BackgroundA new mechanism for intercellular communication has recently emerged that involves intercellular transfer of extracellular vesicles (EVs). Several studies have indicated that EVs may play a potential role in cell‐to‐cell communication between macrophage foam cells and vascular smooth muscle cells (VSMCs) in atherosclerotic lesion.Methods and ResultsThis study involved the comparison of circulating EVs from atherosclerotic patients and control participants. The results showed that the circulation of the patients contained more leukocyte‐derived EVs and that these EVs promoted more VSMC adhesion and migration than those of healthy participants. We then established a macrophage foam cell model and characterized the EVs from the macrophages. We used flow cytometric analyses and cell migration and adhesion assays and determined that the foam cells generated more EVs than the normal macrophages and that the foam cell–derived EVs were capable of promoting increased levels of VSMC migration and adhesion. Furthermore, we performed a proteomic analysis of the EVs. The data showed that the foam cell–derived EVs may promote VSMC adhesion and migration by regulating the actin cytoskeleton and focal adhesion pathways. In addition, Western blotting revealed that foam cell–derived EVs could promote the phosphorylation of ERK and Akt in VSMCs in a time‐dependent manner. We also found that foam cell–derived EVs could enter the VSMCs and transfer integrins to the surface of these cells.ConclusionsThe data in our present study provide the first evidence that EVs from foam cells could promote VSMC migration and adhesion, which may be mediated by the integration of EVs into VSMCs and the subsequent downstream activation of ERK and Akt.

Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan–poly-L-lysine–palmitic acid (NSC–PLL–PA) to co-deliver doxorubicin (Dox) and siRNA–P-glycoprotein (P-gp) (Dox–siRNA-micelle). Dox–siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox–siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox–siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox–siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.

Heat shock proteins (Hsps) have been reported to protect cells, tissues, and organisms against damage from a wide variety of stressful stimuli. Whether they protect against deoxyribonucleic acid (DNA) damage in individuals exposed to environmental stresses and chemical carcinogens is unknown. In the study, we investigated the association between Hsp70 levels (the most abundant mammalian Hsp) and genotoxic damage in lymphocytes of workers exposed to coke-oven emission using Western dot blot and 2 DNA damage assays, the comet assay and the micronucleus test. The data show that there is a significant increase in Hsp70 levels, DNA damage score, and micronucleus rates in lymphocytes of workers exposed to coke-oven emission as compared with the control subjects. Furthermore, there was a significant negative correlation of Hsp70 levels with DNA damage scores in the comet assay (r = -0.663, P < 0.01) and with micronucleus rates (r = -0.461, P < 0.01) in the exposed group. In the control group, there was also a light negative correlation between Hsp70 with DNA damage and micronuclei rate (r = -0.236 and r = 0.242, respectively), but it did not reach a statistically significant level (P > 0.05). Our results show that individuals who had high Hsp70 levels generally showed lower genotoxic damage than others. These results suggest a role of Hsp70 in the protection of DNA from genotoxic damage induced by coke-oven emission.

Drug development involves various evaluation processes to ascertain drug effects and rigorous analysis of biological indicators during in vitro preclinical studies. Twodimensional (2D) cell cultures are commonly used in numerous in vitro studies, which are poor facsimiles of the in vivo conditions. Recently, three-dimensional (3D) tumor models mimicking the tumor microenvironment and reducing the use of experimental animals have been developed generating great interest to appraise tumor response to treatment strategies in cancer therapy. In this study, silk fibroin (SF) protein and chitosan (CS), two natural biomaterials, were chosen to construct the scaffolds of 3D cell models. Human non-small cell lung cancer A549 cells in the SF/CS scaffolds were found to have a great tendency to gather and form tumor spheres. A549 cell spheres in the 3D scaffolds showed biological and morphological characteristics much closer to the in vivo tumors. Besides, the cells in 3D models displayed better invasion ability and drug resistance than 2D models. Additionally, differences in drug-resistant and immune-related protein levels were found, which indicated that 3D models might resemble the real-life situation. These findings suggested that these 3D tumor models composed of SF/CS are promising to provide a valuable biomaterial platform in the evaluation of anticancer drugs.