Enhanced Anti-Atherosclerotic Efficacy of pH-Responsively Releasable Ganglioside GM3 Delivered by Reconstituted High-Density Lipoprotein

• Published in: International journal of molecular sciences 2021-12, Vol.22 (24), p.13624
• Main Authors: Rong, Tong, Wei, Bo, Ao, Meiying, Zhao, Haonan, Li, Yuanfang, Zhang, Yang, Qin, Ying, Zhou, Jinhua, Zhou, Fenfen, Chen, Yong
• Format: Article
• Language: English
• Subjects: Acidification; Animals; Antibodies; Aorta; ApoA-I; Apolipoprotein E; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - immunology; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biocompatibility; Cardiovascular disease; Cell adhesion & migration; Cholesterol; drug delivery system; Drug Delivery Systems; Efficiency; Erythrocytes; Experiments; G(M3) Ganglioside - pharmacology; G(M3) Ganglioside - therapeutic use; Ganglioside GM3; Hemoglobin; High density lipoprotein; High fat diet; Humans; Hydrogen-Ion Concentration; Lipid Metabolism; Lipids; Lipoproteins; Lipoproteins, HDL; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Knockout, ApoE; Nanoparticles; Nanoparticles - chemistry; Plaque, Atherosclerotic - drug therapy; Plaques; RAW 264.7 Cells; reconstituted high-density lipoprotein (rHDL); SR-B1; Vein & artery diseases
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222413624

Recently, the atheroprotective role of endogenous GM3 and an atherogenesis-inhibiting effect of exogenous GM3 suggested a possibility of exogenous GM3 being recruited as an anti-atherosclerotic drug. This study seeks to endow exogenous GM3 with atherosclerotic targetability via reconstituted high-density lipoprotein (rHDL), an atherosclerotic targeting drug nanocarrier. Unloaded rHDL, rHDL loaded with exogenous GM3 at a low concentration (GM3 -rHDL), and rHDL carrying GM3 at a relatively high concentration (GM3 -rHDL) were prepared and characterized. The inhibitory effect of GM3-rHDL on lipid deposition in macrophages was confirmed, and GM3-rHDL did not affect the survival of red blood cells. In vivo experiments using ApoE mice fed a high fat diet further confirmed the anti-atherosclerotic efficacy of exogenous GM3 and demonstrated that GM3 packed in HDL nanoparticles (GM3-rHDL) has an enhanced anti-atherosclerotic efficacy and a reduced effective dose of GM3. Then, the macrophage- and atherosclerotic plaque-targeting abilities of GM3-rHD, most likely via the interaction of ApoA-I on GM3-rHDL with its receptors (e.g., SR-B1) on cells, were certified via a microsphere-based method and an aortic fragment-based method, respectively. Moreover, we found that solution acidification enhanced GM3 release from GM3-rHDL nanoparticles, implying the pH-responsive GM3 release when GM3-rHDL enters the acidic atherosclerotic plaques from the neutral blood. The rHDL-mediated atherosclerotic targetability and pH-responsive GM3 release of GM3-rHDL enhanced the anti-atherosclerotic efficacy of exogenous GM3. The development of the GM3-rHDL nanoparticle may help with the application of exogenous GM3 as a clinical drug. Moreover, the data imply that the GM3-rHDL nanoparticle has the potential of being recruited as a drug nanocarrier with atherosclerotic targetability and enhanced anti-atherosclerotic efficacy.