Hyaluronic Acid-Bilirubin Nanoparticles as a Tumor Microenvironment Reactive Oxygen Species-Responsive Nanomedicine for Targeted Cancer Therapy.

Introduction: The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the TME may act as a stimulus for drug release. In this study, we have developed ROS-responsive hyaluronic acid-bilirubin nanoparticles (HABN) loaded with doxorubicin (DOX@HABN) for the specific delivery and release of DOX in tumor tissue. The hyaluronic acid shell of the nanoparticles acts as an active targeting ligand that can specifically bind to CD44-overexpressing tumors. The bilirubin core has intrinsic anti-cancer activity and ROS-responsive solubility change properties. Methods & Results: DOX@HABN showed the HA shell-mediated targeting ability, ROS-responsive disruption leading to ROS-mediated drug release, and synergistic anti-cancer activity against ROS-overproducing CD44-overexpressing HeLa cells. Additionally, intravenously administered HABN-Cy5.5 showed remarkable tumor-targeting ability in HeLa tumor-bearing mice with limited distribution in major organs. Finally, intravenous injection of DOX@HABN into HeLa tumor-bearing mice showed synergistic anti-tumor efficacy without noticeable side effects. Conclusion: These findings suggest that DOX@HABN has significant potential as a cancer-targeting and TME ROS-responsive nanomedicine for targeted cancer treatment.

Oral Nanomedicines for siRNA Delivery to Treat Inflammatory Bowel Disease.

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA to the target site and the action of siRNA drugs at the target site. In this review, we first discuss various physicochemical and biological barriers in the GI tract. Furthermore, we present recent strategies and the progress of oral siRNA delivery strategies to treat IBD. Finally, we consider the challenges faced in the use of these strategies and future directions of oral siRNA delivery strategies.

Smart pH-responsive nanomedicines for disease therapy.

Background: Currently nanomedicines are the focus of attention from researchers and clinicians because of the successes of lipid-nanoparticles-based COVID-19 vaccines. Nanoparticles improve existing treatments by providing a number of advantages including protection of cargo molecules from external stresses, delivery of drugs to target tissues, and sustained drug release. To prevent premature release-related side effects, stable drug loading in nanoformulations is required, but the increased stability of the formulation could also lead to a poor drug-release profile at the target sites. Thus, researchers have exploited differences in a range of properties (e.g., enzyme levels, pH, levels of reduced glutathione, and reactive oxygen species) between non-target and target sites for site-specific release of drugs. Among these environmental stimuli, pH gradients have been widely used to design novel, responsive nanoparticles. Area covered: In this review, we assess drug delivery based on pH-responsive nanoparticles at the levels of tissues (tumor microenvironment, pH ~ 6.5) and of intracellular compartments (endosome and lysosome, pH 4.5-6.5). Upon exposure to these pH stimuli, pH-responsive nanoparticles respond with physicochemical changes to their material structure and surface characteristics. These changes include swelling, dissociation, or surface charge switching, in a manner that favors drug release at the target site (the tumor microenvironment region and the cytosol followed by endosomal escape) rather than the surrounding tissues. Expert opinion: Lastly, we consider the challenges involved in the development of pH-responsive nanomedicines.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

The effects of a newsletter on bedding control on house dust mite allergen concentrations in childcare centers in Korea.

OBJECTIVES: Bedding in childcare centers (CCCs) can hold house dust mite (HDM) allergens. This study examined whether HDM allergen levels can be reduced through the distribution of an educational newsletter on bedding control to parents of CCC children in Korea. METHODS: All 38 CCCs were measured for Der 1 (sum of Der f 1 and Der p 1) concentrations on classroom floors and bedding before the intervention. Educational newsletters on children's bedding control were sent to 21 CCCs by mail, and teachers were asked to distribute the newsletters to the parents of the children (intervention group). The remaining 17 CCCs were not sent newsletters (control group). The measurement of Der 1 concentrations in 38 CCCs was repeated after the intervention. Dust samples were collected with a vacuum cleaner and analyzed using enzyme-linked immunosorbent assay methods. RESULTS: The Der 1 concentrations on the bedding were significantly higher than those on the floors in 38 CCCs at baseline (p<0.05). Although changes of the Der 1 concentrations for the control group (n=17) were not significant, Der 1 concentrations for the intervention group (n=21) decreased significantly from 2077.9 ng/g dust to 963.5 ng/g dust on the floors and from 3683.9 ng/g dust to 610.4 ng/g dust on bedding (p<0.05). CONCLUSIONS: The distribution of educational newsletters on bedding control to parents may be an effective means of controlling HDMs in CCCs.

