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Ultrathin metal-organic layer-mediated radiotherapy-radiodynamic therapy enhances immunotherapy of metastatic cancers.

ABSTRACT: Checkpoint blockade immunotherapy (CBI) is effective in promoting a systemic immune response against some metastatic tumors. The reliance on the pre-existing immune environment of the tumor, however, limits the efficacy of CBI on a broad spectrum of cancers. Herein, we report the design of a novel nanoscale metal-organic layer (nMOL), Hf-MOL, for effective treatment of local tumors by enabling radiotherapy-radiodynamic therapy (RT-RDT) with low-dose X-rays and, when in combination with an immune checkpoint inhibitor, regression of metastatic tumors by re-activating anti-tumor immunity and inhibiting myeloid-derived suppressor cells. Owing to the reduced dimensionality, nMOLs allow facile diffusion of reactive oxygen species and exhibit superior RT-RDT effects. The synergy of Hf-MOL-enabled RT-RDT immune activation and anti-programmed death ligand 1 (anti-PD-L1) CBI led to robust abscopal effects on a series of bilateral models of colon, head and neck, and breast cancers and significant anti-metastatic effects on an orthotopic model of breast cancer.

SUBMITTER: Ni K

PROVIDER: S-EPMC7442115 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Ultrathin metal-organic layer-mediated radiotherapy-radiodynamic therapy enhances immunotherapy of metastatic cancers.

Ni Kaiyuan K Lan Guangxu G Chan Christina C Duan Xiaopin X Guo Nining N Veroneau Samuel S SS Weichselbaum Ralph R RR Lin Wenbin W

Matter 20190828 5

Checkpoint blockade immunotherapy (CBI) is effective in promoting a systemic immune response against some metastatic tumors. The reliance on the pre-existing immune environment of the tumor, however, limits the efficacy of CBI on a broad spectrum of cancers. Herein, we report the design of a novel nanoscale metal-organic layer (nMOL), Hf-MOL, for effective treatment of local tumors by enabling radiotherapy-radiodynamic therapy (RT-RDT) with low-dose X-rays and, when in combination with an immune ...[more]

PMID: 32832885

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Project description:Cancer immunotherapy, particularly checkpoint blockade immunotherapy (CBI), has revolutionized the treatment of some cancers by reactivating the antitumor immunity of hosts with durable response and manageable toxicity. However, many cancer patients with low tumor antigen exposure and immunosuppressive tumor microenvironments do not respond to CBI. A variety of methods have been investigated to reverse immunosuppressive tumor microenvironments and turn "cold" tumors "hot" with the goal of extending the therapeutic benefits of CBI to a broader population of cancer patients. Immunostimulatory adjuvant treatments, such as cancer vaccines, photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT), promote antigen presentation and T cell priming and, when used in combination with CBI, reactivate and sustain systemic antitumor immunity. Cancer vaccines directly provide tumor antigens, while immunoadjuvant therapies such as PDT, RT, RT-RDT, and CDT kill cancer cells in an immunogenic fashion to release tumor antigens in situ. Direct administration of tumor antigens or indirect intratumoral immunoadjuvant therapies as in situ cancer vaccines initiate the immuno-oncology cycle for antitumor immune response.With the rapid growth of cancer nanotechnology in the past two decades, a large number of nanoparticle platforms have been studied, and some nanomedicines have been translated into clinical trials. Nanomedicine provides a promising strategy to enhance the efficacy of immunoadjuvant therapies to potentiate cancer immunotherapy. Among these nanoparticle platforms, nanoscale metal-organic frameworks (nMOFs) have emerged as a unique class of porous hybrid nanomaterials with metal cluster secondary building units and organic linkers. With molecular modularity, structural tunability, intrinsic porosity, tunable stability, and biocompatibility, nMOFs are ideally suited for biomedical applications, particularly cancer treatments.In this Account, we present recent breakthroughs in the design of nMOFs as nanocarriers for cancer vaccine delivery and as nanosensitizers for PDT, CDT, RT, and RT-RDT. The versatility of nMOFs allows them to be fine-tuned to effectively load tumor antigens and immunoadjuvants as cancer vaccines and significantly enhance the local antitumor efficacy of PDT, RT, RT-RDT, and CDT via generation of reactive oxygen species (ROS) for in situ cancer vaccination. These nMOF-based treatments are further combined with cancer immunotherapies to elicit systemic antitumor immunity. We discuss novel strategies to enhance light tissue penetration and overcome tumor hypoxia in PDT, to increase energy deposition and ROS diffusion in RT, to combine the advantages of PDT and RT to enable RT-RDT, and to trigger CDT by hijacking aberrant metabolic processes in tumors. Loading nMOFs with small-molecule drugs such as an indoleamine 2,3-dioxygenase inhibitor, the toll-like receptor agonist imiquimod, and biomacromolecules such as CpG oligodeoxynucleotides and anti-CD47 antibody synergizes with nMOF-based radical therapies to enhance their immunotherapeutic effects. Further combination with immune checkpoint inhibitors activates systemic antitumor immune responses and elicits abscopal effects. With structural and compositional tunability, nMOFs are poised to provide a new clinically deployable nanotechnology platform to promote immunostimulatory tumor microenvironments by delivering cancer vaccines, mediating PDT, enhancing RT, enabling RT-RDT, and catalyzing CDT and potentiate cancer immunotherapy.

Dataset Information

Ultrathin metal-organic layer-mediated radiotherapy-radiodynamic therapy enhances immunotherapy of metastatic cancers.

Publications

Ultrathin metal-organic layer-mediated radiotherapy-radiodynamic therapy enhances immunotherapy of metastatic cancers.

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