Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
J Nanobiotechnology. 2021 Oct 2;19(1):302. doi: 10.1186/s12951-021-01034-9.
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.
缺氧是大多数实体恶性肿瘤的固有特征，导致化疗、放疗和免疫治疗失败。抗疟药阿托伐醌通过抑制线粒体复合物 III 的活性来减轻肿瘤缺氧。本研究利用阿托伐醌/白蛋白纳米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。
我们制备了负载阿托伐醌的人血清白蛋白（HSA）纳米粒，该纳米粒由分子内二硫键稳定，称为 HSA-ATO NPs。通过粒子大小分析仪测量 HSA-ATO NPs 的平均粒径和 Zeta 电位。通过透射电子显微镜（TEM）对 HSA-ATO NPs 的形态进行了表征。通过动物实验评估 HSA-ATO NPs 的生物利用度和安全性。流式细胞术和 ELISA 检测用于评估肿瘤免疫微环境。
我们的数据首次验证了阿托伐醌通过抑制线粒体活性在体外和体内有效缓解肿瘤缺氧，并成功地将阿托伐醌包裹在白蛋白囊泡中，形成直径约为 164nm 的 HSA-ATO NPs。然后，我们证明了 HSA-ATO NPs 具有优异的生物利用度、肿瘤靶向性和良好的生物安全性。当与抗 PD-1 抗体联合使用时，我们观察到 HSA-ATO NPs 通过减轻肿瘤缺氧微环境强烈增强了荷瘤小鼠对免疫治疗的反应。从机制上讲，HSA-ATO NPs 通过减轻肿瘤缺氧微环境促进了肿瘤内 CD8 T 细胞的募集，从而增强了抗 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，通过减轻缺氧肿瘤微环境来增强癌症免疫治疗。