Pyrrolidone carboxylic acid levels or caspase-14 expression in the corneocytes of lesional skin correlates with clinical severity, skin barrier function and lesional inflammation in atopic dermatitis.

BACKGROUND: Dry skin in atopic dermatitis (AD) mainly results from barrier impairment due to deficiency of ceramide and natural moisturizing factors including pyrrolidone carboxylic acid (PCA) in stratum corneum (SC). Caspase-14 cleaves filaggrin monomers to free amino acids and their derivatives such as PCA, contributing natural moisturizing factors. Cytokines in the corneocytes represent cutaneous inflammation severity of AD patients. OBJECT: To analyze the correlations of PCA, caspase-14 and cytokines in corneocytes with clinical severity, barrier function and skin inflammation, those were quantitated. METHODS: A total of 73 persons were enrolled: 21 patients with mild AD, 21 with moderate-to-severe AD, 13 with X-linked ichthyosis (XLI) as a negative control for filaggrin gene (FLG) mutation, and 18 healthy controls. Skin barrier functions such as basal transepidermal water loss (TEWL), stratum corneum (SC) hydration and skin surface pH were measured. To collect corneocytes, stripping with D-squame discs was done on lesional and non-lesional skin. And then PCA was isolated from D-squame discs and quantitated by LC-MS/MS. Cytokine assays were performed. RESULTS: The quantity of PCA and caspase-14 was decreased in inflammatory lesions compared to non-lesion in AD patients. And the amounts of PCA and caspase-14 in the lesion of AD patients correlated with clinical severity as determined by eczema area and severity index score and the skin barrier functions. Also, the expressions of TNF-α and IL-13 inversely correlated with PCA quantity. CONCLUSION: The quantity of PCA or caspase-14 in the corneocytes of the lesional skin of AD patients reflects the clinical severity, skin barrier function and the degree of lesional inflammation.

Correlation between serum vitamin d level and the severity of atopic dermatitis associated with food sensitization.

PURPOSE: A growing body of literature has linked vitamin D deficiency with allergic diseases, particularly atopic dermatitis (AD). In this study, we investigated the association between serum vitamin D status and the clinical manifestation of AD. We also developed an analytical method for the simultaneous determination of 25-hydroxy vitamin D3 (25(OH)D3), using liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS). METHODS: This study included 157 patients (79 males and 78 females) with AD, aged 4 months to 56 years. We evaluated disease severity using the SCORing Atopic Dermatitis (SCORAD) index. Serum levels of 25(OH)D3 were determined by LC coupled with MS/MS. Total IgE and specific IgE levels were assayed using the immunoCAP system. ANOVA was used for statistical evaluation. RESULTS: We found mild, moderate, and severe AD in 30 (11.1%), 87 (55.4%), and 40 (25.5%) patients, respectively. There was no significant correlation between serum levels of 25(OH)D3 and AD severity. However, among the 36 patients with food sensitization, the mean±SD serum levels of 25(OH)D3 were significantly higher (P<0.05) in patients with mild disease (21.2±5.18 ng/mL) compared with the levels in patients with moderate (17.9±4.02 ng/mL) or severe AD (13.3±5.11 ng/mL) disease. CONCLUSIONS: These results suggest that vitamin D deficiency is related to the severity of AD associated with food sensitization. Thus, these data suggest a role for vitamin D in a select group of AD patients.