Nanoparticle‐Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy

• Published in: Advanced materials (Weinheim) 2019-03, Vol.31 (10), p.e1802228-n/a
• Main Authors: Chen, Qian, Chen, Jiawen, Yang, Zhijuan, Xu, Jun, Xu, Ligeng, Liang, Chao, Han, Xiao, Liu, Zhuang
• Format: Article
• Language: English
• Subjects: Antigens; Beams (radiation); Cancer; Catalase; Cell death; checkpoint blockade; Hydrogen peroxide; Hypoxia; Immunology; immunotherapy; Materials science; Metastasis; Nanoparticles; Proteins; Radiation therapy; Radiation tolerance; radiotherapy; tumor hypoxia relief; Tumors
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.201802228

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H2O2 to generate O2, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation. Radiotherapy with polylactic‐co‐glycolic acid‐R837@Cat nanoparticles is able to induce immunogenic cell death and generate tumor debris as tumor‐associated antigens, which, with the help of those adjuvant nanoparticles, can induce robust antitumor immune responses. With further combination of checkpoint blockade, such treatment effectively targets distant metastatic tumors with a strong abscopal effect, and offers a long‐term immune memory protective effect afterward.