Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma.

Background: The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin's lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling. Methods: Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107. Results: We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells. Conclusions: Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials. Funding: Yang's laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).

Associations between underlying diseases with COVID-19 and its symptoms among adults: a cross-sectional study.

Background: Specific underlying diseases were reported to be associated with severe COVID-19 outcomes, but little is known about their combined associations. The study was aimed to assess the relations of number of and specific underlying diseases to COVID-19, severe symptoms, loss of smell, and loss of taste. Methods: A total of 28,204 adult participants in the National Health Interview Survey 2021 were included. Underlying diseases (including cardiovascular diseases, cancer, endocrine diseases, respiratory diseases, neuropsychiatric diseases, liver and kidney diseases, fatigue syndrome, and sensory impairments), the history of COVID-19, and its symptoms were self-reported by structured questionnaires. Multivariable logistic regression models were used to assess the combined relation of total number of underlying diseases to COVID-19 and its symptoms, while mutually adjusted logistic models were used to examine their independent associations. Results: Among the 28,204 participants (mean ± standard deviation: 48.2 ± 18.5 years), each additional underlying disease was related to 33, 20, 37, and 39% higher odds of COVID-19 (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.29-1.37), severe symptoms (OR: 1.20, 95% CI: 1.12-1.29), loss of smell (OR: 1.37, 95% CI: 1.29-1.46), and loss of taste (OR: 1.39, 95% CI: 1.31-1.49). In addition, independent associations of sensory impairments with COVID-19 (OR: 3.73, 95% CI: 3.44-4.05), severe symptoms (OR: 1.37, 95% CI: 1.13-1.67), loss of smell (OR: 8.17, 95% CI: 6.86-9.76), and loss of taste (OR: 6.13, 95% CI: 5.19-7.25), cardiovascular diseases with COVID-19 (OR: 1.13, 95% CI: 1.03-1.24), neuropsychiatric diseases with severe symptoms (OR: 1.41, 95% CI: 1.15-1.74), and endocrine diseases with loss of taste (OR: 1.28, 95% CI: 1.05-1.56) were observed. Conclusion: A larger number of underlying diseases were related to higher odds of COVID-19, severe symptoms, loss of smell, and loss of taste in a dose-response manner. Specific underlying diseases might be individually associated with COVID-19 and its symptoms.

Tumor microenvironment responsive Mn3O4 nanoplatform for in vivo real-time monitoring of drug resistance and photothermal/chemodynamic synergistic therapy of gastric cancer.

BACKGROUND: Postoperative chemotherapy for gastric cancer often causes multidrug resistance (MDR), which has serious consequences for therapeutic effects. Individualized treatment based on accurate monitoring of MDR will greatly improve patient survival. RESULTS: In this article, a self-enhanced Mn3O4 nanoplatform (MPG NPs) was established, which can react with glutathione to produce Mn2+ to enhance T1-weighted magnetic resonance imaging (MRI) and mediate in vivo real-time MDR monitoring. In vitro MRI results showed that MRI signals could be enhanced in the presence of hydrogen peroxide and glutathione and at acidic pH. In vivo MRI results indicated that MPG NPs could specifically target MDR cells, thereby realizing real-time monitoring of MDR in gastric cancer. Furthermore, MPG NPs have good chemodynamic activity, which can convert the endogenous hydrogen peroxide of tumor cells into highly toxic hydroxyl radical through Fenton-like reaction at acidic pH to play the role of chemodynamic therapy. In addition, Mn3O4 can significantly enhance the chemodynamic therapy effect because of its good photothermal conversion effect. Furthermore, in situ photothermal/chemodynamic synergistic therapy obtained remarkable results, the tumors of the mice in the synergistic therapy group gradually became smaller or even disappeared. CONCLUSIONS: MPG NPs have good biocompatibility, providing a good nanoplatform for real-time monitoring and precise diagnosis and treatment of MDR in gastric cancer.

DNA Origami-Anthraquinone Hybrid Nanostructures for In Vivo Quantitative Monitoring of the Progression of Tumor Hypoxia Affected by Chemotherapy.

Hypoxia is a well-known feature of malignant solid tumors. To explain the misinterpretation of tumor hypoxia variation during chemotherapy, we developed a DNA origami-based theranostic nanoplatform with an intercalated anticancer anthraquinone as both the chemotherapeutic drug and the photoacoustic contrast agent. The size distribution of the DNA origami nanostructure is 44.5 ± 2.3 nm, whereas the encapsulation efficiency of the drug is 90.7 ± 1.0%, and the drug loading content is 92.2 ± 0.1%. The controlled cumulative release rates were measured in vitro, showing an acidic environment induced rapid drug release. The values of free energy of binding between the drugs and the DNA double helix were calculated through molecular simulations. The cell viability assay was used to characterize cytotoxicity, and fluorescence confocal cell imaging illustrates the biodistribution of the probe in vitro. Photoacoustic and fluorescence imaging were used to indicate drug delivery, release, and biodistribution to predict the drug's chemotherapeutic effect in vivo, whereas the photoacoustic signals were compared with those of deoxygenated/oxygenated hemoglobin to represent the tissue hypoxia/normoxia maps during the chemotherapeutic process and indicate alleviated tumor hypoxia. Staining of tissue sections taken from organs and tumors was used to verify the results of photoacoustic imaging. Our results suggest that photoacoustic imaging can visualize this DNA origami-based theranostic nanoplatform and reveal the mechanisms of chemotherapy on tumor hypoxia.

