The Multifaceted Uses and Therapeutic Advantages of Nanoparticles for Atherosclerosis Research

Figure 1. Overall analysis of literature examples chosen for this review. Inset shows percentages of delivered therapeutic in studies for burgeoning field of biotherapeutic delivery with high potential in atherosclerosis research.

Figure 2. Analysis of Table 1 showing importance of the characteristics of certain materials used to fabricate nanoparticles for atherosclerosis research.

Figure 3. Nanoparticle strategies arising from material properties. (A) Core-shell formulations of PEG, polystyrene, and mucic acid of varying compositions modulate physical properties. Increasing hydrophobic cores mimic modified LDL and can compete with its uptake via scavenger receptors, ultimately reducing macrophage lipid uptake. (*) indicates statistical significance from oxLDL control (p ≤ 0.05). Reproduced (adapted) with permission from [105]; (B) CuS nanoparticles act as infrared thermotransducers to control cationic channels important for atherosclerosis processes. Upon irradiation, CuS NPs targeted to TRPV1 heat up and trigger the cation channel to open, allowing a flood of calcium and activation of autophagy processes, preventing atherosclerosis in the aortic root as well as in the entire aorta. Reproduced (adapted) from [108].

Figure 4. Recent examples of nanoparticle biotherapeutics and their targets in preventing atherosclerosis. Insights and techniques gained from siRNA studies has led to the delivery of larger and more complex molecules even up to cells.

Figure 5. Targeted delivery of biotherapeutics from various nanoparticle formulations. (A) Surgical models of atherosclerosis lead to disturbed blood flow in ligated artery (LCA) vs. non-surgery control normal flow (RCA) resulting in overexpression of VCAM-1 used by targeted lipoparticles delivering miRNA. Targeted liposomes (VHPK-CCL anti-miR-712) resulted in decreased plaque size, collagen content, and other markers of inflammation (* p < 0.05). Reprinted (adapted) with permission from [51]; (B) PEI-mediated delivery of athero-protective miRNA encapsulated in silica microparticles targeting E-selectin reduced overall macrophage content within plaques, marking a reduced inflammatory response. Reprinted (adapted) from [60]; (C) Collagen-IV targeted PLGA NPs encapsulating anti-inflammatory cytokine IL-10 also localized to the plaque and reduced necrotic core size and generation of ROS. Reprinted (adapted) with permission from Kamaly, N. et al. Targeted Interleukin-10 Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis. ACS Nano 2016, 10, 5280–5292. Copyright 2016 American Chemical Society.

Figure 6. Recent nanoparticle formulations enhancing drug delivery properties in atherosclerosis. (A) Solid lipid nanoparticles (SLN) are typically formed by lipids in various phases, however, the novel use of nucleolipids allows for added fine-tunability and stability, leading to the ability to encapsulate active principal ingredients (API) such as the platelet inhibitor prostacyclin (PGI2) and imaging modalities (MRI contrast agents). Reprinted (adapted) with permission from Oumzil, K. et al. Solid Lipid Nanoparticles for Image-Guided Therapy of Atherosclerosis. Bioconjug Chem 2016, 27, 569–575. Copyright 2016 American Chemical Society. (B) hydrophobic pockets within β-cyclodextrin (BCD) molecules allow for the encapsulation of potent drugs, such as rapamycin (RAP). The low toxicity and wide range of functionalization possibilities make BCD a promising tool for many studies. Reproduced (adapted) with permission from [56]. (C) Disulfide-linked Poly(l-lysine) (PLL) and heparin, a well-known natural anti-coagulant, form cationic nanoparticles that can adhere to red blood cells and ‘hitch a ride’ to the site of thrombus formation, releasing heparin as the particles degrade. Reproduced…

Figure 7. Summary of selected nanoparticle strategies capable of intervening at any stage of atherosclerosis. I—Lipid Accumulation NPs passively accumulate as well as lipids because of their size and surface functional chemistries and can even be made to mimic LDL. In addition, they can carry imaging contrast agents, drugs to lower cholesterol levels, and even nucleic acids to genetically regulate expression of cholesterol ester transfer proteins (CETPs). II—Non-resolving inflammation (A) NPs can target inflammatory recruitment receptors with conjugated moieties (peptides, aptamers, antibodies) and enter the plaque to deliver therapeutic nucleic acids, drugs, and/or imaging agents. (B) They can also interfere with macrophage uptake of oxLDL to form foam cells via competitive interaction with scavenger receptors. (C) Passive accumulation in the spleen allows for therapeutic delivery to the progenitor cells and macrophages that would normally egress to populate the plaque. III—Plaque cap destabilization NPs targeting damaged and exposed components of the fibrous cap (collagen/elastin) can deliver therapeutics and/or imaging agents as in panel II. These can lower destructive activity of…