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Radiotherapy, as one of the most common strategies for clinical cancer treatment, suffers from failure due to the hypoxia, inflammation, and radiosensitivity difference of malignant tumors, side effects, and radioresistance. Heterojunction‐based radiosensitizers attract great attention to the lower excitation energy and remarkable catalytic activity as compared to typical transition metal radiosensitizers. However, the bio‐application of heterojunction radiosensitizers is in its infancy due to the challenges in structure engineering, rational energy band alignment, and ideal photogenerated carrier migration. Herein, a bimetallic metal‐organic framework (MOF)‐based heterojunction radiosensitizer is reasonably designed to enhance the radiodynamic therapeutic efficiency of Ru complex, and to activate natural killer (NK) cell‐mediated innate immune responses for promoted tumor immunotherapy. This study not only designs a novel bimetallic MOF‐based heterojunction structure but also elucidates the underlying action mechanisms in inhibiting cancer proliferation, which sheds light on the practicable design of radiosensitizers and the tumor combination treatment. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy 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. Results: Therefore, 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. Conclusion: 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 nanosystems with radiosensitizing function. [ABSTRACT FROM AUTHOR]

Radioresistance and limitation of irradiative dosage usually lead to failure in depletion of hypoxic tumors. Herein we developed multifunctional mesoporous silica nanoparticles (MSNs) as a carrier of a novel anticancer selenoamino acid (selenocystine, SeC), to achieve synergistic chemo-/radiotherapy. This multifunctional nanosystem effectively sensitizes cancer cells to X-ray radiotherapy. Conjugation of TAT cell penetrating peptide and transferrin to the surface of MSNs significantly enhances its internalization in cancer cells through receptor-mediated endocytosis. SeC@MSNs-Tf/TAT significantly enhanced X-ray-induced growth inhibition in cervical cancer cells by induction of apoptosis, mainly through death receptor-mediated extrinsic apoptotic pathway. Upon radiation, SeC@MSNs-Tf/TAT promoted intracellular ROS overproduction, which induced apoptotic cell death by affecting p53, AKT and MAPKs pathways. Furthermore, SeC@MSNs-Tf/TAT also significantly inhibited HeLa tumor growth in nude mice model through suppression of cell proliferation and induction of apoptosis. In vivo toxicity of the SeC@MSNs-Tf/TAT nanoparticles was investigated using the mouse model. The results of histological analysis revealed that, the nanoparticles did not show any obvious damage to these major organs under the experimental conditions, including heart, liver, spleen, lung and kidney. Taken together, this study demonstrates an effective and safe strategy for cancer-targeted chemo-/radiotherapy of human cancers. [ABSTRACT FROM AUTHOR]

Radiotherapy is an important therapeutic modality in the treatment of cancers. Nevertheless, the characteristics of the tumor microenvironment (TME), such as hypoxia and high glutathione (GSH), limit the efficacy of radiotherapy. Manganese-based (Mn-based) nanomaterials offer a promising prospect for sensitizing radiotherapy due to their good responsiveness to the TME. In this review, we focus on the mechanisms of radiosensitization of Mn-based nanosystems, including alleviating tumor hypoxia, increasing reactive oxygen species production, increasing GSH conversion, and promoting antitumor immunity. We further illustrate the applications of these mechanisms in cancer radiotherapy, including the development and delivery of radiosensitizers, as well as their combination with other therapeutic modalities. Finally, we summarize the application of Mn-based nanosystems as contrast agents in realizing precision therapy. Hopefully, the present review will provide new insights into the biological mechanisms of Mn-based nanosystems, as well as their applications in radiotherapy, in order to address the difficulties and challenges that remain in their clinical application in the future. [ABSTRACT FROM AUTHOR]

X-ray induced photodynamic therapy (X-ray-PDT) is a promising approach for synergistic cancer radiotherapy and development of suitable radiosensitizers is highly desired. In this paper, we propose black phosphorus/Bi 2 O 3 (BP/Bi 2 O 3 ) heterostructures as efficient and biocompatible radiosensitizers for synergistic cancer radiotherapy. The heterostructures are synthesized by growth of ultrasmall Bi 2 O 3 nanoparticles onto BP nanosheets. The Bi 2 O 3 decoration inhibits the rapid degradation of BP nanosheets by occupation of the defect sites, and the synergistic effects of BP and Bi 2 O 3 enable 1 O 2 overproduction under X-ray irradiation. This X-ray-PDT effect of the BP/Bi 2 O 3 nanosheets enhances the radiotherapy activity towards cancer cells by inducing cell apoptosis and cycle arrest. In vivo treatment of melanoma conducted on a clinical radiotherapeutic instrument demonstrates that the BP/Bi 2 O 3 sensitized radiotherapy inhibits tumor growth efficiently. Furthermore, the BP/Bi 2 O 3 nanosheets composed of biological friendly P, O, and Bi elements shows good biocompatibility in vitro and in vivo . This radiosensitizer thus has immense clinical potential for cancer therapy, and our findings reveal a general strategy to fabricate stable BP-based heterostructures for different applications. [ABSTRACT FROM AUTHOR]

