细胞凋亡
载脂蛋白E
癌症研究
神经球
化学
细胞生长
维莫德吉
药理学
分子生物学
生物
刺猬信号通路
生物化学
医学
内科学
信号转导
体外
内皮干细胞
疾病
成体干细胞
作者
Qiyue Wang,Virender Kumar,Lin Feng,Bharti Sethi,Don W. Coulter,Timothy R. McGuire,Ram I. Mahato
标识
DOI:10.1016/j.jconrel.2020.04.053
摘要
Treatment of medulloblastoma (MB) is challenging due to diverse genetic make-up, chemoresistance and inefficient drug transport across the blood brain barrier (BBB). Since hedgehog (Hh) signaling regulates cancer cell proliferation and tumorigenicity, Hh inhibitors have the potential to treat sonic Hh driven MB (SHH-MB), but their repeated use develops chemoresistance due to mutations in smoothened (SMO). Herein, we aimed to overcome these problems by modulating GLI transcription using JQ1, which is a small molecule BRD4 inhibitor. JQ1 inhibited HD-MB03 and DAOY cell proliferation, with the IC50 of 402 and 4220 nM, respectively. JQ1 inhibited colony formation, but increased apoptosis in HD-MB03 and DAOY cells. Western blot analysis confirmed significant inhibition of GLI1 and c-MYC protein expression in DAOY and HD-MB03 cells, respectively. JQ1 was encapsulated into apolipoprotein (ApoE) mimetic peptide decorated nanoparticles (ApoE-NPs), with the mean particle size of 64 nm and drug loading of 10% (w/w). ApoE-NPs increased JQ1 concentration in the tumor by 5 and 8 folds at 6 and 24 h after systemic administration into orthotopic MB tumor bearing NSG mice compared to non-targeted JQ1 loaded NPs. Although there was also modest increase in JQ1 delivery to the liver, there was no hepatotoxicity as evidenced by H&E staining and little increase in serum ALT and AST after treatment with JQ1 loaded ApoE-NPs. There was also significant decrease in the orthotopic MB tumor burden after systemic administration of JQ1 loaded ApoE- NPs at the dose of 10 mg/kg every 3rd day for a total of 8 injections. In conclusion, JQ1 loaded NPs have the potential to treat Group 3 and SHH driven MB in mice.
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