Abstract
Accumulation of lipid-laden macrophages (foam cells) is characteristic of atherosclerosis development in the arterial walls. Ferritin nanocages have been found to passively accumulate in the atherosclerotic plaque. Ferritin has been actively investigated as a carrier for contrast agents in atherosclerosis diagnosis. We demonstrate the potential of ferritin as a carrier for therapeutic molecules to mediate cholesterol reduction from foam cells. Cyclodextrin molecules are chemically conjugated to the ferritin nanocages surface or encapsulated within the nanocages using metal co-loading methods. The cyclodextrin-conjugated ferritin has nanomolar affinity to cholesterol molecules. Treatment of foam cells with the conjugates shows decreased levels of intracellular accumulated cholesterol. The preferential localization of ferritin to foam cells is due to transferrin receptor-mediated endocytosis process. These findings show that ferritin nanocages as carriers localize cyclodextrin molecules to foam cells which mediate intracellular cholesterol reduction, thus highlighting its potential use as a therapeutic agent.
Highlights
Atherosclerosis is the leading cause of mortality globally [1]
Unlike the receptor mediated endocytosis pathway of AfFtnAA, uptake of fluorescein isothiocyanate (FITC)-MβCD has been shown to be mediated via micropinocytosis pathway in Caco cells [35]. This pathway, known as cell drinking, does not involve receptors specific to the ligand (CDs in this case) and results in uptake of the ligands along with other extracellular matrix proteins. Since this pathway is common to both foam cells and macrophage cells, no appreciable difference in FITC-MβCD uptake is observed between the two cell types as we have shown using fluorescence imaging
Ferritin protein nanocages have been proposed to be used as contrast agents due to enhanced permeability and retention (EPR) mediated preferential accumulation property in the plaque region
Summary
Exercise and cholesterol lowering drugs such as statins, are prescribed in response to atherosclerosis diagnosis. Statins, being a preventive drug, maintain cholesterol homeostasis but contribute minimally to plaque area reduction and cause side effects such as muscle degeneration with chronic use [2]. Stability of the vectors, scalability issues, and cost of these methods have limited their clinical translation [3]. To overcome these limitations, other approaches for foam cell targeting and atherosclerosis regression that could be used in conjunction or as an alternative to current therapeutic approaches are being investigated
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