Stimuli-Responsive Nanotechnology for RNA Delivery.

Ribonucleic acid (RNA) drugs have shown promising therapeutic effects for various diseases in clinical and preclinical studies, owing to their capability to regulate the expression of genes of interest or control protein synthesis. Different strategies, such as chemical modification, ligand conjugation, and nanotechnology, have contributed to the successful clinical translation of RNA medicine, including small interfering RNA (siRNA) for gene silencing and messenger RNA (mRNA) for vaccine development. Among these, nanotechnology can protect RNAs from enzymatic degradation, increase cellular uptake and cytosolic transportation, prolong systemic circulation, and improve tissue/cell targeting. Here, a focused overview of stimuli-responsive nanotechnologies for RNA delivery, which have shown unique benefits in promoting RNA bioactivity and cell/organ selectivity, is provided. Many tissue/cell-specific microenvironmental features, such as pH, enzyme, hypoxia, and redox, are utilized in designing internal stimuli-responsive RNA nanoparticles (NPs). In addition, external stimuli, such as light, magnetic field, and ultrasound, have also been used for controlling RNA release and transportation. This review summarizes a wide range of stimuli-responsive NP systems for RNA delivery, which may facilitate the development of next-generation RNA medicines.

ROS-Responsive Nanoparticle Delivery of mRNA and Photosensitizer for Combinatorial Cancer Therapy.

Messenger RNA (mRNA) therapy has shown tremendous potential for different diseases including cancer. While mRNA has been extensively used in cancer vaccine development as antigen or in cancer immunotherapy as immunomodulatory agent, the combination of mRNA therapy with photodynamic therapy has not been explored in cancer treatment. Herein, we report a reactive oxygen species (ROS)-responsive polymeric nanoparticle (NP) platform for first-in-field codelivery of mRNA and photosensitizer for effective cancer treatment. We developed ROS-responsive oligomer-based polymeric NPs and applied them to test a combination of p53 mRNA and indocyanine green (ICG). The ROS-triggered disassembly of the NPs could promote mRNA translation efficiency, whereby p53 expression induced apoptosis of lung tumor cells. Meanwhile, the released ICG could lead to generation of ROS under 808 nm laser irradiation to induce photodynamic therapy. The NP codelivery of p53 mRNA and ICG demonstrated an effective and safe anti-tumor effect in a lung cancer model.

Cinnamic acid hybrids as anticancer agents: A mini-review.

Cancer, as a long-lasting and dramatic disease, affects almost one-third of human beings globally. Chemotherapeutics play an important role in cancer treatment, but multidrug resistance and severe adverse effects have already become the main causes of failure in tumor chemotherapy. Therefore, it is an urgent need to develop novel chemotherapeutics. Cinnamic acid contains a ubiquitous α,ß-unsaturated acid moiety presenting potential therapeutic effects in the treatment of cancer as these derivatives could act on cancer cells by diverse mechanisms of action. Accordingly, cinnamic acid derivatives are critical scaffolds in discovering novel anticancer agents. This review provides a comprehensive overview of cinnamic acid hybrids as anticancer agents. The structure-activity relationship, as well as the mechanisms of action, are also discussed, covering articles published from 2012 to 2021.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure-activity relationship, and mechanisms of action (2019-2021).

Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exert anticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole-based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure-activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy.

Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.

A Second Near-Infrared Ru(II) Polypyridyl Complex for Synergistic Chemo-Photothermal Therapy.

The clinical success of cisplatin ushered in a new era of the application of metallodrugs. When it comes to practice, however, drug resistance, tumor recurrence, and drug systemic toxicity make it implausible to completely heal the patients. Herein, we successfully transform an electron acceptor [1, 2, 5]thiadiazolo[3,4-g]quinoxaline into a novel second near-infrared (NIR-II) fluorophore H7. After PEGylation and chelation, HL-PEG2k exhibits a wavelength bathochromic shift, enhanced photothermal conversion efficiency (41.77%), and an antineoplastic effect against glioma. Its potential for in vivo tumor tracking and image-guided chemo-photothermal therapy is explored. High levels of uptake and high-resolution NIR-II imaging results are thereafter obtained. The hyperthermia effect could disrupt the lysosomal membranes, which in turn aggravate the mitochondria dysfunction, arrest the cell cycle in the G2 phase, and finally lead to cancer cell apoptosis. HL-PEG2k displays a superior biocompatibility and thus can be a potential theranostic platform to combat the growth and recurrence of tumors.

