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A tumor microenvironment responsive biodegradable CaCO₃/MnO₂- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy.

ABSTRACT: The low efficiency of photodynamic therapy (PDT) is caused by tumor hypoxia and the adaptive immune resistance/evasion of tumor cells, while the currently emerging immune checkpoint therapy restores the intrinsic immune capacities but can't directly attack the tumor cells. Methods: Herein we report an integrated nanoplatform that combines PDT with immunotherapy to enhance photodynamic therapeutic effects and simultaneously inhibit tumor cells resistance/evasion. To achieve this, we fabricated Mn@CaCO₃/ICG nanoparticles and loaded them with PD-L1-targeting siRNA. Results: Thanks to the protection of CaCO₃ on the loaded ICG and the oxygen produced by MnO₂, an enhanced photodynamic therapeutic effect in vitro was observed. In vivo experiments demonstrated that the nanoplatform could efficiently deliver the loaded drug to the tumor tissues and significantly improve tumor hypoxia, which further contributes to the therapeutic effect of PDT in vivo. Moreover, the synergistic benefits derived from the siRNA, which silenced the checkpoint gene PD-L1 that mediates the immune resistance/evasion, resulted in a surprising therapeutic effect to rouse the immune system. Conclusions: The combination treatment strategy has great potential to be developed as a new and robust method for enhanced PDT therapy with high efficiency and a powerful antitumor immune response based on PD-L1 blockade.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6815945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRadiotherapy is a commonly used tool in clinical practice to treat solid tumors. However, due to the unique microenvironment inside the tumor, such as high levels of GSH, overexpressed H2O2 and hypoxia, these factors can seriously affect the effectiveness of radiotherapy.ResultsTherefore, to further improve the efficiency of radiotherapy, a core-shell nanocomposite CeO2-MnO2 is designed as a novel radiosensitizer that can modulate the tumor microenvironment (TME) and thus improve the efficacy of radiation therapy. CeO2-MnO2 can act as a radiosensitizer to enhance X-ray absorption at the tumor site while triggering the response behavior associated with the tumor microenvironment. According to in vivo and in vitro experiments, the nanoparticles aggravate the killing effect on tumor cells by generating large amounts of ROS and disrupting the redox balance. In this process, the outer layer of MnO2 reacts with GSH and H2O2 in the tumor microenvironment to generate ROS and release oxygen, thus alleviating the hypoxic condition in the tumor area. Meanwhile, the manganese ions produced by degradation can enhance T1-weighted magnetic resonance imaging (MRI). In addition, CeO2-MnO2, due to its high atomic number oxide CeO2, releases a large number of electrons under the effect of radiotherapy, which further reacts with intracellular molecules to produce reactive oxygen species and enhances the killing effect on tumor cells, thus having the effect of radiotherapy sensitization. In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystem with radiosensitizing function.ConclusionIn conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystems with radiosensitizing function.

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A tumor microenvironment responsive biodegradable CaCO₃/MnO₂- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy.

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OmicsDI is part of the ELIXIR infrastructure

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A tumor microenvironment responsive biodegradable CaCO3/MnO2- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy.

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OmicsDI is part of the ELIXIR infrastructure

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A tumor microenvironment responsive biodegradable CaCO₃/MnO₂- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy.