Location: Jean Mayer Human Nutrition Research Center On AgingTitle: Anti-atherogenic effects of CD36-targeted epigallocatechin gallate-loaded nanoparticles
|ZHANG, JIA - Texas Tech University|
|NLE, SHUFANG - Texas Tech University|
|ZU, YUJIAO - Texas Tech University|
|ABBASI, MEHRNAZ - Texas Tech University|
|CAO, JUN - Texas Tech University|
|LI, CHUAN - Texas Tech University|
|WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|LABIB, SAFAA - Texas Tech University|
|BRACKEE, GORDON - Texas Tech University|
|SHEN, CHWAN-LI - Texas Tech University|
|WANG, SHU - Texas Tech University|
Submitted to: Journal of Controlled Release
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/12/2019
Publication Date: 4/15/2019
Citation: Zhang, J., Nle, S., Zu, Y., Abbasi, M., Cao, J., Li, C., Wu, D., Labib, S., Brackee, G., Shen, C., Wang, S. 2019. Anti-atherogenic effects of CD36-targeted epigallocatechin gallate-loaded nanoparticles. Journal of Controlled Release. 303:263-273. https://doi.org/10.1016/j.jconrel.2019.04.018.
Interpretive Summary: Atherosclerosis, a condition where fatty deposits clog arteries, is a key biological factor in heart disease. Green tea component, known as epigallocatechin gallate (EGCG), has the capacity to reduce the risk of atherosclerosis, but its bioavailability is low, and its effect is not target-specific. Thus, we are seeking a novel approach to increase ability of EGCG to target the formation of fatty deposits at a clinically significant level. In this study, we successfully synthesized EGCG-loaded nanoparticles, ultrafine particles, that have a high affinity to macrophages, a type of immune cell that plays a key role in atherosclerosis formation. Administration of EGCG nanoparticles to the atherosclerosis model animals significantly reduced the fatty deposits on the aorta of the heart. EGCG was accumulated mostly in the target tissue (aorta) and had no adverse effect on other vital organs. Our results indicate that using nanoparticle technique to deliver bioactive dietary components such as green tea EGCG can increase their effectiveness in suppressing biological changes in atherosclerosis and thus might potentially help prevent heart disease.
Technical Abstract: Intimal macrophages play a critical role in atherosclerotic lesion initiation and progression by taking up oxidized low-density lipoprotein (oxLDL) and promoting inflammatory process. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a major type of oxidized phosphatidylcholines (PC) found on oxLDL, has a high binding affinity to the macrophage scavenger receptor CD36 and participates in CD36-mediated recognition and uptake of oxLDL by intimal macrophages. We successfully synthesized epigallocatechin gallate (EGCG)-loaded nanoparticles (Enano), which were composed of EGCG, PC, (plus) alpha-tocopherol acetate, and surfactant. We also incorporated KOdiA-PC on the surface of Enano to make ligand-coated Enano (L-Enano) to target intimal macrophages. The objectives of this study were to determine the anti-atherogenic effects of Enano and L-Enano in LDL receptor null (LDLr knock out mice. Our in vitro data demonstrated that L-Enano had a higher binding affinity to mouse peritoneal macrophages than Enano. This high binding affinity was diminished by CD36 antibodies or knockdown of the CD36 receptor in mouse peritoneal macrophages, confirming the specific binding of L-Enano to the macrophage CD36 receptor. LDLr knock out mice were randomly divided to six groups and received weekly tail vein injection with PBS, EGCG, void nanoparticles (Vnano), Enano, ligand-coated Vnano (L-Vnano), or L-Enano once per week for 22 weeks. The dose of EGCG was 25 mg per kg body weight. L-Enano at 20 micrograms/mL significantly decreased production of monocyte chemoattractant protein-1, tumor necrosis factor alpha, and interleukin-6 from mouse macrophages, while having no effect on their plasma levels compared to the PBS control. There were no significant differences in blood lipid profiles among six treatment groups. Mice treated with L-Enano also had significantly smaller lesion surface areas on aortic arches compared to the PBS control. Liver EGCG content was decreased by treatments in the order of EGCG>Enano>L-Enano. Native EGCG had inhibitory effects on liver and body fat accumulation. This molecular target approach signals an important step towards inhibiting atherosclerosis development via targeted delivery of bioactive compounds to intimal macrophages.