Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches
Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applica...
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| Format: | Article |
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MDPI AG
2021-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/8/1236 |
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| author | Yanqing Wang Weijuan Huang Nannan Wang Defang Ouyang Lifeng Xiao Sirui Zhang Xiaozheng Ou Tingsha He Rongmin Yu Liyan Song |
| author_facet | Yanqing Wang Weijuan Huang Nannan Wang Defang Ouyang Lifeng Xiao Sirui Zhang Xiaozheng Ou Tingsha He Rongmin Yu Liyan Song |
| author_sort | Yanqing Wang |
| collection | DOAJ |
| description | Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (<i>D</i><sub>50</sub>). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the <i>IC</i><sub>50</sub> of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate <i>T</i>/<i>C</i> of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications. |
| first_indexed | 2024-03-10T08:28:36Z |
| format | Article |
| id | doaj.art-abd14e8df26a450c977d104a413c322c |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T08:28:36Z |
| publishDate | 2021-08-01 |
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| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-abd14e8df26a450c977d104a413c322c2023-11-22T09:14:46ZengMDPI AGPharmaceutics1999-49232021-08-01138123610.3390/pharmaceutics13081236Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling ApproachesYanqing Wang0Weijuan Huang1Nannan Wang2Defang Ouyang3Lifeng Xiao4Sirui Zhang5Xiaozheng Ou6Tingsha He7Rongmin Yu8Liyan Song9Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 510632, ChinaDepartment of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, ChinaZhuhai Livzon Microsphere Technology Co., Ltd., Zhuhai 519090, ChinaBiotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 510632, ChinaDepartment of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaDepartment of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaBiotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 510632, ChinaDepartment of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaArteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (<i>D</i><sub>50</sub>). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the <i>IC</i><sub>50</sub> of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate <i>T</i>/<i>C</i> of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications.https://www.mdpi.com/1999-4923/13/8/1236arteannuin Bmicrospherepharmacokineticsantitumor activityPLGAsustained release |
| spellingShingle | Yanqing Wang Weijuan Huang Nannan Wang Defang Ouyang Lifeng Xiao Sirui Zhang Xiaozheng Ou Tingsha He Rongmin Yu Liyan Song Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches Pharmaceutics arteannuin B microsphere pharmacokinetics antitumor activity PLGA sustained release |
| title | Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches |
| title_full | Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches |
| title_fullStr | Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches |
| title_full_unstemmed | Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches |
| title_short | Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches |
| title_sort | development of arteannuin b sustained release microspheres for anti tumor therapy by integrated experimental and molecular modeling approaches |
| topic | arteannuin B microsphere pharmacokinetics antitumor activity PLGA sustained release |
| url | https://www.mdpi.com/1999-4923/13/8/1236 |
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