Design and development of Branched Poly(ß-aminoester) nanoparticles for Interleukin-10 gene delivery in a mouse model of atherosclerosis. (15th April 2022)

• Record Type: Journal Article
• Authors: Distasio, Nicholas; Dierick, France; Ebrahimian, Talin; Tabrizian, Maryam; Lehoux, Stephanie
• Is Part Of: Acta biomaterialia. Volume 143(2022)
• Page Start: 356
• Page End: 371
• Publication Date: 2022-04-15
• Subjects: Poly(ß-amino ester) -- Anti-inflammatory cytokine -- Interleukin-10 -- Gene therapy -- Targeting -- VCAM-1 -- Toxicity -- Atherosclerosis; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2022.02.043
• Languages: English
• ISSNs: 1742-7061

Abstract

Abstract: Atherosclerosis progression is a result of chronic and non-resolving inflammation, effective treatments for which still remain to be developed. We designed and developed branched poly(ß-amino ester) nanoparticles (NPs) containing plasmid DNA encoding IL-10, a potent anti-inflammatory cytokine to atherosclerosis. The NPs (NP-VHPK) are functionalized with a targeting peptide (VHPK) specific for VCAM-1, which is overexpressed by endothelial cells at sites of atherosclerotic plaque. The anionic coating affords NP-VHPK with significantly lower toxicity than uncoated NPs in both endothelial cells and red blood cells (RBCs). Following injection of NP-VHPK in ApoE −/− mice, Cy5-labelled IL-10 significantly accumulates in both whole aortas and aortic sinus sections containing plaque compared to injection with a non-targeted control. Furthermore, IL-10 gene delivery results in an attenuation of inflammation locally at the plaque site. NP-VHPK may thus have the potential to reduce the inflammatory component of atherosclerosis in a safe and effective manner. Statement of significance: Atherosclerosis is a chronic inflammatory disease that results in the formation of lipid-laden plaques within vascular walls. Although treatments using drugs and antibodies are now beginning to address the inflammation in atherosclerosis, neither is sufficient for long-term therapy. In this paper, we introduce a strategy to deliver genes encoding the anti-inflammatory protein interleukin-10 (IL-10) in vivo. We showed that Branched Poly(ß-aminoester) carrying the IL-10 gene are able to localize specifically at the plaque via surface-functionalized targeting moieties against inflamed VCAM-1 and/or ICAM-1 and to facilitate gene transcription by ECs to increase the local concentration of the IL-10 within the plaque. To date, there is no report involving non-viral nanotechnology to provide gene-based therapies for atherosclerosis. Graphical abstract: Image, graphical abstract