Abstract
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 (GM3L-rHDL), and rHDL carrying GM3 at a relatively high concentration (GM3H-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.
Highlights
Atherosclerosis is a lifelong cardiovascular disease which is the leading cause of death and disability globally by triggering stroke, coronary artery disease, and other artery diseases
A dynamic light scattering analyzer detected that the average size/diameter of reconstituted high-density lipoprotein (rHDL) nanoparticles is ~161 nm, while the GM3-loaded rHDL nanoparticles have a slightly increasing average diameter (~177 nm and ~210 nm for GM3L-rHDL and GM3H-rHDL, respectively) (Table 1) which was further confirmed by the transmission electron microscopic images (Figure 1)
Prior to the animal experiments, the biocompatibility of GM3-rHDL nanoparticles in blood was evaluated by testing the effect of GM3H-rHDL nanoparticles on the number of red blood cells (RBCs) and the content of hemoglobin released from RBCs (Figure 4)
Summary
Atherosclerosis is a lifelong cardiovascular disease which is the leading cause of death and disability globally by triggering stroke, coronary artery disease, and other artery diseases. The significant increases of GM3 concentration both in the extracellular matrix and in the plasma membrane of cells in atherosclerotic plaques have been reported previously [8,9,10,11] as well as the significantly elevated expression of GM3 synthase in atherosclerotic plaques [6,12] This evidence implies the potential correlation of ganglioside GM3 with atherosclerosis. A drug delivery system rHDL nanoparticle was applied to transport ganglioside GM3 and target atherosclerotic lesions for improving the anti-atherosclerotic efficacy of exogenous GM3. This lowered the efficient dose of GM3 in ingredients, and impaired its potential side effects. We found that the acidic environment in atherosclerotic plaques may help with the release of GM3 from the rHDL nanoparticle
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