Original Article
Repolarization of myeloid derived suppressor cells via magnetic nanoparticles to promote radiotherapy for glioma treatment

https://doi.org/10.1016/j.nano.2018.11.015Get rights and content

Abstract

Although radiotherapy has been established as a major therapeutic modality for glioma, radical new avenues are critically needed to prevent inevitable tumor recurrence. Herein, we utilized a magnetic nanoparticle-based platform with cationic polymer modification to promote radiotherapy for glioma treatment. We found that the nanoplatform induced cytotoxicity to glioma cells under radiation as well as promoting significant survival benefits in both immunocompetent and aythmic mice with glioma. Utilizing the magnetic properties of the nanoparticles, we were able to ascertain that myeloid derived suppressor cells (MDSC) were taking up nanoparticles in the brain tumor. The observed efficacy was attributed to destruction of glioma cells as well as MDSCs repolarization from immunosuppressive phenotype to a pro-inflammatory phenotype, which promoted antitumor effects and synergistically promoted radio-therapeutic effects. Our nanoparticles provide a robust dual-targeting platform for glioma radiotherapy by simultaneous eradication of tumor cells and manipulation of myeloid phenotypes in the central nervous system.

Graphical Abstract

We designed a zinc-doped iron oxide nanoparticle with cationic polymer surface as a radioenhancer that can target both cancer cells and the immunosuppressive tumor microenvironment to boost synergistic effects for radiotherapy of brain cancer. MDSCs were partially jeopardized as well as repolarized into a pro-inflammatory phenotype generating antitumor effect with the nanoparticles post radiation treatment. This platform provides a robust approach for effective glioma radiotherapy by simultaneous eradication of tumor cells and manipulation of myeloid phenotype in the central nervous system.

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Section snippets

Synthesis of MNPs (Zn0.4Fe2.6O4) and surface modification

52.61 mmol of benzyl ether and 3.78 mmol of oleic acid were added into a 50 mL three-neck, which was loaded with 0.8 mmol of iron (III) acetylacetonate and 1.2 mmol zinc(II) acetylacetonate. The mixture was exposed to the sonic machine for 30 min sonication, then it was heated to 290 °C for 30 min under an argon atmosphere and cooled to room temperature. The product was centrifuged, isolated, and dispersed in toluene. Next, a mixture of 40 μl of triethylamine, 32 mg of MNPs dispersed in 8 mL

Enhanced radio-therapeutic effects against glioma cells

In order to maximize the efficacy of the nanomaterials, metal-based nanoparticles were chosen as a radioenhancer in our design due to their good X-ray absorption.26, 27 Here, we first synthesized zinc-doped iron oxide nanoparticles abbreviated as magnetic nanoparticles (MNPs).28, 29 Through transmission electron microscopy (TEM) characterization, MNPs were 60 nm in diameter with cubic shapes (Figure 2, A). The energy-dispersive X-ray spectroscopy (EDS) analysis revealed that the composition of

Discussion

In this study, the zinc-doped iron oxide nanoplatform with dual-targeting effects was designed and synthesized for both tumor cells and the tumor microenvironment. As depicted in Figure 1, our results demonstrated that the zinc-doped iron oxide nanoparticles with PEI modification not only facilitated the internalization by glioma cells but also stimulated phenotypic changes in the tumor milieu. After intratumoral administration, in addition to the improved radio-cytotoxicity against tumor

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    Support: This work was supported by NIH Grant R35CA197725 to (M.S.L.). Y.C. thanks the support from NSFC (No. 81571803), the Thousand Talents Plan, Shanghai Municipal Education Commission Innovative Program (No.2017-01-07-00-07-E00038), Shanghai Science and International Cooperation Program (No.16410724300) and Fundamental Research Funds for the Central Universities.

    Competing interests: The authors declare no competing interests.

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