Tumor Oxygenation and Hypoxia Inducible Factor-1 Functional Inhibition via a Reactive Oxygen Species Responsive Nanoplatform for Enhancing Radiation Therapy and Abscopal Effects

Abstract

Hypoxia, and hypoxia inducible factor-1 (HIF-1), can induce tumor resistance to radiation therapy. To overcome hypoxia-induced radiation resistance, recent studies have described nanosystems to improve tumor oxygenation for immobilizing DNA damage and simultaneously initiate oxygen-dependent HIF-1α degradation. However, HIF-1α degradation is incomplete during tumor oxygenation treatment alone. Therefore, tumor oxygenation combined with residual HIF-1 functional inhibition is crucial to optimizing therapeutic outcomes of radiotherapy. Here, a reactive oxygen species (ROS) responsive nanoplatform is reported to successfully add up tumor oxygenation and HIF-1 functional inhibition. This ROS responsive nanoplatform, based on manganese dioxide (MnO) nanoparticles, delivers the HIF-1 inhibitor acriflavine and other hydrophilic cationic drugs to tumor tissues. After reacting with overexpressed hydrogen peroxide (HO) within tumor tissues, Mn and oxygen molecules are released for magnetic resonance imaging and tumor oxygenation, respectively. Cooperating with the HIF-1 functional inhibition, the expression of tumor invasion-related signaling molecules (VEGF, MMP-9) is obviously decreased to reduce the risk of metastasis. Furthermore, the nanoplatform could relieve T-cell exhaustion via downregulation of PD-L1, whose effects are similar to the checkpoint inhibitor PD-L1 antibody, and subsequently activates tumor-specific immune responses against abscopal tumors. These therapeutic benefits including increased X-ray-induced damage, downregulated resistance, and T-cell exhaustion related proteins expression achieved synergistically the optimal inhibition of tumor growth. Overall, this designed ROS responsive nanoplatform is of great potential in the sensitization of radiation for combating primary and metastatic tumors.

Manganese Oxide Nanomaterials: Synthesis, Properties, and Theranostic Applications

“…Recently, Meng et al successfully encapsulated a potent hypoxia inducible factor 1 (HIF‐1) functional inhibitor acriflavine (ACF) into MnO 2 NPs (ACF@MnO 2 ) for enhanced RT through the combined strategy of tumor oxygenation and HIF‐1 functional inhibition ( Figure a) . Interestingly, except for raised therapeutic effects, the authors also found this nanoplatform could reduce the risk of metastasis by reducing tumor invasion‐related signaling molecules (VEGF, MMP‐9).…”

“…* p < 0.05; ** p < 0.01; *** p < 0.001, NS represented nonsignificance. Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…It is worth mentioning that few research reported that MnO 2 processes glucose oxidase (GOx)‐like activity and is promising for starvation therapy directly . Last but not least, MONs are hopeful to boost immunotherapy by multifarious routes, such as O 2 ‐instructed PDT‐induced immunogenic cell death (ICD), O 2 ‐mediated RT‐guided downregulation of PD‐L1 and hypoxia‐regulated polarization of tumor‐associated macrophages (TAM) . In short, MONs are like universal therapeutic agents for tumor therapy.…”

Immunomodulatory Nanosystems

“…Reproduced with permission [163]. A) Mechanism of ACF-MnO 2 NPs eliminating primary and abscopal tumors by tumor oxygenation and HIF-1 dysfunction.…”

Artificial Red Blood Cells Constructed by Replacing Heme with Perfluorodecalin for Hypoxia‐Induced Radioresistance

“…HIF-1α staining further showed that nnRBCs helped to reverse the tumor hypoxia (Figure 3a,b). For genes in downstream of HIF-1, including P-glycoprotein (P-gp), glucose transporter (GLUT-1), matrix metalloproteinase 9 (MMP-9), and vascular endothelial growth factor (VEGF), [40] Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) Because HIF-1α was induced in hypoxia-associated tumors, immunoblots for HIF-1α were conducted to confirm hypoxia remission by nnRBCs in CT26 tumors (Figure 3e,f, Figure S8, Supporting Information).…”