PMID- 30697048 OWN - NLM STAT- MEDLINE DCOM- 20190225 LR - 20220331 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 14 DP - 2019 TI - Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis. PG - 649-665 LID - 10.2147/IJN.S189819 [doi] AB - 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. FAU - Li, Xiaoxia AU - Li X AD - PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People's Republic of China, chengdu@mail.sysu.edu.cn. FAU - Xiao, Hong AU - Xiao H AD - PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People's Republic of China, chengdu@mail.sysu.edu.cn. FAU - Lin, Chaowen AU - Lin C AD - Department of Cardiovascular Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People's Republic of China, amber23@smu.edu.cn. AD - Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China. FAU - Sun, Weitong AU - Sun W AD - PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People's Republic of China, chengdu@mail.sysu.edu.cn. FAU - Wu, Teng AU - Wu T AD - PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People's Republic of China, chengdu@mail.sysu.edu.cn. FAU - Wang, Jin AU - Wang J AD - Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, People's Republic of China. FAU - Chen, Bin AU - Chen B AD - Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China. FAU - Chen, Xia AU - Chen X AD - Department of Cardiovascular Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People's Republic of China, amber23@smu.edu.cn. FAU - Cheng, Du AU - Cheng D AD - PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People's Republic of China, chengdu@mail.sysu.edu.cn. LA - eng PT - Journal Article DEP - 20190115 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Apolipoproteins E) RN - 0 (Chemokine CCL2) RN - 0 (E-Selectin) RN - 0 (Interleukin-6) RN - 0 (Ligands) RN - 0 (Lipids) RN - 0 (Liposomes) RN - 0 (SELE protein, human) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - A0JWA85V8F (Atorvastatin) RN - IT942ZTH98 (Curcumin) SB - IM MH - Animals MH - Apolipoproteins E/deficiency/metabolism MH - Atherosclerosis/blood/*drug therapy/pathology MH - Atorvastatin/pharmacology/*therapeutic use MH - Cell Death/drug effects MH - Cell Survival/drug effects MH - Chemokine CCL2/metabolism MH - Curcumin/chemistry/*therapeutic use MH - Drug Synergism MH - E-Selectin/metabolism MH - Endothelial Cells/drug effects/metabolism/*pathology MH - Humans MH - Inflammation/blood/drug therapy/pathology MH - Intercellular Adhesion Molecule-1/metabolism MH - Interleukin-6/metabolism MH - Ligands MH - Lipids/blood MH - Liposomes/ultrastructure MH - Mice, Knockout MH - Particle Size MH - Static Electricity PMC - PMC6339643 OTO - NOTNLM OT - antiatherosclerosis OT - atorvastatin calcium OT - combined therapy OT - curcumin OT - targeted codelivery COIS- Disclosure The authors report no conflicts of interest in this work. EDAT- 2019/01/31 06:00 MHDA- 2019/02/26 06:00 PMCR- 2019/01/15 CRDT- 2019/01/31 06:00 PHST- 2019/01/31 06:00 [entrez] PHST- 2019/01/31 06:00 [pubmed] PHST- 2019/02/26 06:00 [medline] PHST- 2019/01/15 00:00 [pmc-release] AID - ijn-14-649 [pii] AID - 10.2147/IJN.S189819 [doi] PST - epublish SO - Int J Nanomedicine. 2019 Jan 15;14:649-665. doi: 10.2147/IJN.S189819. eCollection 2019.