2. Academic Validation
  3. Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer

Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer

  • J Control Release. 2024 Jul:371:470-483. doi: 10.1016/j.jconrel.2024.06.014.
Wenjia Zhang 1,  Gui Chen 1,  Ziqi Chen 2,  Xin Yang 3,  Bingchen Zhang 1,  Shengtao Wang 4,  Zibo Li 1,  Yuanyuan Yang 1,  Yifen Wu 5,  Zhigang Liu 6,  Zhiqiang Yu 7
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523058, China.
  • 2 Hong Yang, Department of Gynecology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
  • 3 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
  • 4 School of Biomedical Engineering and Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, Jiangsu 215123, China.
  • 5 Department of Oncology, Dongguan Institute of Clinical Cancer Research, Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523058, China. Electronic address: 31200195@smu.edu.cn.
  • 6 Cancer Center, Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523058, China. Electronic address: liuzhigang1983@smu.edu.cn.
  • 7 Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523058, China. Electronic address: yuzq@smu.edu.cn.
PMID: 38849094 DOI: 10.1016/j.jconrel.2024.06.014
Abstract

Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian Cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian Cancer subcutaneous model and a high-grade serous ovarian Cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian Cancer.

Keywords

Immunogenic cell death; Immunosuppressive tumor microenvironment; Mitochondrial stress; Ovarian cancer; Polyprodrug nanoparticle.

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