Abstract
Reducing macrophage recruitment by silencing chemokine (C–C motif) receptor 2 (CCR2) expression is a promising therapeutic approach against atherosclerosis. However the transfection of macrophages with siRNA is often technically challenging. EGFP-EGF1-conjugated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (ENPs) have a specific affinity to tissue factor (TF). In this study, the feasibility of ENPs as a carrier for target delivery of CCR2-shRNA to atherosclerotic cellular models of macrophages was investigated. Coumarin-6 loaded ENPs were synthesized using a double-emulsion method. Fluorescence microscopy and flow cytometry assay were taken to examine the uptake of Coumarin-6 loaded ENPs in the cellular model. Then a sequence of shRNA specific to CCR2 mRNA was constructed and encapsulated into ENPs. Target delivery of CCR2-shRNA to atherosclerotic cellular models of macrophages in vitro were evaluated. Results showed more uptake of ENPs by the cellular model than common PLGA nanoparticles. CCR2-shRNA loaded ENPs effectively silenced CCR2 gene in the atherosclerotic macrophages and exhibited a favorable cytotoxic profile to cultured cells. With their low cytotoxicity and efficient drug delivery, ENP could be a useful carrier for target delivery of CCR2-shRNA to inflammatory monocytes/macrophages for the therapy against atherosclerosis.
Highlights
Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large and medium-size arteries
Atherosclerosis starts with the recruitment of inflammatory monocytes on the activated endothelial cells
In response to inflammatory stimuli, these monocytes migrate through the impaired endothelium and further proliferate within the intimal layer, sustaining and amplifying the local inflammatory process by releasing inflammatory factors, which mediate the involved immune cells
Summary
Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large and medium-size arteries. It is at the core of cardiovascular disease leading to myocardial infarctions, stroke, and peripheral vascular disease encountered in most human p opulations[1]. Monocytes do not migrate in response to MCP-1 in CCR2 knockout mice. These cells are less capable of adhering to the endothelium, suggesting the importance of CCR2 in the strong inter-reaction between monocytes and e ndothelium[11]. Blocking CCR2 and inhibiting the recruitment of monocytes to atherosclerotic lesions is one promising strategy to ameliorate the progression of atherosclerosis and stabilize p laques[12]
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