Aggregable Nanoparticles-Enabled Chemotherapy and Autophagy Inhibition Combined with Anti-PD-L1 Antibody for Improved Glioma Treatment

Shaobo Ruan, Rou Xie, Lin Qin, Meinan Yu, Wei Xiao, Chuan Hu, Wenqi Yu, Zhiyong Qian, Liang Ouyang, Qin He, Huile Gao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

152 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8318-8332
Number of pages15
JournalNano Letters
Volume19
Issue number11
DOIs
Publication statusPublished - 13 Nov 2019
Externally publishedYes

Keywords

  • Combination therapy
  • autophagy inhibition
  • glioma
  • immune checkpoint
  • legumain responsive

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