Cyclodextrins bind to cholesterol. This aspect of their biochemistry has been used by the Underdog Pharmaceuticals team to produce a cyclodextrin that binds the form of toxic oxidized cholesterol known as 7-ketocholesterol. 7-ketocholesterol builds up with age and is implicated in a range of age-related conditions, particularly atherosclerosis, as altered cholesterols cause dysfunction in the macrophage cells responsible for removing cholesterols and other lipids from blood vessel walls. The outcome is the creation of fatty lesions that narrow and weaken blood vessels in older individuals, an ultimately fatal condition. Removing 7-ketocholesterol and other problem altered cholesterols is a promising approach to therapy.

In today’s research materials, the authors report on a different way to use an existing cyclodextrin to tackle atherosclerosis. They encapsulate molecules of the cyclodextrin and a statin in nanoparticles. The nanoparticles release the statin in atherosclerotic lesions, and take in cholesterol molecules that bind to the cyclodextrin. This sequestering of cholesterol aids macrophages in their work, most likely through binding some fraction of the altered cholesterols that cause issues, and results in a sizable reduction in the lesion size in a mouse model. Around a 50% reversal of atherosclerotic lesions is about the best that has been achieved in mice, and this is in that ballpark, averaged over different portions of the aorta. We might take this as helpful support for the Underdog Pharmaceuticals approach.

New nanoparticle drug combination for atherosclerosis

Physicochemical cargo-switching nanoparticles (CSNP) can help significantly reduce cholesterol and macrophage foam cells in arteries, which are the two main triggers for atherosclerotic plaque and inflammation. The CSNP-based combination drug delivery therapy was proved to exert cholesterol-lowering, anti-inflammatory, and anti-proliferative functions of cyclodextrin and statin, two common medications for treating and preventing atherosclerosis.

Researchers reported that the polymeric formulation of cyclodextrin with a diameter of approximately 100 nm can accumulate within the atherosclerotic plaque and effectively reduce the plaque even at lower doses, compared to cyclodextrin in a non-polymer structure. Moreover, although cyclodextrin is known to have a cytotoxic effect on hair cells in the cochlea, which can lead to hearing loss, cyclodextrin polymers developed by the research group exhibited a varying biodistribution profile and did not have this side effect.

The researchers exploited the fact that cyclodextrin and statin form the cyclodextrin-statin self-assembly drug complex, based on previous findings that each drug can exert local anti-atherosclerosis effect within the plaque. The complex formation processes were optimized to obtain homogeneous and stable nanoparticles with a diameter of about 100 nm for systematic injection. The therapeutic synergy of cyclodextrin and statin could reportedly enhance plaque-targeted drug delivery and anti-inflammation. Cyclodextrin led to the regression of cholesterol in the established plaque, and the statins were shown to inhibit the proliferation of macrophage foam cells.

Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy

Atherosclerotic plaques exhibit high deposition of cholesterol and macrophages. These are not only the main components of the plaques but also key inflammation-triggering sources. However, no existing therapeutics can achieve effective removal of both components within the plaques. Here, we report cargo-switching nanoparticles (CSNP) that are physicochemically designed to bind to cholesterol and release anti-inflammatory drug in the plaque microenvironment. CSNP have a core-shell structure with a core composed of an inclusion complex of methyl-β-cyclodextrin (cyclodextrin) and simvastatin (statin), and a shell of phospholipids.

Upon interaction with cholesterol, which has higher affinity to cyclodextrin than statin, CSNP release statin and scavenge cholesterol instead through cargo-switching. CSNP exhibit cholesterol-sensitive multifaceted anti-atherogenic functions attributed to statin release and cholesterol depletion in vitro. In mouse models of atherosclerosis, systemically injected CSNP target atherosclerotic plaques and reduce plaque content of cholesterol and macrophages, which synergistically leads to effective prevention of atherogenesis and regression of established plaques. These findings suggest that CSNP provide a therapeutic platform for interfacing with cholesterol-associated inflammatory diseases such as atherosclerosis.