Moghe:NanoLipoBlockers

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A prime example of nanoscale interactions of cells and matrix is initiated within the vascular circulation (blood vessels). Low density lipoproteins trapped within the vascular intima are progressively oxidized and modified. The oxidized LDL is rapidly internalized within blood immune cells such as macrophages, which transform into foamy cells, secrete cytokines that trigger the excessive proliferation of smooth muscle cells, and ultimately undergo apoptosis. These inflammatory events, in conjunction with thrombosis, escalate the development of atherosclerotic plaques, and pose a major risk factor for plaque growth, plaque destabilization, and narrowing of blood vessels (stenosis).

The Moghe laboratory, in collaboration with Professor Uhrich (Chemistry, Rutgers), has designed nanoscale self-assembled particles whose backbone chemistry and architecture can be systematically varied to exhibit controlled amphiphilicity and anionic groups. The particles are self-assembled from unimers comprised of acylated derivatives of biocompatible mucic acid conjugated with poly(ethylene glycol), where anionic functional groups can be derivatized to either terminus. In a first publication, such nanoparticles were shown to complex with unoxidized LDL but not with oxidized LDL (Chnari et al., 2005). A coarse grain and molecular dynamics simulation study is ongoing to describe the lipoprotein retentivity of the nanoparticles (Li et al., 2006). Subsequent studies in the Moghe laboratory report that the anionic nanoparticles reduce the kinetics of unoxidized LDL by complexation with LDL but reduce the kinetics of oxidized LDL by binding to scavenger receptors (Chnari et al., 2006). Recent efforts have identified SRA and CD36 to be the key scavenger receptor targets for the anionic nanoparticles; consequently, blockage of scavenger receptors by the nanoparticles reduced cytokine secretion, foam cell formation, and cholesterol accumulation (Chnari et al., 2006). Certain characteristics of the nanoparticles were found to be requisite to maximal scavenger receptor binding. For example, positioning of anionic groups on hydrophobic termini were found to reduce oxLDL uptake but not if the anionic groups were displayed from hydrophobic termini. Recent studies implicate the size as well as anionic charge density to be important variables that further accentuate the ability of nanoparticles to inhibit oxLDL uptake (Wang et al., 2006). These studies are promising as nanotechnology affords a possible avenue to effectively alter the dynamics of lipoportein matrix retention within the intima. Systematic studies of binding affinities between the nanoparticles and major scavenger receptors are being pursued using surface plasmon resonance. Further studies are proposed to elucidate how the nanoparticle structure influences the receptor binding, cross-linking, and possible conformational changes leading to receptor internalization. The goals are to identify nanoparticle structures that maximally occupy scavenger receptors with minimal degree of receptor internalization. Animal models are currently being tested to examine the potential for the nanoparticles to reduce inflammation and atherogenesis. The advances in this project have been highlighted recently by news release from the American Chemical Society and Nanobiotechnology News, and industrial partnering is envisioned for successful translation of this project for further development and possible testing for therapeutic potential.