A modelling study of OH, NO3 and H2SO4 in 2007-2018 at SMEAR II, Finland: analysis of long-term trends.

Major atmospheric oxidants (OH, O3 and NO3) dominate the atmospheric oxidation capacity, while H2SO4 is considered as a main driver for new particle formation. Although numerous studies have investigated the long-term trend of ozone in Europe, the trends of OH, NO3 and H2SO4 at specific sites are to a large extent unknown. The one-dimensional model SOSAA has been applied in several studies at the SMEAR II station and has been validated by measurements in several projects. Here, we applied the SOSAA model for the years 2007-2018 to simulate the atmospheric chemical components, especially the atmospheric oxidants OH and NO3, as well as H2SO4 at SMEAR II. The simulations were evaluated with observations from several shorter and longer campaigns at SMEAR II. Our results show that daily OH increased by 2.39% per year and NO3 decreased by 3.41% per year, with different trends of these oxidants during day and night. On the contrary, daytime sulfuric acid concentrations decreased by 2.78% per year, which correlated with the observed decreasing concentration of newly formed particles in the size range of 3-25 nm with 1.4% per year at SMEAR II during the years 1997-2012. Additionally, we compared our simulated OH, NO3 and H2SO4 concentrations with proxies, which are commonly applied in case a limited number of parameters are measured and no detailed model simulations are available.

Eigen microstates and their evolution of global ozone at different geopotential heights.

Studies on stratospheric ozone have attracted much attention due to its serious impacts on climate changes and its important role as a tracer of Earth's global circulation. Tropospheric ozone as a main atmospheric pollutant damages human health as well as the growth of vegetation. Yet, there is still a lack of a theoretical framework to fully describe the variation of ozone. To understand ozone's spatiotemporal variance, we introduce the eigen microstate method to analyze the global ozone mass mixing ratio between January 1, 1979 and June 30, 2020 at 37 pressure layers. We find that eigen microstates at different geopotential heights can capture different climate phenomena and modes. Without deseasonalization, the first eigen microstates capture the seasonal effect and reveal that the phase of the intra-annual cycle moves with the geopotential heights. After deseasonalization, by contrast, the collective patterns from the overall trend, El Niño-Southern Oscillation (ENSO), quasi-biennial oscillation, and tropopause pressure are identified by the first few significant eigen microstates. The theoretical framework proposed here can also be applied to other complex Earth systems.

Site-Specific Biomimicry of Antioxidative Melanin Formation and Its Application for Acute Liver Injury Therapy and Imaging.

Biocompatible nano-antioxidants composed of natural molecules/materials, such as dopamine and melanin, are of great interest for diverse biomedical applications. However, the lack of understanding of the precise structure of these biomaterials and thus the actual dose of effective components impedes their advancement to translation. Herein, a strategy to mimic in situ melanin formation and explore its antioxidative applications is reported, by developing a PEGylated, phenylboronic-acid-protected L-DOPA precursor (PAD) that can self-assemble into well-defined nanoparticles (PADN). Exposure to oxidative species leads to deprotection of phenylboronic acids, transforming PADN to PEG-L-DOPA, which, similar to the biosynthetic pathway of melanin, can be oxidized and polymerized into an antioxidative melanin-like structure. With ultrahigh stability and superior antioxidative activity, the PADN shows remarkable efficacy in prevention and treatment of acute liver injury/failure. Moreover, the in situ structure transformation enables PADN to visualize damaged tissue noninvasively by photoacoustic imaging. Overall, a bioinspired antioxidant with precise structure and site-specific biological activity for theranostics of oxidative stress-related diseases is described.

Oxidative-Species-Selective Materials for Diagnostic and Therapeutic Applications.

With the increasing recognition of the diverse roles and significance of oxidative species in the pathogenesis of many diseases, a tremendous amount of work on the development of oxidative-species-responsive materials has been conducted for 1) detecting oxygen metabolites or diagnosis of oxidative-stress-relevant diseases, 2) reducing oxidative stress in the disease sites, and/or 3) delivering therapeutic and diagnostic agents. In this review, we first discuss the distinct features and biological functions of each oxidative species. Then the selectivity and sensitivity of chemical linkers/groups to specific oxidative species and the underlying chemistry of their particular interactions are systematically elucidated. Their potential biomedical applications are also highlighted. We expect that this comprehensive review will provide more insights for the design and development of oxidative-species-selective materials for more effective diagnostic and therapeutic applications.