Hyaluronic acid functionalized biodegradable mesoporous silica nanocomposites for efficient photothermal and chemotherapy in breast cancer.

Chemotherapy is one of conventional treatment methods for breast cancer, but drug toxicity and side effects have severely limited its clinical applications. Photothermal therapy has emerged as a promising method that, upon combination with chemotherapy, can better treat breast cancer. In this context, a biodegradable mesoporous silica nanoparticle (bMSN NPs) system was developed for loading doxorubicin (DOX) and IR780, to be potentially applied in the treatment of breast cancer. IR780 is encapsulated in the pores of bMSN NPs by hydrophobic adsorption, while DOX is adsorbed on the surface of the bMSN NPs by hyaluronic acid electrostatically, to form the bMID NPs. Transmission electron microscopy, fluorescence spectrum and UV absorption spectrum are used to prove the successful encapsulation of IR780 and the loading of DOX. In vitro experiments have shown bMID NPs present an excellent therapeutic effect on breast cancer cells. In vivo fluorescence imaging results have indicated that bMID NPs can accumulate in tumor sites gradually and achieve in vivo long-term circulation and continuous drug release. Furthermore, bMID NPs have provided obvious antitumor effects in breast cancer mouse models, thus evolving as an efficient platform for breast cancer therapy.

Construction of Biocompatible Dual-Drug Loaded Complicated Nanoparticles for in vivo Improvement of Synergistic Chemotherapy in Esophageal Cancer.

Combination chemotherapy is a routine treatment for esophageal cancer, but some shortcomings, such as drug toxicity and side effects, greatly limit the clinical application of combination therapy. To overcome these shortcomings, we have developed a mesoporous silica nanoparticle system that was used to load doxorubicin and ß-elemene. ß-elemene was encapsulated in the pore of mesoporous silica nanoparticle and doxorubicin was electrostatically adsorbed on the surface of mesoporous silica nanoparticle by hyaluronic acid to construct dual drugs synergistic nanoparticles (bMED NPs, ~77.15 nm). In vitro studies demonstrated that bMED NPs had a good treatment effect in esophageal cancer cell lines. In vivo fluorescence imaging results demonstrated that bMED NPs could accumulate in tumor sites and achieve in vivo long-term circulation and continuous drug release. In addition, bMED NPs exhibited significant antitumor effects in the esophageal cancer mouse model, which may provide a great platform for esophageal cancer chemotherapy.

The Antitumor Effects of Britanin on Hepatocellular Carcinoma Cells and its Real-Time Evaluation by In Vivo Bioluminescence Imaging.

BACKGROUND: Hepatocellular carcinoma is cancer with many new cases and the highest mortality rate. Chemotherapy is the most commonly used method for the clinical treatment of hepatocellular carcinoma. Natural products have become clinically important chemotherapeutic drugs due to their great potential for pharmacological development. Many sesquiterpene lactone compounds have been proven to have antitumor effects on hepatocellular carcinoma. OBJECTIVE: Britanin is a sesquiterpene lactone compound that can be considered for the treatment of hepatocellular carcinoma. The present study aimed to investigate the antitumor effect of britanin. METHODS: BEL 7402 and HepG2 cells were used to study the cytotoxicity and antitumor effects of britanin. Preliminary studies on the nuclear factor kappa B pathway were conducted by western blot analysis. A BEL 7402-luc subcutaneous tumor model was established for the in vivo antitumor studies of britanin. In vivo bioluminescence imaging was conducted to monitor changes in tumor size. RESULTS: The results of the cytotoxicity analysis showed that the IC50 values for britanin in BEL 7402 and HepG2 cells were 2.702µM and 6.006µM, respectively. The results of the colony formation demonstrated that the number of cells in a colony was reduced significantly after britanin treatment. And the results of transwell migration assays showed that the migration ability of tumor cells was significantly weakened after treatment with britanin. Tumor size measurements and staining results showed that tumor size was inhibited after britanin treatment. The western blot analysis results showed the inhibition of p65 protein expression and reduced the ratio of Bcl-2/Bax after treatment. CONCLUSION: A series of in vitro and in vivo experiments demonstrated that britanin had good antitumor effects and provided an option for hepatocellular carcinoma treatment.

