Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
Department of Biomedical Engineering, McCormick School of Engineering, Evanston, Illinois 60208, United States.
ACS Appl Mater Interfaces. 2020 Dec 9;12(49):54415-54425. doi: 10.1021/acsami.0c15679. Epub 2020 Nov 25.
An overlay of local ablation and immunotherapies could be one of the promising approaches to treat solid tumors, but finding the synergistic combination is still challenging with immune tolerance. Herein, electric pulse responsive iron-oxide-nanocube clusters (IONCs) loaded with indoleamine 2,3-dioxygenase inhibitors (IDOi) are prepared for the enhancement of irreversible electroporation (IRE) cell killing and modulation of the tumor immunosuppressive microenvironment (TIM). IDOi-loaded-IONCs (IDOi-IONCs) show highly responsive movement upon the application of IRE electric pulses inducing local magnetic fields. and IRE cell-killing efficiency are significantly enhanced by the IDOi-IONCs. The IRE with IDOi-IONCs also triggers IDOi release from IONCs for TIM modulation. The enhanced cell death and local IDOi release of the IRE with IDOi-IONCs demonstrate a synergistic anticancer effect with overturning the TIM. The increased infiltration of CD8 T cells and the elevated ratio of CD8 T cells to regulatory T cells are confirmed after the IRE with IDOi-IONCs. Further, synergistic interaction between IRE and IDOi-modulated TIM resulted in enhanced elimination of primary and secondary tumors. This proof-of-concept work illustrates a robust modality to guide immune-modulating nanoparticle-mediated immuno-ablation cancer therapies that can be easily tailored to improve its therapeutic outcome.
局部消融与免疫疗法的联合可能是治疗实体瘤的一种很有前途的方法，但在免疫耐受的情况下，找到协同组合仍然具有挑战性。在此，我们制备了负载吲哚胺 2,3-双加氧酶抑制剂（IDOi）的电脉冲响应氧化铁纳米立方簇（IONCs），以增强不可逆电穿孔（IRE）细胞杀伤和调节肿瘤免疫抑制微环境（TIM）。IRE 电脉冲会在肿瘤部位产生局部磁场，使负载 IDOi 的 IONCs（IDOi-IONCs）产生高响应性运动。IDOi-IONCs 显著增强了 IRE 的细胞杀伤效率。IRE 与 IDOi-IONCs 联合作用还可触发 IONCs 中 IDOi 的释放，从而调节 TIM。IRE 与 IDOi-IONCs 联合作用后，增强了细胞死亡和局部 IDOi 释放，表现出协同抗癌作用，颠覆了 TIM。IRE 与 IDOi-IONCs 联合作用后，CD8 T 细胞的浸润增加，CD8 T 细胞与调节性 T 细胞的比值升高。此外，IRE 和 IDOi 调节的 TIM 之间的协同相互作用增强了对原发性和继发性肿瘤的消除。这项概念验证工作说明了一种强大的方法来指导免疫调节纳米颗粒介导的免疫消融癌症治疗，这种方法可以很容易地进行调整，以提高其治疗效果。
