Cyclodextrin-mediated conjugation of macrophage and liposomes for treatment of atherosclerosis

• Published in: Journal of controlled release 2022-09, Vol.349, p.2-15
• Main Authors: Gao, Cheng, Liu, Conghui, Chen, Qian, Wang, Yan, Kwong, Cheryl H.T., Wang, Qingfu, Xie, Beibei, Lee, Simon M.Y., Wang, Ruibing
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Cell-based carriers; Drug delivery; Host-guest interaction; β-Cyclodextrin
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.06.053

Current pharmacological treatments of atherosclerosis often target either cholesterol control or inflammation management, to inhibit atherosclerotic progression, but cannot lead to direct plaque lysis and atherosclerotic regression, partly due to the poor accumulation of medicine in the atherosclerotic plaques. Due to enhanced macrophage recruitment during atheromatous plaque progression, a macrophage-liposome conjugate was facilely constructed for targeted anti-atherosclerosis therapy via synergistic plaque lysis and inflammation alleviation. Endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with a β-cyclodextrin (β-CD) derivative to form β-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between β-CD and ADA to form macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries liposome “hand-in-hand” to significantly increase the accumulation of anchored QT-NP in the aorta plaque in response to the plaque inflammation. In addition to anti-inflammation effects of QT, MP-QT-NP efficiently regresses atherosclerotic plaques from both murine aorta and human carotid arteries via CD-MP mediated cholesterol efflux, due to the binding of cholesterol by excess membrane β-CD. Transcriptome analysis of atherosclerotic murine aorta and human carotid tissues reveal that MP-QT-NP may activate NRF2 pathway to inhibit plaque inflammation, and simultaneously upregulate liver X receptor to promote cholesterol efflux. In order to facilely a macrophage-hitchhiking delivery system for targeted anti-atherosclerosis therapy via precise plaque lysis and anti-inflammation in preclinical and even potentially clinical settings, 1, 2-distearoyl-sn-glycero-3- phosphoethanolamine-poly (ethylene glycol)-β-CD (DSPE-PEG-β-CD) and quercetin (QT)-loaded liposome (QT-NP) was developed for simple and quick construction of macrophage-liposome conjugate (MP-QT-NP) shortly before in vivo administration. Due to enhanced macrophage recruitment during atheromatous plaque progression, endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with ββ- CD derivative to form β-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between β-CD and ADA to construct macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries