Mahdi Karimi, 1 Hossein Zare, 2 Amirala Bakhshian Nik, 3 Narges Yazdani, 2 Mohammad Hamrang, 2 Elmira Mohamed,2 Parham Sahandi Zangabad, 4 Seyed Masoud Moosavi Basri, 5 , 6 Leila Bakhtiari, 2 and Michael R Hamblin* 7 , 8 , 9
Nanotechnology could provide a new complementary approach to treat coronary artery disease (CAD) which is now one of the biggest killers in the Western world. The course of events, which leads to atherosclerosis and CAD, involves many biological factors and cellular disease processes which may be mitigated by therapeutic methods enhanced by nanotechnology. Nanoparticles can provide a variety of delivery systems for cargoes such as drugs and genes that can address many problems within the arteries. In order to improve the performance of current stents, nanotechnology provides different nanomaterial coatings, in addition to controlled-release nanocarriers, to prevent in-stent restenosis. Nanotechnology can increase the efficiency of drugs, improve local and systematic delivery to atherosclerotic plaques and reduce the inflammatory or angiogenic response after intravascular intervention. Nanocarriers have potential for delivery of imaging and diagnostic agents to precisely targeted destinations. This review paper will cover the current applications and future outlook of nanotechnology, as well as the main diagnostic methods, in the treatment of CAD.
Coronary artery disease (CAD) describes a disease process in which atherosclerotic plaque accumulates in the lining of coronary artery, producing a narrowing of the lumen of the artery, reducing the compliance of the vessel wall and gradually or suddenly causing a loss of blood supply to a portion of the myocardium . Angina or chest pain that can occur either after exercise or even at rest results, when blood supply to the heart muscle is seriously restricted. Another major problem occurs when a coronary thrombosis suddenly blocks the blood supply to the heart, precipitating a heart attack or a myocardial infarction. The commonest cause of this sudden thrombosis is the rupture of an atherosclerotic plaque in a coronary artery . The plaques that are prone to rupture have certain characteristics which are described as ‘vulnerable’. These characteristics include the presence of a thin collagen cap, a lipid-rich interior, a high metabolic rate, many activated macrophages, a high degree of inflammation, a necrotic core resulting from macrophage apoptosis and a content rich in tissue factor that precipitates the actual thrombosis . Recent reviews have widened the concept of vulnerability to heart attack to include vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia). Therefore, the term ‘vulnerable patient’ may be more appropriate to describe the high likelihood of developing cardiac events in the near future .
Atherosclerosis is a thickening of the arterial vessel wall that becomes inflamed due to atheromatous plaque formation . The propagation of the lesions in atherosclerosis leads to angiogenesis or the formation of new blood vessels within the artery wall similar to that seen in growth of cancerous tumors. Increased metabolic activity of the growing plaque requires a higher supply of nutrients and oxygen to the underlying proliferating cells. To satisfy this nutritional need, endothelial cells rapidly proliferate and form atypical blood vessels that are defective and immature. This state alters the dynamics of macromolecular transport to and from the lesion, and is responsible for the enhanced permeability and retention (EPR) effect that allows accumulation of systemically delivered macromolecules . Furthermore, tissue inflammation causes constant leukocyte recruitment through the release of proinflammatory cytokines. As leukocytes traverse through the endothelium into the extravascular space, the transport of circulating nanomaterials is facilitated by the leaky endothelial cell-to-cell junctions. This condition increases endothelial permeability and allows for selective delivery of therapeutic nanocarriers in the inflamed area .
Restenosis occurs after balloon angioplasty has been employed to widen the arterial lumen, where the vessel closes upon itself again, caused by a different mechanism than the original atherosclerosis . This pathological state caused by balloon angioplasty has been attributed to three different processes: the elastic response that occurs after the overstretching of the vessel, neointimal formation and chronic remodeling .
Current therapies for atherosclerosis focus on lessening the burden of atherosclerotic plaque, stabilizing vulnerable plaques defined as those plaques likely to rupture and cause thrombosis . To reduce the risk of in-stent thrombosis and/or restenosis caused by bare metal stents, new types of stents were designed that function as drug-eluting stents (DES). A wide range of dissimilar classes of drugs have been tested with DES in order to prevent smooth muscle cell (SMC) growth and proliferation including anticancer and anti-inflammatory agents. Another approach is the modulation of gene expression with plasmid DNA or RNA interference to generate an imbalance in local concentrations of specific signaling molecules that can inhibit the growth of certain cells, while promoting the growth of others .
