Prodrug nanoparticles potentiate tumor chemo-immunometabolic therapy  by disturbing oxidative stress

【作者】Hongjuan Zhao, Yatong Li, Haiyu Shi, Mengya Niu, Dan Li, Zhenzhong Zhang,  Qianhua Feng, Yi Zhang, Lei Wang

【期刊名】 Journal of Controlled Release

【影响因子】 2022年: 9.776

【作者单位】 School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China

Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China

【年，卷(期)：页码】2022 (352) 909–919

【关键词】 Oxidative stress  Chemo-immunometabolic therapy  Triple-negative breast cancer  Tumor immunogenicity  Tumor microenvironment

【摘要】 Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their  concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein,  reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for  metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating  oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia  and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1  release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of  oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor  glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME).  Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor  immunogenicity and potentiate systemic immune responses through antigen processing and presentation  pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival.  Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy  strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC.

【全文链接】

https://doi.org/10.1016/j.jconrel.2022.11.011