He Wenya, Li Xiaozhe, Morsch Marco, Ismail Muhammad, Liu Yanjie, Rehman Fawad Ur, Zhang Dongya, Wang Yibin, Zheng Meng, Chung Roger, Zou Yan, Shi Bingyang
Center for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
ACS Nano. 2022 Apr 26;16(4):6293-6308. doi: 10.1021/acsnano.2c00320. Epub 2022 Mar 30.
Glioblastoma (GBM) is among the most treatment-resistant solid tumors and often recurrs after resection. One of the mechanisms through which GBM escapes various treatment modalities is the overexpression of anti-apoptotic Bcl-2 family proteins (., Bcl-2, Bcl-xl, and Mcl-1) in tumor cells. Small-molecule inhibitors such as ABT-263 (ABT), which can promote mitochondrial-mediated cell apoptosis by selectively inhibiting the function of Bcl-2 and Bcl-xl, have been proven to be promising anticancer agents in clinical trials. However, the therapeutic prospects of ABT for GBM treatment are hampered by its limited blood-brain barrier (BBB) penetration, dose-dependent thrombocytopenia, and the drug resistance driven by Mcl-1, which is overexpressed in GBM cells and further upregulated upon treatment with ABT. Herein, we reported that the Mcl-1-specific inhibitor A-1210477 (A12) can act synergistically with ABT to induce potent cell apoptosis in U87 MG cells, drug-resistant U251 cells, and patient-derived GBM cancer stem cells. We further designed a biomimetic nanomedicine, based on the apolipoprotein E (ApoE) peptide-decorated red blood cell membrane and pH-sensitive dextran nanoparticles, for the brain-targeted delivery of ABT and A12. The synergistic anti-GBM effect was retained after encapsulation in the nanomedicine. Additionally, the obtained nanomedicine possessed good biocompatibility, exhibited efficient BBB penetration, and could effectively suppress tumor growth and prolong the survival time of mice bearing orthotopic GBM xenografts without inducing detectable adverse effects.
胶质母细胞瘤（GBM）是最难治疗的实体瘤之一，切除后常复发。GBM逃避各种治疗方式的机制之一是肿瘤细胞中抗凋亡Bcl-2家族蛋白（如Bcl-2、Bcl-xl和Mcl-1）的过表达。小分子抑制剂如ABT-263（ABT），可通过选择性抑制Bcl-2和Bcl-xl的功能来促进线粒体介导的细胞凋亡，在临床试验中已被证明是有前景的抗癌药物。然而，ABT用于GBM治疗的前景受到其血脑屏障（BBB）穿透有限、剂量依赖性血小板减少以及由Mcl-1驱动的耐药性的阻碍，Mcl-1在GBM细胞中过表达，在用ABT治疗后进一步上调。在此，我们报道Mcl-1特异性抑制剂A-1210477（A12）可与ABT协同作用，在U87 MG细胞、耐药U251细胞和患者来源的GBM癌症干细胞中诱导强效细胞凋亡。我们进一步设计了一种仿生纳米药物，基于载脂蛋白E（ApoE）肽修饰的红细胞膜和pH敏感的葡聚糖纳米颗粒，用于ABT和A12的脑靶向递送。包裹在纳米药物中后，协同抗GBM效应得以保留。此外，所获得的纳米药物具有良好的生物相容性，表现出高效的BBB穿透能力，可有效抑制肿瘤生长并延长原位GBM异种移植小鼠的存活时间，且不诱导可检测到的不良反应。
