TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer

Abstract Background Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic cond...

Full description

Bibliographic Details
Main Authors: Zhixiong Wang, Menglin Zhu, Runyu Dong, Danping Cao, Yanna Li, Zhiqiang Chen, Juan Cai, Xueliang Zuo
Format: Article
Language:English
Published: BMC 2023-11-01
Series:Journal of Nanobiotechnology
Subjects:
Online Access:https://doi.org/10.1186/s12951-023-02203-8
_version_ 1797451633921097728
author Zhixiong Wang
Menglin Zhu
Runyu Dong
Danping Cao
Yanna Li
Zhiqiang Chen
Juan Cai
Xueliang Zuo
author_facet Zhixiong Wang
Menglin Zhu
Runyu Dong
Danping Cao
Yanna Li
Zhiqiang Chen
Juan Cai
Xueliang Zuo
author_sort Zhixiong Wang
collection DOAJ
description Abstract Background Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. Methods We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. Results TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. Conclusion TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.
first_indexed 2024-03-09T14:57:28Z
format Article
id doaj.art-c040308af17441519cbe11ebe65279ee
institution Directory Open Access Journal
issn 1477-3155
language English
last_indexed 2024-03-09T14:57:28Z
publishDate 2023-11-01
publisher BMC
record_format Article
series Journal of Nanobiotechnology
spelling doaj.art-c040308af17441519cbe11ebe65279ee2023-11-26T14:07:52ZengBMCJournal of Nanobiotechnology1477-31552023-11-0121111710.1186/s12951-023-02203-8TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancerZhixiong Wang0Menglin Zhu1Runyu Dong2Danping Cao3Yanna Li4Zhiqiang Chen5Juan Cai6Xueliang Zuo7Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver TransplantationAnhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical CollegeDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical CollegeAbstract Background Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. Methods We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. Results TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. Conclusion TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.https://doi.org/10.1186/s12951-023-02203-8TH-302NanodrugHypoxiaImmune escapePD-1 blockade
spellingShingle Zhixiong Wang
Menglin Zhu
Runyu Dong
Danping Cao
Yanna Li
Zhiqiang Chen
Juan Cai
Xueliang Zuo
TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
Journal of Nanobiotechnology
TH-302
Nanodrug
Hypoxia
Immune escape
PD-1 blockade
title TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
title_full TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
title_fullStr TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
title_full_unstemmed TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
title_short TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer
title_sort th 302 loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances pd 1 blockade efficacy in gastric cancer
topic TH-302
Nanodrug
Hypoxia
Immune escape
PD-1 blockade
url https://doi.org/10.1186/s12951-023-02203-8
work_keys_str_mv AT zhixiongwang th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT menglinzhu th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT runyudong th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT danpingcao th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT yannali th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT zhiqiangchen th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT juancai th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer
AT xueliangzuo th302loadednanodrugreshapesthehypoxictumourmicroenvironmentandenhancespd1blockadeefficacyingastriccancer