Plasmonic Nanophotothermal Therapy of Atherosclerosis

Cardiovascular disease (CVD) is one of the main cause of disability and death worldwide. The underlying cause generally is atherosclerosis and more in particular thrombotic rupture of an atherosclerotic plaque in a vital artery. The restoration of blood flow to ischemic myocardium is established as the preeminent objective for the treatment of patients with CVD. Some modern angioplasty techniques generally just manipulate the form of the plaque and have some clinical and technical restrictions, relatively high complication rate and restenosis risk.

The most common techniques in current practice are angioplasty with stenting, and CABG surgery (for patients with multivessel disease). Balloon angioplasty and stenting, in fact, manage the form of the plaque and does not create a significant problem of plaque residue flowing from the site. Once a role for elective stent implantation was established, the next goal was to overcome the complications of subacute stent thrombosis (first of all, with the use of drug-eluting stents) and neointimal hyperplasia (bare-metal stents) through pharmacologic and physical means. Among unresolved issues, the investigators can describe restrictions in patients with stenosis of an unprotected left main coronary artery, multivessel disease, diabetes mellitus, still rather high rate of in-stent restenosis, and as a solution of the problem with a foreign body in a vessel, the development of biodegradable stents. Among physical obstacles for stenting, the investigators may note that atherosclerotic plaque build-up can exist in a number of different forms. The plaque can be quite hard and scaly, or more fatty and pliable. Moreover, Dr Peters D. with colleagues from Santa-Barbara (2009) published own data about new modular, multifunctional micelles that contain a targeting element, a fluorophore, and, when desired, a drug component in the same particle. Targeting atherosclerotic plaques in ApoE-KO mice fed a high-fat diet was accomplished with the pentapeptide cysteine-arginine-glutamic acid-lysine-alanine, which binds to clotted plasma proteins. The fluorescent micelles bind to the entire surface of the plaque, and notably, concentrate at the shoulders of the plaque, a location that is prone to rupture. They also show that the targeted micelles deliver an increased concentration of the anticoagulant drug hirulog to the plaque compared with untargeted micelles that may reduce bleeding complications and atherogenesis.

Moreover, the ability of statin drugs to reduce the volume of atherosclerotic plaque in the coronary artery wall, termed plaque regression, has received much attention. The statins have a remarkable track record of lowering cholesterol and improving survival. Apart from lowering low-density lipoprotein cholesterol (LDL-C) levels, they also have a multitude of other actions, often collectively described as pleiotropic effects. JUPITER (2003), REVERSAL (2004), PROVE IT (2004), ESTABLISH (2004), and ASTEROID (2006) trials have shown that low LDL levels after intensive statin therapy when accompanied by raised HDL, can regress, or partially reverse, the plaque buildup in the coronary arteries. The findings suggest that the various components of atheroma respond differently to treatment with medical therapies, and can be used to target plaques that are likely to respond. Thus, lipid pool, inflammatory reaction in the forms of cellular migration, humoral substance release, and oedema are still the most likely to be targets of pharmacotherapy. But, for instance, fibrous tissue, mineral deposits, and ground substance would seem to be irreversible despite metabolic manipulation.

Numerous devices recently have been described that utilize the application of heat to resolve atherosclerotic plaque (laser technique, electrosurgical removing of plaque, or with the use of radio frequency sparking, and others). Plasmonics is a novel invasive approach in medicine, and metal nanoparticles are a new type of optically active composite spherical one consisting of a dielectric core covered by a thin metallic shell which is typically gold. When nanoparticles are irradiated with a near-infrared laser, they absorb energy, which is quickly transferred through nonradiative relaxation into heat and accompanying effects, and eventually leads to irreparable damage of tissue. In oncology, metal nanoparticles may provide a novel means of targeted plasmonic photothermal therapy (PPTT) in tumour tissue, minimizing damage to surrounding healthy tissue. However, this approach does not use in cardiology today possessing the great potential for angioplasty. The efficiency of nanotechnologies, however, is limited by gaps in the current understanding of the thermal interactions between nanoparticles and laser light pulses or continuous waves in the context of complex biological environments. Irradiation, even with moderate pulses of energy, can induce melting, evaporation, and fragmentation of nanoparticles. These events can drastically alter the intended therapeutic effects and lead to the formation of vapour bubbles as well as acoustic waves and shock waves. But the last disadvantages can become advantages depending on the purposes of the treatment. Thus the study opens a new chapter in the history of plasmonics.

