Nanoparticles allow targeting of inflammation progression in cardiovascular disease

Cardiovascular disease, the leading cause of death in the industrialized world, is currently treated with statins, which lower cholesterol levels in the blood. While this does reduce risk of heart attacks by slowing the formation of atherosclerotic plaque (accumulations of fat and white blood cells), it doesn’t prevent them, so the search for better therapies continues. Because the attribute that makes plaques deadly is their ability to break free and block arteries at narrower points downstream, one promising strategy is to prevent the transition to this necrotic, breakage-prone state. This transition results from chronic inflammation, so drugs that promote the resolution of inflammation would keep plaques from becoming necrotic.

The challenge in developing such a therapy is that allowing it to distribute throughout the body would have massive immune side effects and likely reduce its ability to fight infection. To overcome this, a team at Columbia University led by Ira Tabas collaborated with nanoengineers at MIT, led by Omid Farokhzad. The Farokhzad group specializes in targeted drug delivery, and had previously shown that incorporating a collagen IV-binding peptide increases accumulation of nanoparticles at sites of inflammation, where this component of the vascular wall becomes exposed. As this also occurs surrounding atherosclerotic plaques, the team used the same nanoparticles to deliver an inflammation-resolving peptide, and found that it decreases plaque necrotic area in mice by almost two-thirds (Fredman et al., Sci Transl Med 2015).

These impressive results could still be improved, as the strategy for enhancing accumulation in plaques was not based on a screen of many targeting moieties or surface coatings. The collagen IV-binding peptide they use may indeed be among the most efficient strategies available, as it doubles accumulation in plaque and reduces that in the liver and spleen (all nanoparticles accumulate in those organs, which function to clear exogenous particles from the bloodstream).

The potential for nanoparticles to carry drugs to atherosclerotic plaques has led others to work on this problem as well, but the pro-resolving peptide results are at least as promising as anything else yet published. Other notable work in this area includes delivery of statins to plaques by loading in high-density lipoprotein (HDL), a natural cholesterol carrier, which reduces plaque area and collagen-degrading enzyme activity (Duivenvoorden et al., Nat Comm 2014). A nanoparticle system shown to block uptake of oxidized low-density lipoprotein (LDL) in vitro (previously covered on this site) had similar effects in a mouse model of atherosclerosis (Lewis et al., Proc Nat Acad Sci 2015). The clinical potential of all of these systems remains unknown, however, since heart attacks do not result from atherosclerosis in mice and none have yet been tested in larger animals.