Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China.
Hepatobiliary 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 Transplantation, Nanjing, China.
J Nanobiotechnology. 2023 Nov 22;21(1):440. doi: 10.1186/s12951-023-02203-8.
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.
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.
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.
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.
缺氧是肿瘤微环境的一个共同特征，它参与肿瘤的进展和免疫逃逸。靶向缺氧微环境已被认为是一种有前途的抗肿瘤治疗策略。TH-302 可以在缺氧条件下选择性激活。然而，TH-302 在胃癌联合免疫治疗中的疗效尚不清楚。
我们设计了 mPEG-PLGA 包裹的 TH-302（TH-302 NPs）以靶向肿瘤组织的缺氧区域。使用颗粒分析仪测量 TH-302 NPs 的平均粒径和 zeta 电位。通过透射电子显微镜和扫描电子显微镜观察形态。使用 pimonidazole 进行免疫荧光检测来检测肿瘤组织的缺氧区域。通过流式细胞术分析测量 TNF-α、IFN-γ 和 granzyme B 的水平。体外和体内评估 TH-302 NPs 与抗 PD-1（α-PD-1）治疗联合的协同抗肿瘤活性。对主要器官进行苏木精和伊红染色和生化指标检测，以研究 TH-302 NPs 在体内的生物安全性。
TH-302 NPs 在缺氧条件下抑制胃癌细胞的增殖并促进其凋亡。体外和体内实验证实，TH-302 NPs 可有效缓解肿瘤缺氧。TH-302 NPs 具有高生物利用度、有效的肿瘤靶向能力和满意的生物安全性。此外，TH-302 NPs 与 α-PD-1 的联合使用显著提高了体内的免疫治疗效果。机制上，TH-302 NPs 降低了 HIF-1α 和 PD-L1 的表达，促进了 CD8 T 细胞的浸润，并增加了肿瘤中 TNF-α、IFN-γ 和 granzyme B 的水平，从而增强了 α-PD-1 治疗的效果。
TH-302 NPs 缓解了肿瘤缺氧微环境，增强了 PD-1 阻断的疗效。我们的结果表明，TH-302 NPs 可用作治疗胃癌的联合免疫治疗的安全有效的纳米药物。
