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.

Effect of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The present systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to investigate the effects of pulmonary rehabilitation in individuals with chronic obstructive pulmonary disease (COPD). METHODS: The RCTs of pulmonary rehabilitation programs published between 1999 and 2021 were retrieved from electronic databases (PubMed, Cochrane Library, and Embase). Two reviewers independently assessed the topical relevance and trial quality and extracted data for meta-analysis using the Stata software version 14.0. RESULTS: A total of 39 trials involving 2,397 participants with COPD were evaluated. We found that patients who received pulmonary rehabilitation program had significant improvement in the 6-min walk test (6MWT), St. George Respiratory Questionnaire score, and the modified British Medical Research Council score as compared to those who received usual care. Yoga and Tai Chi showed significant improvement in the forced expiratory volume (FEV1)% in 1 s predicted value. However, no significant difference was detected in the modified Borg score, forced vital capacity (FVC), and FEV1/FVC predicted value between the pulmonary rehabilitation and usual care groups. CONCLUSION: Yoga and Tai Chi showed a significant improvement in the FEV1% predicted value. Also, pulmonary rehabilitation program improved the exercise capacity, the quality of life, and dyspnoea in patients with COPD.Key messagesA total of 39 trials involving 2,397 participants with COPD were evaluated.We found that patients who received pulmonary rehabilitation program had significant improvement in the 6MWT, St. George Respiratory Questionnaire score, and the modified British Medical Research Council score as compared to those who received usual care.Yoga and Tai Chi showed significant improvement in the FEV1% predicted value.No significant difference was detected in the modified Borg score, FVC, and FEV1/FVC predicted value between the pulmonary rehabilitation and usual care groups.

Intelligent Pore Switch of Hollow Mesoporous Organosilica Nanoparticles for High Contrast Magnetic Resonance Imaging and Tumor-Specific Chemotherapy.

Hollow mesoporous organosilica nanoparticles (HMONs) are widely considered as a promising drug nanocarrier, but the loaded drugs can easily leak from HMONs, resulting in the considerably decreased drug loading capacity and increased biosafety risk. This study reports the smart use of core/shell Fe3O4/Gd2O3 (FG) hybrid nanoparticles as a gatekeeper to block the pores of HMONs, which can yield an unreported large loading content (up to 20.4%) of DOX. The conjugation of RGD dimer (R2) onto the DOX-loaded HMON with FG capping (D@HMON@FG@R2) allowed for active tumor-targeted delivery. The aggregated FG in D@HMON@FG@R2 could darken the normal tissue surrounding the tumor due to the high r2 value (253.7 mM-1 s-1) and high r2/r1 ratio (19.13), and the intratumorally released FG as a result of reducibility-triggered HMON degradation could brighten the tumor because of the high r1 value (20.1 mM-1 s-1) and low r2/r1 ratio (7.01), which contributed to high contrast magnetic resonance imaging (MRI) for guiding highly efficient tumor-specific DOX release and chemotherapy.

Early identification of neonatal mild hypoxic-ischemic encephalopathy by amide proton transfer magnetic resonance imaging: A pilot study.

PURPOSE: This study aimed to evaluate the amide proton transfer (APT) values in neonates with mild hypoxic-ischemic encephalopathy (HIE) using APT imaging. METHOD: A total of 30 full-term neonates with mild HIE (16 males and 14 females; mean postnatal age 4.2 days, age range 2-7 days) and 12 normal neonates (six males and six females; mean postnatal age 3.3 days, age range 2-5 days) underwent conventional magnetic resonance imaging and APT imaging. APT measurements were performed in multiple regions of interest (ROIs) in the brain. APT values were statistically analyzed to assess for significant differences between the mild HIE and normal neonates in different regions of the brain, and correlation with neonatal gestational age. RESULTS: In 30 neonates with mild HIE, 10% (3/30) of the HIE patients had normal conventional MRI. There were significant differences in APT values of the HIE group in bilateral caudate, bilateral thalamus, bilateral centrum semiovale and left globus pallidus/putamen (p < 0.05), and no statistical difference was observed in right globus pallidus/putamen (p = 0.051) and brainstem (p = 0.073) between the two groups. Furthermore, APT values in bilateral caudate, bilateral globus pallidus/putamen, bilateral thalamus, and brainstem regions (p < 0.05) exhibited positive linear correlations with gestational age in the control group, except for bilateral centrum semiovale (right: Pearson's r = 0.554, p = 0.062; left: Pearson's r = 0.561, p = 0.058). In the mild HIE groups, no significant correlation with gestational age was found in all regions. CONCLUSIONS: APT imaging is a feasible and useful technique with diagnostic capability for neonatal HIE.

Multifunctional NIR-responsive poly(vinylpyrrolidone)-Cu-Sb-S nanotheranostic agent for photoacoustic imaging and photothermal/photodynamic therapy.

Ternary copper-based chalcogenide nanomaterials have become rather attractive due to the near-infrared (NIR) response in cancer theranostic fields. However, it is still challenging to further improve the theranostic efficiency of these nanomaterials. Herein, Cu-Sb-S nanoparticles (NPs) around 24 nm are synthesized facilely and functionalized with poly(vinylpyrrolidone) (PVP). Under the NIR irradiation, the resultant PVP-Cu-Sb-S NPs exhibit a relatively high photothermal conversion efficiency of 53.16% and a simultaneous reactive oxygen species (ROS) generation effect. Due to these outstanding photothermal/photodynamic effects, excellent tumor ablation results can be achieved by the combination of PVP-Cu-Sb-S NPs and 808 nm NIR laser treatments without obvious side effect. In addition, they show remarkable contrast enhancement according to in vitro and in vivo photoacoustic (PA) imaging. These PVP-Cu-Sb-S NPs could be served as a multifunctional nanotheranostic agent for PA imaging, photothermal/photodynamic cancer therapy. STATEMENT OF SIGNIFICANCE: Highly theranostic efficiency ternary copper-based chalcogenide nanomaterials has not been fully developed yet. Herein we report the PVP-Cu-Sb-S nanoparticles (NPs) with relatively high photothermal efficiency, simultaneous reactive oxygen species generation effect and photoacoustic imaging capability. The photothermal conversion efficiency of PVP-Cu-Sb-S NPs is higher than most of copper-based chalcogenide nanomaterials reported before. These findings provide a new kind of ternary copper-based chalcogenide with an enhanced theranostic effect, which could be served as a promising multifunctional nanotheranostic agent in the field of biomedical application.