Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma
Yu-Ling Lin, 1,* Xiao-Fan Huang, 2, 3,* Kai-Fu Chang, 2, 3,* Kuang-Wen Liao, 4–6 Nu-Man Tsai 2, 7 1Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, Republic of China; 2Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Tai...
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| Format: | Article |
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Dove Medical Press
2020-01-01
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| Series: | International Journal of Nanomedicine |
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| Online Access: | https://www.dovepress.com/encapsulated-n-butylidenephthalide-efficiently-crosses-the-bloodndashb-peer-reviewed-article-IJN |
| _version_ | 1828975448808226816 |
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| author | Lin YL Huang XF Chang KF Liao KW Tsai NM |
| author_facet | Lin YL Huang XF Chang KF Liao KW Tsai NM |
| author_sort | Lin YL |
| collection | DOAJ |
| description | Yu-Ling Lin, 1,* Xiao-Fan Huang, 2, 3,* Kai-Fu Chang, 2, 3,* Kuang-Wen Liao, 4–6 Nu-Man Tsai 2, 7 1Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, Republic of China; 2Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, Republic of China; 3Institute of Medicine of Chung Shun Medical University, Taichung 40201, Taiwan, Republic of China; 4Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan, Republic of China; 5Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 30010, Taiwan, Republic of China; 6Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China; 7Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, Republic of China*These authors contributed equally to this workCorrespondence: Nu-Man TsaiDepartment of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung 40201, TaiwanTel +886-4-24730022 ext. 12411Fax +886-4-23248171Email numan@csmu.edu.twBackground: n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo.Methods: DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood–brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism.Results: In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G 0/G 1 phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression.Conclusion: BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.Keywords: glioblastoma, n-butylidenephthalide, blood–brain barrier, drug delivery |
| first_indexed | 2024-12-14T14:21:20Z |
| format | Article |
| id | doaj.art-d70ca8a6260647eeaed52dae7e9da38e |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-14T14:21:20Z |
| publishDate | 2020-01-01 |
| publisher | Dove Medical Press |
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| series | International Journal of Nanomedicine |
| spelling | doaj.art-d70ca8a6260647eeaed52dae7e9da38e2022-12-21T22:58:05ZengDove Medical PressInternational Journal of Nanomedicine1178-20132020-01-01Volume 1574976051497Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of GlioblastomaLin YLHuang XFChang KFLiao KWTsai NMYu-Ling Lin, 1,* Xiao-Fan Huang, 2, 3,* Kai-Fu Chang, 2, 3,* Kuang-Wen Liao, 4–6 Nu-Man Tsai 2, 7 1Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, Republic of China; 2Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, Republic of China; 3Institute of Medicine of Chung Shun Medical University, Taichung 40201, Taiwan, Republic of China; 4Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan, Republic of China; 5Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 30010, Taiwan, Republic of China; 6Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China; 7Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, Republic of China*These authors contributed equally to this workCorrespondence: Nu-Man TsaiDepartment of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung 40201, TaiwanTel +886-4-24730022 ext. 12411Fax +886-4-23248171Email numan@csmu.edu.twBackground: n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo.Methods: DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood–brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism.Results: In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G 0/G 1 phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression.Conclusion: BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.Keywords: glioblastoma, n-butylidenephthalide, blood–brain barrier, drug deliveryhttps://www.dovepress.com/encapsulated-n-butylidenephthalide-efficiently-crosses-the-bloodndashb-peer-reviewed-article-IJNglioblastoman-butylidenephthalideblood–brain barrierdrug delivery |
| spellingShingle | Lin YL Huang XF Chang KF Liao KW Tsai NM Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma International Journal of Nanomedicine glioblastoma n-butylidenephthalide blood–brain barrier drug delivery |
| title | Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma |
| title_full | Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma |
| title_fullStr | Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma |
| title_full_unstemmed | Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma |
| title_short | Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma |
| title_sort | encapsulated n butylidenephthalide efficiently crosses the blood ndash brain barrier and suppresses growth of glioblastoma |
| topic | glioblastoma n-butylidenephthalide blood–brain barrier drug delivery |
| url | https://www.dovepress.com/encapsulated-n-butylidenephthalide-efficiently-crosses-the-bloodndashb-peer-reviewed-article-IJN |
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