Diffuse reflectance spectroscopy in Barrett's esophagus: developing a large field-of-view screening method discriminating dysplasia from metaplasia.

We evaluated diffuse reflectance spectroscopy implemented as a small field-of-view technique for discrimination of dysplasia from metaplasia in Barrett's esophagus as an adjuvant to autofluorescence endoscopy. Using linear discriminant analysis on 2579 spectra measured in 54 patients identified an optimum a 4-wavelength classifier (at 485, 513, 598 and 629 nm). Sensitivity and specificity for a test data set were 0.67 and 0.85, respectively. Spectroscopic results show that this technique could be implemented in wide-field imaging mode to improve the accuracy of existing endoscopy techniques for finding early pre-malignant lesions in Barrett's esophagus. Results show that the discrimination occurs likely due to redistribution of blood content in the tissue sensed by the optical probing with the wavelength-dependent sampling depth.

Assessment of photobleaching during endoscopic autofluorescence imaging of the lower GI tract.

BACKGROUND AND OBJECTIVES: In autofluorescence endoscopy, the difference in the fluorescence of intrinsic fluorophores is imaged to help visualize pre-malignant lesions, as in the system evaluated here. In this, blue light is used for excitation and the green autofluorescence is normalized by the red diffuse reflectance and presented using a false color scale. The present study was designed to quantify the degree of fluorescence photobleaching induced by the excitation light during use in the colon, since significant photobleaching could lead to false interpretation of the images, particularly false-positive lesions. STUDY DESIGN: Measurements were made ex vivo and in vivo, both using the endoscopic imaging system and a separate fiberoptic spectroscopy probe in externalized rat jejunum and in patients undergoing routine colonoscopy, using exposures typical of autofluorescence endoscopic examination. RESULTS: Photobleaching could be potentially caused at blue light exposure. However, at light intensities and exposure times that are typically used in clinical practice, the average photobleaching (% loss of peak fluorescence intensity) was <1% and <6% in the rat and human tissues, respectively. Nevertheless, the range was large: from -17% to +18% in rats and -33% to +43% in patients, where negative values denote an apparent increase in fluorescence. Both the large positive and negative deviations are believed in part to be due to a measurement artifact caused by uncontrollable tissue motility. SUMMARY AND CONCLUSIONS: It is concluded that, using exposures typically encountered in clinical practice, there is minimal photobleaching during fluorescence endoscopy at exposure such as are used in the Onco-LIFE and comparable systems. The small changes in fluorescence intensity and spectral shift that do occur are not likely to be detectable by eye, and so should not impact significantly on the diagnostic accuracy of the technique.

Hydrothermal synthesis of PbS hollow spheres with single crystal-like electron diffraction patterns.

PbS hollow spheres were successfully prepared by a sodium citrate-assisted hydrothermal process at 120 degrees C for 12 h, employing lead acetate trihydrate, thiourea and sodium citrate as precursors. The diameter of PbS hollow spheres is 200-400 nm, which is composed of about 50-80 nm nanoparticles. The synthesized product was characterized by powder X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), electron diffraction (ED), Fourier transform-infrared (FT-IR) spectroscopy, ultraviolet-visible spectrometer (UV-vis) and near-infrared absorption spectrometer (NIR). The effects of the reaction conditions on morphologies of PbS structures were investigated. Star-shaped and flat PbS crystals were obtained by changing some experiment conditions. The results show that temperature, sodium citrate concentration, sulfur sources and solvent play key roles on the final morphologies formation of PbS crystals. Especially, ED result indicates that PbS hollow spheres hold single crystal-like electron diffraction patterns. And the possible formation mechanism of hollow spheres was proposed.

Gastric calcifying fibrous tumor.

Intramucosal gastric tumours are most commonly found to be gastrointestinal stromal tumours or leiomyomas (smooth muscle tumours); however, a variety of other uncommon mesenchymal tumours can occur in the stomach wall. A rare benign calcifying fibrous tumour is reported and the endoscopic appearance, ultrasound findings and morphology are documented. A review of the literature found only two similar cases.

Neurological symptoms suggestive of demyelination in Crohn's disease after infliximab therapy.

Anti-TNFalpha drugs are currently used in the treatment of patients with Crohn's disease. Studies have reported neurological side effects occurring after anti-TNFalpha treatment, including infliximab-induced complications.