Cancer radiotherapy with 125I seeds demonstrates higher long-term efficacy and fewer side effects than traditional X-ray radiotherapy owing to its low-dose and continuous radiation but is still limited by radioresistance in clinical applications. Therefore, the design and synthesis of sensitizers that could enhance the sensitivity of cancer cells to 125I seeds is of great importance for future radiotherapy. Selenium nanoparticles (SeNPs) have been found to exhibit high potential in cancer chemotherapy and as drug carriers. In this study, we found that, based on the Auger-electron effect and Compton effect of Se atoms, cancer-targeted SeNPs in combination with 125I seeds achieve synergetic effects to inhibit cancer-cell growth and colony formation through the induction of cell apoptosis and cell cycle arrest. Detailed studies on the action mechanisms reveal that the combined treatments effectively activate intracellular reactive oxygen species (ROS) overproduction to regulate p53-mediated DNA damage apoptotic signaling pathways and mitogen-activated protein kinase (MAPK) phosphorylation and to prevent the self-repair of cancer cells simultaneously. Taken together, the combination of SeNPs with 125I seeds could be further exploited as a safe and effective strategy for next-generation cancer chemo-radiotherapy in clinical applications. [ABSTRACT FROM AUTHOR]

Disrupting redox homeostasis in the tumor microenvironment (TME), like excessive H 2 O 2 , glutathione (GSH) and weak acidity, has been proved as an effective tumor therapeutic strategy. Herein, we constructed a TME-responsive nanozyme, DOX@HMSN/Mn 3 O 4 (R), with reversible Mn3+/Mn2+ transition in situ triggered by TME to perturb the intrinsic redox homeostasis and catalyze reactive oxygen species (ROS) overproduction. In addition, this nanozyme could react with excess GSH in TME to produce GSSG, resulting in the consumption of reducing agents to suppress ROS clearance. Density functional theory calculations further confirmed that the nanozyme mainly exhibited the oxidase-like activity to catalyze the formation of hydroxyl radicals from O 2 , thus strengthening the oxidation environment in the TME. Combined with radiotherapy, the high-energy X-ray could excite the outer-layer electrons in the nanozyme, forming photoelectrons that participate in the oxidase-like enzymatic reaction, thus intensifying ROS accumulation and amplifying the radio-/chemotherapeutic efficacy. [ABSTRACT FROM AUTHOR]

Resistance of cancer to radiotherapy and/or chemotherapy is one of the important reasons of clinical treatment failure and recurrence. Chemoradiation is an optional method to over-coming of radioresistance and chemoresistance. Selenium nanoparticles (SeNPs) with special chemical and physical properties, has been identified as a novel nanocarrier and therapy agent with broad-spectrum anticancer activities due to generate ROS in cells. Herein, X-ray responsive selenium nanoparticles were facilely fabricated by using PEG as surface decorator and template. This nanosystem (PEG-SeNPs) demonstrated X-ray responsive property that was attributed to its amorphous characteristic. Interestingly, the nanosystem demonstrated significant radiosensitization effects with X-ray. Specifically, co-treatment of cancer cells with PEG-SeNPs and X-ray significantly and synergistically enhanced the cells growth inhibition through induction of cell apoptosis, as evidenced by DNA fragmentation and activation of caspase-3. In the cell model, we found that internalized nanoparticles could degrade upon X-ray exposure, which further confirm the X-ray responsive property of the nanoparticles. Moreover, the nanosystem could significantly induced intracellular ROS generation in a time-dependent manner, which peaked at about 40 min and gradually decreased thereafter. As a results, ROS overproduction led to mitochondria fragmentation and the cell apoptosis. Taken together, this study provides a novel strategy for rational design and facile synthesis of chemo-radio therapeutic radiosensitization nanomaterials. [ABSTRACT FROM AUTHOR]

