Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, Republic of China.
Int J Nanomedicine. 2020 Jan 31;15:749-760. doi: 10.2147/IJN.S235815. eCollection 2020.
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.
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.
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/G 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.
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.
丁烯基苯酞（BP）对神经胶质瘤有抗肿瘤作用。然而，BP 用于临床应用的局限性在于其不稳定的结构。已开发出一种带正电荷的脂质体聚乙烯亚胺（PEI）和聚乙二醇（PEG）复合物（LPPC）来包裹 BP，以保护药物结构。本研究旨在探讨 BP/LPPC 复合物对体外和体内神经胶质瘤的抗癌作用。
用 BP 和 BP/LPPC 处理携带 DBTRG-05MG 肿瘤的异种移植小鼠，然后测量其肿瘤大小、生存情况和药物生物分布。还对携带 RG2 肿瘤的 F344 大鼠用 BP 和 BP/LPPC 进行治疗，然后通过磁共振成像评估血脑屏障（BBB）的通透性和药物治疗效果。在体外用 BP/LPPC 处理后，分析细胞摄取、细胞周期和凋亡调节因子，以评估治疗机制。
在无胸腺小鼠中，BP/LPPC 能有效抑制肿瘤生长并延长生存时间。在 F334 大鼠中，BP/LPPC 能穿过 BBB 并导致肿瘤缩小。BP/LPPC 促进细胞周期停滞在 G0/G1 期，并触发细胞外和细胞内凋亡途径，导致细胞死亡。BP/LPPC 还能有效抑制 VEGF、VEGFR1、VEGFR2、MMP2 和 MMP9 的表达。
BP/LPPC 能快速有效地穿过 BBB 进入肿瘤区域，并在体外和体内诱导细胞凋亡、抗血管生成和抗转移作用。
