Anti-atherosclerotic effect of lipid/cholesterol-cyclodextrin inclusion complexes similar to free cyclodextrins in ApoE-/- mice fed a high-fat diet

Cyclodextrins have long been used as a drug excipient (e.g., drug-cyclodextrin inclusion complex) to ameliorate the water solubility and taste of drugs. Cyclodextrins are cyclic oligosaccharide molecules featuring a hydrophobic inner cavity and a hydrophilic outer surface. Drugs are physically encapsulated within the cyclodextrin cavity, forming inclusion complexes through non-covalent interactions with the hydrophobic interior of cyclodextrins. Recently, increasing evidence shows that cyclodextrins have an inhibitory effect against atherosclerosis, a chronic disease inducing atherosclerotic cardiovascular diseases (ASCVDs). We hypothesized that drug-cyclodextrin inclusion complexes probably also have anti-atherosclerotic effects because free cyclodextrins will exist for a period of time in vivo after the release of drugs from drug-cyclodextrin inclusion complexes. To test this hypothesis, hydroxypropyl-β-cyclodextrin (HPβCD) encapsulating cholesterol or lipids was utilized to mimic drug-cyclodextrin inclusion complexes. The cholesterol- or lipids-HPβCD inclusion complexes were prepared and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and dynamic light scattering (DLS). Subsequently, the anti-atherosclerotic efficacy of the cholesterol-/lipids-HPβCD inclusion complexes was evaluated in an atherosclerotic animal model (high-fat-fed ApoE -/- mice) by analyzing blood lipid profiles and atherosclerotic lesions in the entire aorta, the aortic arch, and the aortic root. The results reveal that both cholesterol- and lipids-HPβCD inclusion complexes significantly reversed blood lipid increase and plaque formation, implying that similar to free cyclodextrins drug-cyclodextrin inclusion complexes potentially also have anti-atherosclerotic efficacy. The data provide strong evidence for the notion and guideline that drug-cyclodextrin inclusion complexes are potentially a dual-use drug and the possibility of using drug-cyclodextrin inclusion complexes instead of free cyclodextrins for the treatment of atherosclerosis or ASCVDs. It also implies that the anti-atherosclerotic efficacy of the cyclodextrin part should be considered/excluded while evaluating the anti-atherosclerotic efficacy of a specific drug in its cyclodextrin inclusion complexes. Preparation and effect of cholesterol-HPβCD and lipid-HPβCD inclusion complexes. Schematic diagram of drug-cyclodextrin inclusion complexes dual-use mechanisms in atherosclerosis. The drug acts on other sites and HPβCD acts on atherosclerotic plaques.