A photo-triggered conjugation approach for attaching RGD ligands to biodegradable mesoporous silica nanoparticles for the tumor fluorescent imaging.

Fluorescent probes conjugated to peptide or antibody directing groups, which exhibit high signal to background ratios, have been widely used to image tumors and monitor their growth. A photo-triggered cycloaddition reaction between the arginine-glycine-aspartic acid -N-ɛ-acryllysine (RGD-Acrk) peptides and the tetrazole compounds bound to the surface of biodegradable mesoporous silica nanoparticles (bMSN) has been used to construct a fluorescent nanoprobe (bMSN@T2-RGD-Acrk), which showed fluorescent emission at 550 nm and could selectively image the 4T1 cells and breast cancer. This means that the bMSN@T2-RGD-Acrk nanoprobe made by photo-triggered conjugation approach is a promising fluorescent imaging agent for visualizing tumors. Thus, the photo-triggered one-spot reaction can give a stable crosslinker in a biocompatible manner for bioconjugation with nanoparticles and produce a fluorescent group that is suitable for imaging in vivo.

Novel vinyl-modified RGD conjugated silica nanoparticles based on photo click chemistry for in vivo prostate cancer targeted fluorescence imaging.

Molecular imaging is a powerful tool for non-invasive visualization of tumors that plays an important role in their diagnosis and treatment. The specificity of molecular imaging probes for cancer cells is important for accurate tumor visualization, with antibody and polypeptide nanoprobe conjugates having often been used as targeting agents for tumor detection. However, many traditional chemical conjugation methods employ complex conjugation reactions that result in poor efficiency and poor bioactivity. Herein, we describe the use of photo click methodology for the rapid synthesis of nanoprobes comprised of silica nanoparticles functionalized with RGD targeting units (SiO2@T1-RGDk NPs) (∼80 nm) for in vivo prostate cancer fluorescent imaging applications. These SiO2@T1-RGDk NPs exhibit a maximum absorption wavelength of 380 nm in their UV absorption spectra with a maximum fluorescence emission wavelength of 550 nm. Confocal immunofluorescent imaging reveal that SiO2@T1-RGDk NPs exhibit excellent targeting ability for visualizing cancer cells, with in vivo fluorescence imaging intensity in a subcutaneous tumor model of prostate cancer reaching a maxima after 4 h. Biosafety assessments showed that SiO2@T1-RGDk NPs demonstrate no obvious toxicity in mice, thus demonstrated that these novel NPs may prove to be promising fluorescent imaging agents for the accurate detection and treatment of tumors.

In vivo near infrared fluorescence imaging and dynamic quantification of pancreatic metastatic tumors using folic acid conjugated biodegradable mesoporous silica nanoparticles.

Cancer metastasis is one of the biggest challenges in cancer treatments since it increases the likelihood that a patient will die from the disease. Therefore, the availability of techniques for the early detection and quantification of tumors is very important. We have prepared cyanine 7.5 NHS ester (Cy7.5) and folic acid (FA) conjugated biodegradable mesoporous silica nanoparticles (bMSN@Cy7.5-FA NPs) (~100 nm) for visualizing tumors in vivo. The fluorescence spectra revealed that the emission peak of bMSN@Cy7.5-FA NPs had a red-shift of 1 nm. Confocal immunofluorescent images showed that bMSN@Cy7.5-FA NPs had an excellent targeting ability for visualizing cancer cells. In vivo fluorescence imaging has been conducted using an orthotopic model for pancreatic cancer within 48 h, and the fluorescence intensity reached a maximum at a post injection time-point of 12 h, which demonstrated that the use of bMSN@Cy7.5-FA NPs provides an excellent imaging platform for tumor precision therapy in mice.

In Vivo Dual-Modality Fluorescence and Magnetic Resonance Imaging-Guided Lymph Node Mapping with Good Biocompatibility Manganese Oxide Nanoparticles.

Multifunctional manganese oxide nanoparticles (NPs) with impressive enhanced T1 contrast ability show great promise in biomedical diagnosis. Herein, we developed a dual-modality imaging agent system based on polyethylene glycol (PEG)-coated manganese oxide NPs conjugated with organic dye (Cy7.5), which functions as a fluorescence imaging (FI) agent as well as a magnetic resonance imaging (MRI) imaging agent. The formed Mn3O4@PEG-Cy7.5 NPs with the size of ~10 nm exhibit good colloidal stability in different physiological media. Serial FI and MRI studies that non-invasively assessed the bio-distribution pattern and the feasibility for in vivo dual-modality imaging-guided lymph node mapping have been investigated. In addition, histological and biochemical analyses exhibited low toxicity even at a dose of 20 mg/kg in vivo. Since Mn3O4@PEG-Cy7.5 NPs exhibited desirable properties as imaging agents and good biocompatibility, this work offers a robust, safe, and accurate diagnostic platform based on manganese oxide NPs for tumor metastasis diagnosis.