Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment.
Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment.
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DOI：
10.1186/s12951-021-01034-9
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发表时间：
2021-10-02
影响因子：
10.2
通讯作者：
Hou P
中科院分区：
文献类型：
--
作者：
Wang S;Zhou X;Zeng Z;Sui M;Chen L;Feng C;Huang C;Yang Q;Ji M;Hou P
缺氧是大多数实体恶性肿瘤的固有特征，导致化疗、放疗和免疫治疗的失败。阿托伐醌是一种抗疟疾药物，可以通过抑制线粒体复合物III活性来缓解肿瘤缺氧。本研究利用阿托伐醌/白蛋白纳米颗粒来提高阿托伐醌的生物利用度和肿瘤靶向性，通过使肿瘤缺氧正常化来增强抗 PD-1 治疗的疗效。我们制备了通过分子内二硫键稳定的负载阿托伐醌的人血清白蛋白（HSA）纳米颗粒，称为HSA-ATO NP。通过粒度分析仪测量HSA-ATO NPs的平均尺寸和zeta电位。 HSA-ATO NPs 的形貌通过透射电子显微镜（TEM）进行表征。通过动物实验评估HSA-ATO NPs的生物利用度和安全性。使用流式细胞术和ELISA测定来评估肿瘤免疫微环境。我们的数据首先在体外和体内验证了阿托伐醌通过抑制线粒体活性有效缓解肿瘤缺氧，并成功地将阿托伐醌与白蛋白封装在囊泡中，形成直径约164 nm的HSA-ATO NPs。然后我们证明 HSA-ATO NP 具有优异的生物利用度、肿瘤靶向性和非常有利的生物安全性。当与抗 PD-1 抗体结合时，我们观察到 HSA-ATO NP 强烈增强了携带肿瘤异种移植物的小鼠对免疫治疗的反应。从机制上讲，HSA-ATO NPs通过缓解肿瘤缺氧微环境来促进肿瘤内CD8+ T细胞的募集，从而增强抗PD-1免疫治疗的疗效。我们的数据提供了强有力的证据，表明HSA-ATO NPs可以作为安全有效的纳米药物，通过缓解缺氧的肿瘤微环境来增强癌症免疫治疗。在线版本包含可在 10.1186/s12951-021-01034-9 获取的补充材料。
Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment. The online version contains supplementary material available at 10.1186/s12951-021-01034-9.
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影响因子：
15.9
作者：
Jayaprakash, Priyamvada;Ai, Midan;Curran, Michael A.
通讯作者：
Curran, Michael A.
影响因子：
2.5
作者：
Kim Y;Lin Q;Glazer PM;Yun Z
通讯作者：
Yun Z
影响因子：
28.2
作者：
Palazon, Asis;Martinez-Forero, Ivan;Melero, Ignacio
通讯作者：
Melero, Ignacio
影响因子：
5.8
作者：
Jiang, Liqun;Xu, Yisheng;Liu, Jianping
通讯作者：
Liu, Jianping
DOI：
10.1016/j.bbrc.2018.06.049
发表时间：
2018-10-02
影响因子：
3.1
作者：
Ke, Feng;Yu, Jinqiang;Zuo, Zhigang
通讯作者：
Zuo, Zhigang