Fighting cardiovascular disease with nanoparticles that mimic cholesterol carriers

A creative group of nanomedicine researchers at Rutgers University led by Kathryn Uhrich and Prabhas Moghe have spent the past several years fine-tuning “nanolipoblockers,” nanoparticles that block the uptake of cholesterol by macrophages, the inflammatory cells that make up atherosclerotic plaques. These nanoparticles resemble oxidized low density lipoprotein (LDL) particles, binding to macrophages’ receptors for the cholesterol carriers so that the oxidized LDL itself cannot. This innovation is an example of how nanotechnology expands the range of ways to treat disease: rather than designing a small molecule to inactivate the receptor, which has so far proven unsuccessful, the tools of nanomedicine allow those working to treat cardiovascular disease to create structures that mimic the scale, charge, and other physical properties of the natural ligand. Further, because nanolipoblockers are assemblies of many parts, they can incorporate small molecule drugs to target other steps in the process of plaque formation carried out by macrophages.

Though atherosclerosis, the accumulation of fatty plaques in the arteries that causes heart attack and stroke, is a massive public health challenge, its treatment has only advanced incrementally in the past twenty years with the introduction of new types of statins. While these drugs were the first to actually address the underlying cause of atherosclerosis rather than simply lower blood pressure or treat chest pain, they only slow its development. Nanolipoblockers could represent a long sought-after next-generation therapy that would effectively block the accumulation of fatty material in artery walls in combination with statins.

Uhrich and Moghe’s breakthrough stemmed from their recognition that the low efficacy of small molecule blockers of the oxidized LDL receptor likely resulted from the fact that the receptor is designed to bind nanoscale particles. Inhibitors designed to form nanoscale complexes could therefore bind more effectively to the receptor, reducing the necessary dose. After finding that micelles (spherical assemblies of detergent-like molecules) they had previously designed for drug delivery inhibited the uptake of oxidized LDL by macrophages, they have spent the past seven years optimizing their structure to maximize uptake inhibition. Uhrich and Moghe have recently altered the stereochemistry (the orientation of various parts relative to one another) of the molecule composing the micelle to yield a version that inhibits uptake by 89% at submicromolar concentrations (1) (100 times lower than the effective concentrations of inhibitors studied by other groups) (2). These investigators have already shown that using these oxidized LDL receptor (specifically, the type A scavenger receptor)-blocking micelles to deliver a drug that promotes cholesterol efflux does indeed further reduce cholesterol accumulation and macrophage recruitment in vivo, though they did not examine effects on atherosclerosis itself (they studied acute carotid injury) (3).

Nanolipoblockers prevent uptake of oxidized low density lipoprotein (oxLDL)
Nanolipoblockers prevent uptake of oxidized low density lipoprotein (oxLDL). oxLDL was labeled with a red dye prior to uptake experiments in primary macrophages. Top, without, and below, with nanolipoblockers. Image from Poree et al., Biomacromolecules 2013.

The Rutgers team’s approach is quite clever, but the impact of these investigations will only become clear upon in vivo tests of whether nanolipoblockers block or slow atherosclerosis development in animal models. Given the complexity of the atherogenic process, accumulation of oxidized LDL in the extracellular space of the vessel wall (rather than in macrophages) might have other harmful effects. However, the results of a study in which uptake of oxidized LDL was blocked in a mouse atherosclerosis model by transduction of a gene for a soluble form of the type A scavenger receptor suggests that this therapy would be beneficial (4), as the authors observed a noticeable decrease in atherosclerotic lesion area. If results in atherosclerosis models are as impressive as those in carotid injury, Uhrich and Moghe could become well-known in the cardiovascular field.  

 

1. D. E. Poree, K. Zablocki, A. Faig, P. V. Moghe, K. E. Uhrich, Biomacromolecules,  (2013).
2.  K. Yoshiizumi, F. Nakajima, R. Dobashi, N. Nishimura, S. Ikeda, Bioorganic & Medicinal Chemistry 10, 2445 (2002).
3. N. M. Iverson et al., Biomaterials 32, 8319 (2011).
4. J. Jalkanen et al., Mol Ther 8, 903 (2003).