ICAM-1 targeted and ROS-responsive nanoparticles for the treatment of acute lung injury.

Acute lung injury (ALI) is an inflammatory disease caused by multiple factors such as infection, trauma, and chemicals. Without effective intervention during the early stages, it usually quickly progresses to acute respiratory distress syndrome (ARDS). Since ordinary pharmaceutical preparations cannot precisely target the lungs, their clinical application is limited. In response, we constructed a γ3 peptide-decorated and ROS-responsive nanoparticle system encapsulating therapeutic dexamethasone (Dex/PSB-γ3 NPs). In vitro, Dex/PSB-γ3 NPs had rapid H2O2 responsiveness, low cytotoxicity, and strong intracellular ROS removal capacity. In a mouse model of ALI, Dex/PSB-γ3 NPs accumulated at the injured lung rapidly, alleviating pulmonary edema and cytokine levels significantly. The modification of NPs by γ3 peptide achieved highly specific positioning of NPs in the inflammatory area. The ROS-responsive release mechanism ensured the rapid release of therapeutic dexamethasone at the inflammatory site. This combined approach improves treatment accuracy, and drug bioavailability, and effectively inhibits inflammation progression. Our study could effectively reduce the risk of ALI progressing to ARDS and hold potential for the early treatment of ALI.

Inflammation Control and Tumor Growth Inhibition of Ovarian Cancer by Targeting Adhesion Molecules of E-Selectin.

OBJECTIVE: The aim is to use E-selectin-binding peptide (ESBP) to actively recognize E-selectin, so allowing a drug delivery system to actively recognize the cells and inhibit the tumor growth of ovarian cancer by targeting adhesion molecules of E-selectin. An ovarian-cancer-directed drug delivery system was designed based on the high affinity of E-selectin-binding peptide (ESBP) to E-selectin. The effects and mechanisms of ESBP-bovine serum albumin (BSA) polymerized nanoparticles were investigated. METHODS: BSA polymerized nanoparticles (BSANPs) and ESBP-BSANPs-paclitaxel (PTX) were prepared and their characteristics were measured. The in vitro targetability and cytotoxicity of ESBP-BSANPs-PTX were evaluated through in vitro drug uptake and MTT experiments. The mechanisms of ESBP-BSANPs-PTX were investigated via apoptosis, wound healing and immunohistochemistry assays. The in vivo targeting properties and drug effects were observed in a mouse tumor-bearing model. RESULTS: In vitro experiments revealed an increase in the uptake of ESBP-BSANPs-FITC. The cytotoxicity of ESBP-BSANPs-PTX in A2780/CP70, HUVEC, RAW264.7 and ID8 cells was higher than that of PTX alone. ESBP-BSANPs-PTX increased cell apoptosis in a dose-dependent manner and exhibited a greater ability to inhibit cell migration than BSANPs-PTX. In vivo experiments demonstrated the targetability and good effects of ESBP-BSANPs. CONCLUSIONS: ESBP-BSANPs-PTX improve PTX targetability, provide tumor-specific and potent therapeutic activities, and show promise for the development of agents in preclinical epithelial ovarian cancer.

The inhibitory effect and mechanism of small molecules on acetic anhydride-induced BSA acetylation and aggregation.

Protein acetylation is a significant post-translational modification, and hyperacetylation results in amyloid aggregation, which is closely related to neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and so on). Therefore, it is significant to inhibit the hyperacetylation of proteins and their induced aggregation. In the present study, we aimed to explore the anti-acetylation and anti-amyloid properties of five small molecules (gallic acid, menadione, resveratrol, apigenin, and quercetin) in the process of acetic anhydride-induced protein hyperacetylation and its aggregation. Optical detection methods, such as SDS-PAGE, inverted fluorescence microscopy, and endogenous fluorescence spectroscopy, were used to investigate the effects of small molecules on protein acetylation, aggregation, and structure. In addition, fluorescence quenching and molecular docking techniques were used to explore the relationship between small molecules and acetylation. The results showed that gallic acid (200 µM), menadione (100 µM), quercetin (40 µM), resveratrol (5 µM), and apigenin (20 µM) (unmodified rates were 61.12 %, 67.76 %, 65.11 %, 62.66 %, and 67.81 %, respectively) had strong inhibitory effects on acetylation, and there was no significant difference (P < 0.05). In addition, gallic acid (200 µM), menadione (100 µM), and resveratrol (5 µM) (inhibition rates of 29.89 %, 26.53 %, and 26.09 %, respectively) had more substantial inhibitory effects on protein aggregation, indicating that the five small molecules could inhibit acetic anhydride-induced hyperacetylation and protein aggregation. The underlying mechanism might be that it could inhibit hyperacetylation and resist amyloid aggregation by interacting with proteins to occupy acetylation sites. Collectively, our findings showed that gallic acid, menadione, and resveratrol could potentially prevent and treat neurodegenerative diseases, such as Alzheimer's disease, by inhibiting acetylation and acetylation-induced aggregation.

Targeting of gallbladder megalin receptors with DHA-conjugated limonene albumin nanoparticles.

Gallbladder stones are a major pathogenic factor leading to cholecystitis, and it is increasingly important to explore innovative drug delivery methods for gallstones. In the present study, docosahexaenoic acid-coupled limonene bovine serum albumin nanoparticles (LIM-DHA-BSA-NPs) were constructed. The LIM-DHA-BSA-NPs are spherical structures, and the distribution was relatively uniform, and, more importantly, it has low cytotoxicity and good safety. The LIM-DHA-BSA-NPs solution shows higher uptake rates by RAW264.7 cells when compared with free limonene (LIM). The fluorescence intensity of FITC-modified BSA NPs was significantly higher than that of free FITC, which further indicated that the uptake of DHA-conjugated BSA NPs by RAW264.7 cells was stronger than that of the free drugs. Moreover, the in vivo distribution experiment showed that the enrichment of DiD-loaded BSA NPs in the gallbladder was significantly enhanced when compared with that of free DiD. The semi-quantitative fluorescence intensity results showed that the uptake of DiD-DHA-BSA-NPs was 4.5 times higher when compared with the free DiD. It is preliminarily shown that the DHA-conjugated BSA NPs that were constructed, have an ability to target the gallbladder. Furthermore, the Pearson colocalization coefficient Rcoloc from in vivo colocalization results indicates that the DHA-BSA-NPs had a good colocalization effect on the gallbladder epithelial cells (GBECs). In addition, the LIM-DHA-BSA-NPs solution not only significantly reduced the concentration of nitric oxide (NO) secreted by inflammatory model cells and the number of peripheral blood leukocytes in guinea pigs with cholecystitis, but also significantly decreased the activities of the aspartate transaminase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), glutamyl endopeptidase (GGT), total bile acid (TBA), and total bilirubin (TBIL) enzymes. Collectively, the LIM-DHA-BSA-NPs could be used as an effective anti-inflammatory agent at the cellular and animal levels. This experiment, for the first time, showed that DHA-conjugated BSA NPs could be absorbed into GBECs by megalin receptor-mediated endocytosis and then they exert an anti-cholecystitis effect because of the LIM. The active uptake of DHA-conjugated BSA NPs by the megalin receptors of the GBECs is expected to become an effective therapeutic strategy for cholecystolithiasis.