Proton pump inhibitor-enhanced nanocatalytic ferroptosis induction for stimuli-responsive dual-modal molecular imaging guided cancer radiosensitization.

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H+-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular ß-D-glucose for H2O2 self-supply and generation of additional cytoplasm H+. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. STATEMENT OF SIGNIFICANCE: The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H2O2 self-supply and addition of cytoplasm H+ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H+-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.

Functionalized Au@Cu-Sb-S Nanoparticles for Spectral CT/Photoacoustic Imaging-Guided Synergetic Photo-Radiotherapy in Breast Cancer.

BACKGROUND: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research. METHODS: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies. RESULTS: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy). CONCLUSION: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.

[Anti-injury effect of hydrogen-enriched water in a rat model of liver injury induced by aflatoxin B1].

The purpose of this study was to investigate the anti-injury effect and protective mechanism of hydrogen-enriched water in a rat model of acute liver injury induced by aflatoxin B1 (AFB1). Healthy male Sprague-Dawley (SD) rats were randomly divided into control group, model group (AFB1 group) and hydrogen-enriched water treatment group (AFB1+H2 group). The rat model of acute liver injury induced by AFB1 was established by single intragastric administration of AFB1 (2.0 mg/kg), and then the rats were treated with hydrogen-enriched water intragastrically. HE staining was used to observe the pathological changes of liver tissue. Blood samples were taken from vena cava to measure serum liver function indexes. Live tissue was sampled to detect malondialdehyde (MDA) and reduced glutathione (GSH) contents. Western blot was used to detect phosphorylation levels of MAPK signaling pathway proteins (ERK, JNK and p38 MAPK). The results showed that, compared with the AFB1 group, the AFB1+H2 group exhibited increased body weights, alleviated acute liver injury, decreased activities of serum glutamic-pyruvic transaminase and glutamic oxaloacetic transaminase, as well as total bilirubin level in the serum. Meanwhile, hydrogen-enriched water decreased MDA content and increased GSH content in liver tissue. AFB1-increased phosphorylation levels of ERK, JNK and p38 MAPK in liver tissue were down-regulated significantly by hydrogen-enriched water treatment. These results suggest that hydrogen-enriched water can alleviate liver injury induced by AFB1, and its mechanism may be related to the reduction of oxidative stress and the inhibition of MAPK signal transduction pathway activation.