| First Author | Boada C | Year | 2020 |
| Journal | Circ Res | Volume | 126 |
| Issue | 1 | Pages | 25-37 |
| PubMed ID | 31647755 | Mgi Jnum | J:307034 |
| Mgi Id | MGI:6710253 | Doi | 10.1161/CIRCRESAHA.119.315185 |
| Citation | Boada C, et al. (2020) Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation. Circ Res 126(1):25-37 |
| abstractText | RATIONALE: Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. OBJECTIVE: Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. METHODS AND RESULTS: Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108+/-2.3 nm, a surface charge of -15.4+/-14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE(-/-) mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6+/-9.79 %) compared with untreated mice (30.2+/-13.34 %) and rapamycin alone (26.8+/-9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554+/-363.9, P=9.95122x10(-6)). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice. CONCLUSIONS: We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques. |
