Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy , Sichuan University , Chengdu 610041 , P.R. China.
State Key Laboratory of Biotherapy and Center, West China Hospital and collaborative Innovation Center of Biotherapy , Sichuan University , Chengdu 610041 , P.R. China.
Nano Lett. 2019 Nov 13;19(11):8318-8332. doi: 10.1021/acs.nanolett.9b03968. Epub 2019 Oct 17.
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.
由于胶质瘤细胞的生存机制多样，包括自噬和程序性细胞死亡配体 1（PD-L1）表达的上调，靶向化疗治疗胶质瘤的效果仍然远远不够。在此，我们提出了一种联合治疗方案，基于功能化金纳米粒子（AuNPs）实现化疗、自噬抑制和 PD-L1 免疫检查点阻断。具体而言，溶酶体半胱氨酸蛋白酶（legumain）响应型 AuNPs（D&H-A-A&C）可以被动靶向脑胶质瘤部位，并响应溶酶体半胱氨酸蛋白酶形成原位聚集，从而增强阿霉素（DOX）和羟氯喹（HCQ）在脑胶质瘤部位的积累。HCQ 可以抑制 DOX 诱导的细胞保护性自噬，从而使脑胶质瘤细胞对 DOX 重新敏感。同时，抑制自噬也可以抑制脑胶质瘤干细胞形成自噬相关的血管生成拟态（VM）。体内研究表明，D&H-A-A&C 具有良好的抗脑胶质瘤作用。此外，联合使用抗 PD-L1 抗体能够中和免疫抑制的脑胶质瘤微环境，从而释放抗脑胶质瘤免疫反应。体内研究表明，D&H-A-A&C 联合抗 PD-L1 抗体可以进一步增强抗脑胶质瘤作用，并有效防止复发。该策略的有效性为开发更有效、更个性化的脑胶质瘤患者联合治疗方案提供了一个潜在途径。
