Nanodrug shows spatiotemporally controlled release of anti-PD-L1 antibody and STING agonist to effectively inhibit tumor progression after radiofrequency ablation. (April 2022)

• Record Type: Journal Article
• Authors: Guo, Huanling; Huang, Jinsheng; Tan, Yang; Wu, Wenxin; Huang, Tongyi; Zhang, Nan; Chen, Shuling; Zhang, Chunyang; Xie, Xiaoyan; Shuai, Xintao; Xu, Ming
• Is Part Of: Nano today. Volume 43(2022)
• Publication Date: 2022-04
• Subjects: Radiofrequency ablation -- Immune checkpoint blockade -- Stimulator of interferon gene -- Tumor microenvironment -- Nanodrug; P-LPD also named as PEG-LP@ αPD-L1/DMXAAst PEG-coating nanodrug carrying αPD-L1 and DMXAAst -- P-LP PEG-coating nanodrug carrying αPD-L1 -- P-LD PEG-coating nanodrug carrying DMXAAst -- LPD PEG-free nanodrug carrying αPD-L1 and DMXAAst -- PEG-LP@ αPD-L1/DMXAAst&Rho6G PEG-coating nanodrug carrying αPD-L1, DMXAAst, and Rho6G -- PEG-LP@ αPD-L1/ICG PEG-coating nanodrug carrying αPD-L1 and ICG -- LP@ αPD-L1/ICG PEG-free nanodrug carrying αPD-L1 and ICG -- DMXAAst 5, 6-dimethylxanthenone- 4-acetate sodium salt -- FITC fluorescein isothiocyanate -- ICG indocyanine green -- ICB immune checkpoint blockage -- CRLM colorectal cancer liver metastases -- HCC hepatocellular carcinoma -- DCs dendritic cells -- CTLs cytotoxic T lymphocytes -- αPD-L1 anti-PD-L1 antibody -- STING stimulator of interferon gene -- MMP-2 metalloproteinase-2 -- IFN-I type-I interferon -- cGAMP 2′3′-cyclic GMP-AMP -- TIME tumor immune microenvironment -- IrAEs immune-related adverse effects -- APC antigen-presenting cells. TDLNs, tumor-draining lymph nodes -- ANOVA Analysis of variance -- IHC Immunohistochemical stain -- FRET fluorescence resonance energy transfer; Nanotechnology -- Periodicals; Nanosciences -- Périodiques; 620.505
• DOI: 10.1016/j.nantod.2022.101425
• Languages: English
• ISSNs: 1748-0132

Abstract

Highlights: PD-1/PD-L1 blockade only had a temporary tumor inhibition after RFA treatment. Short-term activation of STING affecting tumor infiltration of APCs and CLTs after RFA was found. A pH and MMP-2 dual-sensitive nanodrug was developed to co-deliver α PD-L1 and STING agonist. This nanodrug elicited a robust anti-tumor immunity and long-term immune memory for durable tumor inhibition after RFA. Tumor microenvironment-responsive drug release significantly lower their immune-related adverse effects. Graphical Abstract: A pH and MMP-2 dual-sensitive nanodrug spatiotemporally releasing PD-L1 antibody and STING agonist DMXAAst was developed to elicit a robust antitumor immunity and long-term immune memory for durable inhibition tumor progression after radiofrequency ablation. ga1 Abstract: The PD-1/PD-L1 blockade failed to prolong the progression-free survival of patients after radiofrequency ablation (RFA) treatment of liver metastases from colorectal cancers. We found that the PD-1/PD-L1 immune checkpoint blockade (ICB) therapy after RFA in mice model only had a temporary inhibition of tumor progression due to the limited number of mature dendritic cells (DCs) and the insufficient tumor infiltration/activation of cytotoxic T lymphocytes (CTLs). Our study further revealed that the activation of stimulator of interferon gene (STING) affecting tumor-infiltrating DCs and CD8+ T cells was only transient after RFA of tumor. Therefore, a nanovesicle capable of releasing the anti-PD-L1 antibody ( α PD-L1) and STING agonist inside tumor in a spatiotemporally controlled manner was developed to evoke a robust anti-cancer immune response and immune memory for a long-term inhibition of tumor progression after RFA. The nanovesicle entrapping the hydrophilic STING agonist 5, 6-dimethylxanthenone-4-acetate sodium salt (DMXAAst) in its lumen and anchoring α PD-L1 via an MMP-2-sensitive peptide linker was coated with PEG layer sheddable in acidic tumor microenvironment. The nanodrug design allowed the PEG coating to block off-target interaction between α PD-L1 and PD-L1-positive normal cells in blood and normal tissues, thereby reducing the immune-related adverse effects (irAEs). A PD-L1 was firstly released in response to MMP-2 overexpressed in tumor tissue for ICB therapy, which promote the intracellular delivery of DMXAAst to activate STING in DCs. The synergistic effect of α PD-L1, DMXAAst and RFA evoked a robust anti-tumor immunity and long-term immune memory for a potent cancer therapy.