Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma

International Journal of Nanomedicine

关键词: glioblastoma;    n-butylidenephthalide;    blood–brain barrier;    drug delivery;   

DOI  :  

来源: DOAJ

【 摘 要 】

Yu-Ling Lin, 1,* Xiao-Fan Huang, 2, 3,* Kai-Fu Chang, 2, 3,* Kuang-Wen Liao, 4–6 Nu-Man Tsai 2, 71Agricultural 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 [phone] ext. 12411Fax [phone]Email [e-mail]: 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

【 授权许可】

Unknown