Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis

Abstract

Xiaoxia Li,1,* Hong Xiao,1,* Chaowen Lin,2,3,* Weitong Sun,1 Teng Wu,1 Jin Wang,4 Bin Chen,3 Xia Chen,2 Du Cheng1 1PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China; 2Department of Cardiovascular Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China; 3Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 4Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, People’s Republic of China *These authors contributed equally to this work Background: Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity.Materials and methods: Liposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE-/-) mice.Results: Targeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity.Conclusion: Both in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone. Keywords: combined therapy, atorvastatin calcium, curcumin, antiatherosclerosis, targeted codelivery

Keywords

• Combined therapy
• Atorvastatin calcium
• Curcumin
• Antiatherosclerosis
• Targeted codelivery