Original ArticleRepolarization of myeloid derived suppressor cells via magnetic nanoparticles to promote radiotherapy for glioma treatment
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.
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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Multiple therapeutic approaches of glioblastoma multiforme: From terminal to therapy
2023, Biochimica et Biophysica Acta - Reviews on CancerTargeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy
2022, Acta Pharmaceutica Sinica BCitation Excerpt :Additionally, repolarizing MDSCs is another valid avenue. Wu et al.170 introduced a magnetic nanoparticle-based platform with polyethylenimine modification to complement the effect of radiotherapy for glioma therapy, which could manipulate the repolarization of MDSCs to a pro-inflammatory phenotype that was capable of generating a substantial amount of TNF-α and inducible nitric oxide synthase (iNOS) as well as recognizing and attacking glioma cells. As the most abundant stromal cells in TME, CAFs secret a host of regulatory factors and remodel the extracellular matrix (ECM), thus facilitating the formation of the immunosuppressive TME and tumor progression171.
C3d(g), iron nanoparticles, hemin and cytochrome c may induce oxidative cytotoxicity in tumors and reduce tumor-associated myeloid cells-mediated immunosuppression
2022, Medical HypothesesCitation Excerpt :In turn, MDSCs can also be subject to ferroptosis induction, thus activating T-cell infiltration and suppressing tumor growth [35]. IONs repolarize macrophages and MDSCs from immunosuppressive phenotype to a pro-inflammatory phenotype [36–38], thus inhibiting tumor growth [39–41,38]. IONs with adequate magnetic properties can be used for magnetic resonance imaging (MRI) and magnetically-guided delivery enhancing liposome accumulation in tumors due to the enhanced permeability and retention (EPR) effect of tumor vessels [42–44,5].
Recent advances in drug delivery and targeting to the brain
2022, Journal of Controlled ReleaseRadiosensitizing Fe-Au nanocapsules (hybridosomes®) increase survival of GL261 brain tumor-bearing mice treated by radiotherapy
2022, Nanomedicine: Nanotechnology, Biology, and MedicineCitation Excerpt :This effect is not primarily related to the increase in dose deposition, as in the case of gold, but results from the iron-catalyzed production of reactive oxygen species (ROS) via the Femton or Haber–Weiss reactions.17 More recently, it has been demonstrated that irradiated SPION target the immunosuppressive tumor environment, and re-activate the immune defense at the tumor site.45 Even if iron oxide alone shows no effect, a synergy may occur between gold and iron by combining the effect of strong dose deposition and ROS catalysis.
Cancer nanomedicine based on polyethylenimine-mediated multifunctional nanosystems
2022, Progress in Materials ScienceCitation Excerpt :In another study, Zhang et al. loaded PEI-coated Fe3O4 NPs with siRNA to sensitize glioblastoma cells for RT via knockdown of the DNA repair protein apurinic endonuclease 1 [307]. PEI-Fe3O4 NPs were also used to repolarize myeloid derived suppressor cells (MDSC) from the immunosuppressive phenotype to a pro-inflammatory phenotype for enhanced RT of glioma [308]. Monotherapy often fails to completely eradicate cancer cells and cancer recurrence occurs after treatment.
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.