Encapsulated n-butylidenephthalide efficiently crosses the blood–brain barrier and suppresses growth of glioblastoma

Yu Ling Lin, Xiao Fan Huang, Kai Fu Chang, Kuang Wen Liao, Nu Man Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: 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 G0 /G1 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.

Original languageEnglish
Pages (from-to)749-760
Number of pages12
JournalInternational Journal of Nanomedicine
StatePublished - 31 Jan 2020


  • Blood
  • Brain barrier
  • Drug delivery
  • Glioblastoma
  • N-butylidenephthalide

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