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Aggregable Nanoparticles-Enabled Chemotherapy and Autophagy Inhibition Combined with Anti-PD-L1 Antibody for Improved Glioma Treatment
journal contribution
posted on 2019-10-16, 21:18 authored by Shaobo Ruan, Rou Xie, Lin Qin, Meinan Yu, Wei Xiao, Chuan Hu, Wenqi Yu, Zhiyong Qian, Liang Ouyang, Qin He, Huile GaoGlioma 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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autophagy-related vasculogenic mimicryglioma sitecell death ligand 1HCQAggregable Nanoparticles-Enabled Chemotherapyvivo studiesDOX-induced cytoprotective autophagyresensitize glioma cellsanti-PD-L 1 antibodyGlioma Treatment Glioma treatmentAnti-PD-L 1 AntibodyVMantiglioma effectimmunosuppressed glioma microenvironment
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