The investigators designed this study to check potent clinical opportunities, efficacy and safety of such a novel technique for angioplasty as plasmonic atherodestruction. The investigators have drawn the following research questions: 1) Is it possible to plasmonically entirely destruct a plaque with minimal complications? 2) What level of safety is typical for the different approaches if compare with stenting? 3) What are the advantages and disadvantages of the different delivery techniques - stem cells or magnetic field? 4) What is the meaning of the transplanted mesenchymal CD73+CD105+ stem-progenitor cells for atherosclerosis management? 5) Can plasmonic nanophotothermal therapy (PPTT) get an alternative to stenting?

Plasmonic photothermal therapy (PPTT) can potentially reduce the volume of plaque. PPTT melts an atherosclerotic plaque tissue with irreparable burning of targeted tissues, vapour bubbling of cellular cytoplasm and extracellular matrix with subsequent degradation of tissues, and destructive effects of acoustic and shock waves as the possible plaque-killing mechanisms. NPs are absolutely safe for an organism but entire kinetics is mostly unknown. The most dangerous approach with the lowest level of efficacy and safety is delivery of NPs with microbubbles if compare with stem cell-based one. Mesenchymal stem cells have appropriate effectiveness as a local delivery system with a lot of beneficial properties such as anti-inflammatory, anti-apoptotic, and multi-metabolic effects leading to plaque degradation. Thus, PPTT can become an alternative to stenting.

Among potential problems the investigators may name 1) technique of the delivery of these nanoparticles directly into the plaque (stem cells, aleuronic microbubbles with surfaced antibodies (as a local delivery system), direct injection or infusion into the coronary arteries and plaques during CABG or PCI); 2) high risk of acute fatal atherothrombosis at the heat site due to destruction of the fibrous cap of plaque (role of nanoparticles adhesion on the surface of endothelium); 3) long-term effects of the nanodestruction locally and in entire organism (distribution and effects of accumulation in different organs); 4) mechanism of this effect (plasmonic microexplosion and burning of tissue, lysis of cells due to vapor bubbling of cellular cytoplasm and extracellular tissues, destructive acoustic and shock waves); 5) optimal biophysical parameters and necessary energy levels of nanodetonation to prevent burning of surrounding tissues and perforation of the vessel; 6) plasmonic damage is irreparable, and it means the investigators have to combine it with another biotechnology for the restoration of vessel such as the use of stem cells; 7) optimal type of stem cells (source, origin, level of differentiation, potential, properties).

So, disadvantages of current low-invasive approaches (stenting, statin drugs, and others, laser, electrosurgery devices):

• Foreign body in the heart
• Restenosis, including neointimal hyperplasia (adventitial and circulating stem-progenitor cells of different origin are involved)
• Risk of fatal acute or sub-acute atherothrombosis (including 'in-stent' sub-acute atherothrombosis)
• Non-pathogenetic - cannot reverse or significantly regress the plaque
• No effect for remodeling and calcification (restriction for necessary remodeling)
• Clinical restrictions for some group (multivessel disease, left main CAD, diabetes mellitus, severe CAD and etc), on another hand, CABG is a very traumatic procedure (solution - MICS, including achievements in endoscopic stereotaxic surgery), but CABG is still an approach in charge in severe or high-risk patients

Disadvantages of the studied approach:

• The necessity of the special delivery technique
• The lost function of the artery - irreparable pro-fibrotic damage - the necessity of another clinical management for restoration of tissue - the necessity of the restoration therapy with stem cells
• The threat of acute fatal atherothrombosis due to rupture of (vulnerable) plaque
• Cannot treat non-organic part of plaque - the necessity of the special therapy - stem cells
• The harm of potent detrimental side-effects - vapour bubbling (boiling of cytoplasm and ECM with subsequent lysis of cells, and provocation of pro-apoptotic cascades), acoustic and shock waves due to the plasma-generated laser-related detonation of nanoshells in tissue
• Erratic (uncontrollable) heating - surrounding tissue of the site of interest can achieve a temperature until 38-39°. But at the site of burning final temperature can be at about 50-180 C (cauterization/ searing/ melting effect) with following the pro-fibrous effect of tissue.