胶质瘤
自噬
体内
癌症研究
血管生成拟态
免疫系统
免疫检查点
化疗
阿霉素
免疫原性细胞死亡
化学
细胞凋亡
药理学
医学
免疫疗法
生物
癌症
免疫学
转移
生物化学
内科学
生物技术
作者
Shaobo Ruan,Rou Xie,Lin Qin,Meinan Yu,Wei Xiao,Chuan Hu,Wenqi Yu,Zhiyong Qian,Liang Ouyang,Qin He,Huile Gao
出处
期刊:Nano Letters
[American Chemical Society]
日期:2019-10-15
卷期号:19 (11): 8318-8332
被引量:150
标识
DOI:10.1021/acs.nanolett.9b03968
摘要
Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.
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