Anti-JNK2 peptide-siRNA nanostructures improve plaque endothelium and reduce thrombotic risk in atherosclerotic mice

• Published in: International journal of nanomedicine 2018-01, Vol.13, p.5187-5205
• Main Authors: Pan, Hua, Palekar, Rohun U, Hou, Kirk K, Bacon, John, Yan, Huimin, Springer, Luke E, Akk, Antonina, Yang, Lihua, Miller, Mark J, Pham, Christine Tn, Schlesinger, Paul H, Wickline, Samuel A
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; ApoE-/- mice; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; Apoptosis; Atherosclerosis; Atherosclerosis - complications; Atherosclerosis - pathology; Atherosclerosis - therapy; Blood tests; Canakinumab; Cell division; Cytokines; Cytotoxicity; Disease Models, Animal; Endothelium; Endothelium - pathology; erosions; Granulocytes; Health aspects; Inflammation; Inflammation - metabolism; Interleukins; JNK2; Kinases; Lipids; Low density lipoprotein; Macrophages; Macrophages - metabolism; Male; Messenger RNA; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 9 - metabolism; Motor vehicle drivers; Nanoparticles; Nanoparticles - chemistry; Nanostructures - chemistry; Original Research; peptide nanoparticles; Peptides; Peptides - metabolism; perfluorocarbon nanoparticles; Perfluorocarbons; Permeability; plaque; Plaque, Atherosclerotic - complications; Plaque, Atherosclerotic - pathology; Plaque, Atherosclerotic - therapy; Proteins; RAW 264.7 Cells; Risk Factors; RNA; RNA Interference; RNA, Small Interfering - metabolism; scavenger receptors; Signal Transduction - drug effects; siRNA; Thrombosis; Thrombosis - complications; Thrombosis - pathology; Thrombosis - therapy
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S168556

A direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk. p5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo. Because JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide-siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% ( =0.044) and 42% ( =0.042), respectively. Plaque-macrophage populations were markedly depleted and NFκB and STAT3-signaling pathways inhibited by 47% (