Drugs that can be used to combat restenosis can be classified into four groups: anti-inflammatory, antithrombogenic, antiproliferative and immunosuppressive. Some common agents that have been loaded onto DES to inhibit restenosis are:
Sirolimus/rapamycin: these are potent immunosuppressive drugs that can also prevent migration of SMCs;
Paclitaxel: cytotoxic drug that causes inhibition of SMCs migration and proliferation;
Zotarolimus and Everolimus: bind to cytosolic FK-506-binding protein-12 and inhibit the proliferation of SMCs and T-cells;
Tacrolimus: an immunosuppressive agent;
Actinomycin D: an inhibitor of cellular proliferation like paclitaxel;
Dexamethasone: the corticosteroids are well established as anti-inflammatory drugs .
Several clinical trials have tested oral anti-inflammatory or immunosuppressive methods to prevent in-stent restenosis (ISR), and these studies have shown a significant decrease of angiographic ISR [11,12].
Furthermore, different specific molecular targets have also been used in treatment of restenosis. For instance, examination of the effect of PDGF receptor specific inhibitors, tyrphostin, AG1295 and AGL-2043 on neointimal formation revealed significant inhibition of restenosis . Some of the important studies including in vivo studies with various drugs are reported in Table 1. Additionally, Table 2 looks into couple of clinical trials which are observed related in order to investigate physiological factors such as neointima thickness and stenosis diameter.
†Cobalt chromium stents coated with a poly-lactide and poly lactide-co-glycolide biodegradable polymer and high dose.
Adhesion, activation and accumulation of platelets in injured position is one of the key factors in atherothrombosis . Currently used antiplatelet agents include cyclooxygenase-1 inhibitors (aspirin, indobufen, triflusal), P2Y12 inhibitors (prasugrel and ticagrelor , clopidogrel, cangrelor), phosphodiesterase inhibitors (dipyridamole, cilostazol), glycoprotein (GP) IIb/IIIa blockers (abciximab, etifibatide, tirofiban), thromboxane receptor and thrombin receptor (PAR-1) antagonists .
Aspirin is responsible for interrupting the production of thromboxane A2, one of the influential agents on platelet activation, by blockage of cyclooxygenase-1 enzyme . GP IIb/IIIa blockers attach to GP IIb/IIIa receptors instead of fibrinogen and Von Willebrand factor at the last stage of platelet accumulation and are considered as fast and effective antiplatelet agents . P2Y12-receptor inhibitors are activated via a hepatic metabolism to joint the adenosine diphosphate-binding positions on P2Y12-receptor which are in charge of inducing signaling cascades in platelet accumulation process .
Dual antiplatelet therapy (DAPT) is the simultaneous application of aspirin and a P2Y12-receptor inhibitor  (e.g., ticlopidine, clopidogrel, prasugrel, ticagrelor ). After myocardial infraction, all the patients should follow a DAPT prescription for a year and a single agent (commonly aspirin) afterward . Nevertheless, application of this method over a long time span escalates bleeding risk . Mauri et al. studied the application of DAPT for 12 or 30 months after DES implantation. They reported the risk of ISR was decreased by utilizing this method follow-up to 16 months compared with merely aspirin, however, the risk of bleeding was high .
Plasmonic and photothermal therapies are uprising in the field of atherosclerosis therapy. They consist of a dialectric silica core covered by a metallic shell (commonly gold or silver). While these NPs irradiated with near-infrared (NIR) laser, absorbed energy leads to irreparable damage of the tissue. This approach is like excimer laser angioplasty which uses monochromatic light energy source to excite molecules within atheroma. Acoustic dissection happens when water content is superheated to produce vapor bubbles. So, acoustic energy can be applied for plaque elimination. High-energy UV rays penetrate in the tissue at small depths causes injury of internal elastic lamina, leading to exuberant response of intima and media. On the other hand, NIR laser has little impact on elastic lamina. Three groups of plasmonics are available which could be used in atherosclerosis therapy: microbubble overlapping mode, nanocluster aggregation mode and thermal explosion mode (nanobombs) . Regression of plaque burden was achieved in two different approaches: first, transplantation of bioengineered on-artery patch advanced with stem cells bearing NP; second, trancatheter intravascular infusion or injection of NP loaded with iron containing stem cells or targeted microbubbles coated with protein and delivery to the specific site applying magnetic fields .
(to be continued)
Financial & competing interests disclosure
MR Hamblin was supported by US NIH Grant R01AI050875. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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SOURCE https://www.ncbi.nlm.nih.gov / 2016