Electric Pulse Responsive Magnetic Nanoclusters Loaded with Indoleamine 2,3-Dioxygenase Inhibitor for Synergistic Immuno-Ablation Cancer Therapy

Abstract

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. In vitro and in vivo 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 in vivo 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.

Recent progress in cryoablation cancer therapy and nanoparticles mediated cryoablation

“…Particularly with the advent of immune checkpoint inhibitors, advanced MR, CT, SPECT, and PET image-guided delivery of multifunctional nanoparticles for the immuno-combination treatment can achieve higher therapeutic efficacy compared to conventional monotherapies such as ablation therapies and radiotherapies. In 2020, a novel approach combining immunotherapy with irreversible electroporation ablation reported magnetic iron oxide nanoclusters that vibrated upon an application of an electric field to release indoleamine-2,3 dioxygenase inhibitor for a synergistic immuno-ablation of tumors 179 . MRI-guided, local, sustained release of anti-PD-L1 could also be achieved by capping of mesoporous silica particles with ferumoxytol or metallic nanoparticles 180 , 181 .…”

Intratumoral Immunotherapy and Tumor Ablation: A Local Approach with Broad Potential

“…The combined treatment causes significant tumor regression and resistance to tumor rechallenge. Another novel approach by Yu et al [ 39 ] involved the use of magnetic nanoclusters loaded with an indoleamine 2,3-dioxygenase (IDO) inhibitor. IRE, when delivered after injection of the nanoclusters, induced local magnetic fields, which enhanced direct tumor destruction and triggered release of the IDO inhibitor.…”

Multifunctional Nanocarriers‐Mediated Synergistic Combination of Immune Checkpoint Inhibitor Cancer Immunotherapy and Interventional Oncology Therapy

“…Another novel approach combining IO IRE ablation and ICI immunotherapy using iron oxide nanocarriers was reported in 2020. [ 86 ] A simple overlay of IO local ablation and ICI immunotherapies often results in poor therapeutic outcomes with unexpected immune tolerance. Careful design of synergistic combination of IO local therapy is strongly required for developing a robust combinational ICI cancer immunotherapy.…”

“…Reproduced with permission. [ 86 ] Copyright 2020, American Chemical Society. b) i) Sequential chemo‐ICI cancer immunotherapy that contains aPD‐L1‐loaded UPMSNPs after a standard Cbz chemotherapy of PC.…”