Yonggen Zou4 baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among Yun Ye1,5 the tested organs at all time points and was significantly higher than that of its solution. For the 1 Ling Zhao targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 1Department of Pharmaceutics, 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of School of Pharmacy, Southwest targeting efficacy (T ) to (T ) of lung were increased by a factor of 14.131, 1.893, Medical University, 2Department e liposomes e injection of Biochemistry, The Institute of 3.357, and 3.470, respectively. Furthermore, the results showed that the baicalin-loaded Basic Medical Sciences, Southwest nanoliposomes did not induce lung injury. Importantly, baicalin-loaded nanoliposomes Medical University, Jiangyang District, 3Department of Oncology, The showed better antitumor therapeutic efficacy in the nude mice bearing orthotopic human lung Affiliated Hospital of Southwest cancer with the median survival time of blank liposomes (11.40±0.16 days), baicalin solution 4 Medical University, Department of (17.30±0.47 days), and baicalin-loaded nanoliposomes (25.90±0.53 days). Therefore, the lipo- Orthopedics, The Affiliated Hospital of Traditional Chinese Medicine some is a promising drug carrier with an excellent lung-targeting property and therapeutic effect of Southwest Medical University, for the treatment of lung disease, such as lung cancer. Longma Tan District, 5Department of Keywords: liposomes, biodistribution, lung-targeting drug delivery, cancer therapy, baicalin Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, People’s Republic of China Introduction According to the World Health Organization, lung cancer is the leading cause of cancer-related death.1,2 It was estimated that 1.37 million deaths were caused by lung cancer worldwide.3 Although there are some improvements in lung cancer therapy, the 5-year survival rate is as low as 15.9% for all stages combined.4 At present, Correspondence: Ling Zhao chemotherapy, surgery, and radiotherapy are the main methods for the treatment of Department of Pharmaceutics, School of lung cancer. Unfortunately, 75% of patients with lung cancer diagnosed at the first time Pharmacy, Southwest Medical University, are found to have advanced disease that is incurable and lose the chance of accepting No 3-319, Zhongshan Road, Jiangyang District, Luzhou City, Sichuan Province surgical treatment.4 Therefore, it was suggested that chemotherapy should be the most 646000, People’s Republic of China important measure in the treatment for patients with advanced stage and inoperable lung Tel/fax +86 830 316 2291 Email [email protected] cancer. However, because most of drugs in conventional dosage forms are distributed submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2017:12 251–261 251 Dovepress © 2017 Wei et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/IJN.S119895 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Wei et al Dovepress throughout the body, the treatment of lung cancer is ineffective Shanghai Toshisun Bio-Technology Co., Ltd. (Shanghai, and results in serious side effects.3 Thus, lung-targeted drug China). Matrigel was purchased from Shanghai Shenxiang delivery systems (LTDDS) have been recognized as an ideal Co., Ltd. (Shanghai, China). Citric acid (injection grade), 5 strategy for the treatment of lung cancer. carbonic acid monosodium salt (NaHCO3), Tween-80 (injec- Baicalin is 7-D-glucuronic acid 5,6-dihydroxyflavone tion grade), dehydrated alcohol, and ammonium acetate were derived from the dried root of Scutellaria baicalensis Georgi, obtained from Luzhou Juhe Chemical Co., Ltd., (Luzhou, known as radix scutellariae, a basic and key medicinal China). Acetonitrile and methanol (high-performance composition unit in the traditional Chinese medicine.6,7 liquid chromatography [HPLC] grade) were obtained from Extensive studies have shown that baicalin has strong anti- Chengdu Jinghong Co., Ltd., (Chengdu, China). In all, 0.9% tumor effects.8–10 For the treatment of lung cancer, in vitro of sodium chloride injection was supplied from the Affiliated experiments, baicalin could suppress cell proliferation of Hospital of Southwest Medical University (Luzhou, China). human lung cancer A549 and mouse Lewis lung cancer in a Ultrapure water used in this study was produced by water dose- and time-dependent behavior. In in vivo study, baicalin purification system in the laboratory. could reduce tumor growth and prolong survival period in C57BL/6 mice bearing Lewis lung carcinoma tumor and Cells and animals nude mice bearing A549 carcinoma.11 In order to improve Human lung cancer A549 cells were purchased from Cell treatment efficacy of baicalin in lung cancer, it is necessary Bank, Shanghai Institutes for Biological Sciences, Chinese to develop LTDDS for baicalin. Academy of Sciences (Shanghai, China). The cells were The LTDDS mainly include liposomes, microspheres and cultured in the Roswell Park Memorial Institute 1640 nanoparticles via intravenous route.5,12–17 From the biomedical medium containing 10% fetal bovine serum, streptomycin point of view, the liposomes composed of phospholipids and (100 μg/mL), and penicillin (100 U/mL) in a humidified 5% cholesterol are nontoxic, biocompatible, and biodegradable CO2 atmosphere at 37°C. drug carriers. Liposomes as LTDDS have been extensively New Zealand rabbits weighing 1.5–2.0 kg and Sprague studied and have attracted increasing attentions in the past Dawley rats weighing 150–200 g were provided by the few decades.12,13 To date, no studies have been reported Laboratory Animal Center of Southwest Medical University with respect to the LTDDS for baicalin. In this study, lung- (Luzhou, China). The Balb/c nude mice in the weight range targeting baicalin-loaded nanoliposomes were developed of 17–20 g were obtained from Jianyang Dashuo Biology for the first time. For in vitro evaluation, baicalin-loaded Technology Co., Ltd. (Sichuan, China). The animals were nanoliposomes were evaluated in terms of mean size, polydis- housed in a temperature- and moisture-controlled (20°C±2°C persity index (PDI), encapsulation efficiency, yield, in vitro and 55%±10%, respectively) room with a 12-h light–dark release, stability, and hemolytic study. For in vivo evalua- cycle and allowed free access to food and water. They were tion, tissue distribution and lung-targeting characterization fasted for 12 h before experiment. All procedures involving in rabbits were investigated after intravenous administration animals complied with the requirements of the National Act of baicalin-loaded nanoliposomes and its solutions as the on the Use of Experimental Animals (China). This study control. Besides, we also evaluated the potential lung injury was approved by the Southwest Medical University Animal induced by baicalin-loaded nanoliposomes in rats and inves- Ethical Experimentation Committee (No 2013002). tigated pharmacodynamics in nude mice bearing orthotopic human lung cancer for the first time. Preparation of baicalin-loaded nanoliposomes Materials and methods Baicalin-loaded nanoliposomes were prepared by the Materials effervescent dispersion technique. Briefly, baicalin, HSPC, The reference substance of baicalin used in the analysis was Tween-80, and citric acid (mass ratio =2:2:1:1, respectively) obtained from the National Institutes for Food and Drug were dissolved in ethanol. The solution was added dropwise Control of China (Beijing, China). The general baicalin was to NaHCO3 water
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