Dataset Information

Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation.

ABSTRACT: Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies.

Methods

Herein, we explored a radiation-responsive nanotheranostic system to enhance RT effects on hypoxic tumors by multi-way therapeutic effects. This system was developed by loading S-nitrosothiol groups (SNO, a NO donor) and indocyanine green (ICG, a photosensitizer) onto mesoporous silica shells of Eu³⁺-doped NaGdF₄ scintillating nanocrystals (NSC).

Results

Under X-ray radiation, this system can increase the local dosage by high-Z elements, promote ROS generation by X-ray-induced photodynamic therapy, and produce high levels of NO to enhance tumor-killing effects and improve hypoxia via NO-induced vasodilation. In vitro and in vivo studies revealed that this combined strategy can greatly reinforce DNA damage and apoptosis of hypoxic tumor cells, while significantly suppressing tumor growth, improving tumor hypoxia and promoting p53 up-regulation and HIF1? down-regulation. In addition, this system showed pronounced tumor contrast performance in T₁-weighted magnetic resonance imaging and computed tomography.

Conclusion

This work demonstrates the great potential of scintillating nanotheranostics for multimodal imaging-guided X-ray radiation-triggered tumor combined therapy to overcome radioresistance.

SUBMITTER: Dou Y

PROVIDER: S-EPMC6299445 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation.

Dou Yan Y Liu Yajuan Y Zhao Fangshi F Guo Yanyan Y Li Xue X Wu Menglin M Chang Jin J Yu Chunshui C

Theranostics 20181112 21

Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies.<h4>Methods</h4>Herein, we explored a radiation-responsive nanot ...[more]

PMID: 30613268

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Project description:Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients' survival.

Project description:The acute lung injury (ALI) is an inflammatory disorder associated with cytokine storm, which activates various reactive oxygen species (ROS) signaling pathways and causes severe complications in patients as currently seen in coronavirus disease 2019 (COVID-19). There is an urgent need for medication of the inflammatory lung environment and effective delivery of drugs to lung to reduce the burden of high doses of medications and attenuate inflammatory cells and pathways. Herein, we prepared dexamethasone-loaded ROS-responsive polymer nanoparticles (PFTU@DEX NPs) by a modified emulsion approach, which achieved high loading content of DEX (11.61 %). DEX was released faster from the PFTU@DEX NPs in a ROS environment, which could scavenge excessive ROS efficiently both in vitro and in vivo. The PFTU NPs and PFTU@DEX NPs showed no hemolysis and cytotoxicity. Free DEX, PFTU NPs and PFTU@DEX NPs shifted M1 macrophages to M2 macrophages in RAW264.7 cells, and showed anti-inflammatory modulation to A549 cells in vitro. The PFTU@DEX NPs treatment significantly reduced the increased total protein concentration in BALF of ALI mice. The delivery of PFTU@DEX NPs decreased the proportion of neutrophils significantly, mitigated the cell apoptosis remarkably compared to the other groups, reduced M1 macrophages and increased M2 macrophages in vivo. Moreover, the PFTU@DEX NPs had the strongest ability to suppress the expression of NLRP3, Caspase1, and IL-1β. Therefore, the PFTU@DEX NPs could efficiently suppress inflammatory cells, ROS signaling pathways, and cell apoptosis to ameliorate LPS-induced ALI. STATEMENT OF SIGNIFICANCE: The acute lung injury (ALI) is an inflammatory disorder associated with cytokine storm, which activates various reactive oxygen species (ROS) signaling pathways and causes severe complications in patients. There is an urgent need for medication of the inflammatory lung environment and effective delivery of drugs to modulate the inflammatory disorder and suppress the expression of ROS and inflammatory cytokines. The inhaled PFTU@DEX NPs prepared through a modified nanoemulsification method suppressed the activation of NLRP3, induced the polarization of macrophage phenotype from M1 to M2, and thereby reduced the neutrophil infiltration, inhibited the release of proteins and inflammatory mediators, and thus decreased the acute lung injury in vivo.

Dataset Information

Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation.

Methods

Results

Conclusion

Publications

Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation.

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