Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Control Release. 2020 Jul 10;323:463-474. doi: 10.1016/j.jconrel.2020.04.053. Epub 2020 May 5.
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 IC 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.
由于髓母细胞瘤（MB）的遗传构成多样、化疗耐药性和血脑屏障（BBB）内药物转运效率低下，其治疗极具挑战性。由于 hedgehog（Hh）信号通路调节癌细胞增殖和肿瘤发生，Hh 抑制剂具有治疗 sonic Hh 驱动的 MB（SHH-MB）的潜力，但由于 smoothened（SMO）的突变，它们的重复使用会产生耐药性。在此，我们旨在通过使用小分子 BRD4 抑制剂 JQ1 来调节 GLI 转录，从而克服这些问题。JQ1 抑制 HD-MB03 和 DAOY 细胞增殖，IC 分别为 402 和 4220 nM。JQ1 抑制集落形成，但增加 HD-MB03 和 DAOY 细胞的凋亡。Western blot 分析证实，JQ1 分别显著抑制 DAOY 和 HD-MB03 细胞中 GLI1 和 c-MYC 蛋白的表达。JQ1 被包裹在载脂蛋白（ApoE）模拟肽修饰的纳米颗粒（ApoE-NPs）中，平均粒径为 64nm，载药量为 10%（w/w）。与非靶向载 JQ1 的 NPs 相比，ApoE-NPs 在荷 MB 肿瘤的 NSG 小鼠经系统给药后 6 和 24 小时，肿瘤内 JQ1 浓度分别增加了 5 倍和 8 倍。尽管 JQ1 递送至肝脏也有适度增加，但肝毒性不明显，H&E 染色和 JQ1 负载的 ApoE-NPs 治疗后血清 ALT 和 AST 略有增加。JQ1 负载的 ApoE-NPs 以 10mg/kg 的剂量每 3 天给药一次，共给药 8 次，系统给药后，原位 MB 肿瘤负担也显著降低。总之，JQ1 负载的 NPs 有可能治疗小鼠的 3 组和 SHH 驱动的 MB。