Radiotherapy plays an important role in treatment of cancers with low toxicity to the surrounding normal tissues. However, it still fails to eradicate hypoxic tumors due to the occurrence of radioresistance. Therefore, the search for new radiation sensitizers is of great significance. Platinum (Pt) complexes have been identified as potential radiation sensitizers to increase the sensitivity of cancer cells to radiotherapy. In the present study, we have synthesized four Pt complexes containing (2 – benzimidazole [4, 5-f] – [1, 10] phenanthroline) ligand and found that they could effectively enhance the X-ray-induced growth inhibition against A375 human melanoma cells through induction of G2/M cell cycle arrest. In contrast, they showed much lower cytotoxicity toward human normal cells. The complexes also dramatically inhibited the TrxR activity and caused intracellular ROS overproduction, due to the Auger electron effect of heavy metal element under X-ray radiation. Excessive ROS triggered DNA damage and activated downstream signaling pathways, including the phosphorylation of p53 and p38MAPK, and down-regulation of phosphorylated AKT and ERK, finally resulted in increase of radiosensitivity and inhibition of tumor reproduction. Taken together, our results suggest that the synthetic Pt complexes could be further developed as sensitizers of X-ray radiotherapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Selenadiazole derivatives could be used as an effective and low toxic sensitizer for radiotherapy. [•] Selenadiazole derivatives enhances radiation-induced growth inhibition on A375 cells through induction of G2/M arrest. [•] ROS-mediated signaling pathways play important roles in radiosensitization of selenadiazole derivatives. [Copyright &y& Elsevier]

Developing safe, effective and targeting radiosensitizers with clear action mechanisms to achieve synergistic localized cancer treatment is an important strategy for radiotherapy. Herein, we design and synthesize a ternary heteronanostructure radiosensitizer (SeAuFe-EpC) with core/satellite morphology by a simple method to realize multimodal imaging-guided cancer radiotherapy. The mechanistic studies reveal that Se incorporation could drastically improve the electrical conductivity and lower the energy barrier between the three components, resulting in more electrons transfer between Se-Au interface and migration over the heterogeneous junction of Au-Fe 3 O 4 NPs interface. This synergistic interaction enhanced the energy transfer and facilitated more excited excitons generated by SeAuFe-EpC NPs, thus promoting the transformation of 3O 2 to 1O 2 via resonance energy transfer, finally resulting in irreversible cancer cell apoptosis. Additionally, based on the X-ray attenuation ability and high NIR absorption of AuNPs and the superparamagnetism of Fe 3 O 4 , in vivo computer tomography, photoacoustic and magnetic resonance tri-modal imaging have been employed to visualize the tracking and targeting ability of the NPs. As expected, the NPs specifically accumulated in orthotopic breast tumor area and achieved synergistic anticancer efficacy, but showed no toxic side effects on main organs. Collectively, this study sheds light on the potential roles of core/satellite heteronanostructure in imaging-guided cancer radiotherapy. Image 1 • A radiosensitive core/satellite heteronanostructure has been synthesized to achieve synergistic cancer radiotherapy. • Se incorporation could enhance energy transfer and facilitate more 1O 2 generation. • The radiosensitizer enables tri-modal imaging-guided cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Although radiotherapy technology has progressed rapidly in the past decade, the inefficiency of radiation and cancer cell resistance mean that the 5-year survival rate of patients with nasopharyngeal carcinoma (NPC) is low. Radioactive 125I seed implantation has received increasing attention as a clinical treatment for cancers. Vascular endothelial growth factor-A (VEGF-A) is one of the most important members of the VEGF family and plays an important role in cell migration through the extracellular-signal-regulated kinase (ERK) pathway. Here we show that radioactive 125I seeds more effectively inhibit NPC cell growth through DNA damage and subsequent induction of apoptosis, compared with X-ray irradiation. Moreover, cell migration was effectively inhibited by 125I seed irradiation through VEGF-A/ERK inactivation. VEGF-A pretreatment significantly blocked 125I seed irradiation-induced inhibition of cell migration by recovering the levels of phosphorylated ERK (p-ERK) protein. Interestingly, in vivo study results confirmed that 125I seed irradiation was more effective in inhibiting tumor growth than X-ray irradiation. Taken together, these results suggest that radioactive 125I seeds exert novel anticancer activity by triggering DNA damage and inactivating VEGF-A/ERK signaling. Our finding provides evidence for the efficacy of 125I seeds for treating NPC patients, especially those with local recurrence. [ABSTRACT FROM AUTHOR]