Plasmonic Nanophotothermal Therapy of Atherosclerosis
Plasmonic Nanophotothermal Therapy of Atherosclerosis
The investigators hypothesize that the nanoburning is a very challenging technique to
 demolish and reverse the plaque especially in combination with stem cell technologies
 promising the functional restoration of the vessel wall.

 The completed (in July 2012) interventional three arms (n=180) first-in-man trial (the
 NANOM-FIM trial) assessed (NCT01270139) the safety and feasibility of two delivery techniques
 for nanoparticles (NP), and plasmonic photothermal therapy (PPTT) of atherosclerotic lesions.
 Patients were assigned in a 1:1:1 ratio to receive either (1) nano-intervention with delivery
 of silica-gold NP in mini-surgery implanted bioengineered on-artery patch (n=60), or (2)
 nano-intervention with delivery of silica-gold iron-bearing NP with targeted micro-bubbles or
 stem cells in hands of magnetic navigation system (n=60) versus (3) stent implantation
 (n=60). The primary outcome was TAV at 12 months.

 The observational prospective cohort analysis (an amendment to the protocol of August 29th
 2012 with a decision to extend a 1-year study for another 4 years with the assessment of the
 5-year clinical outcomes both retro- and prospectively) of the long-term clinical outcomes at
 the intention-to-treat population of 180 patients with CAD and angiographic SYNTAX score ≤22
 enrolled initially to NANOM-FIM trial will be performed at 5 years after the intervention.
 The primary outcome will be a MACE-free survival. The secondary outcomes will be MACE,
 cardiac death, TLR (target lesion revascularization) and TVR (target vessel
 revascularization). Imaging endpoints will be assessed pre-, post- procedure and at 12-month
 follow-up. Clinical endpoints will be analyzed at the baseline and at 12 and 60-month
 follow-up (the release of results is expected after October 2016). Parameters of nanotoxicity
 will be assessed. The independent adjudication analysis of the clinical outcomes is scheduled
 in 2017-2019.

 The subset post-hoc analysis will be conducted at 1- and 5-year follow-up (by the Amendment
 of August 29th 2012). At the first subset, patients underwent stenting with XIENCE V stent
 proximal to the site of nano-intervention (n=13). Subjects in the second subset were
 undergone drug-coated balloon pre-dilation with further nano-technique (n=20). Lesions in
 patients of the third subset were not prepared for the nano-approach (n=147) (neither
 stenting nor balloon angioplasty). The analysis will be performed and results will be
 released after 2018 with the same clinical outcomes.

 This project and related manuscripts were not prepared or funded in any part by a commercial
 organization. Nanoparticles and biomedical equipment were supplied free for the study by the
 non-profit Agiko and De Haar Research Task Force (Rotterdam-Amsterdam, the Netherlands). All
 rights of the authors are reserved. The access of the international academic or governmental
 organizations to the essential and primary data of the trial is restricted by the Russian
 governmental authorities due to the interest of the Russian Federal Security Service (FSB).
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.
Inclusion Criteria:

 -  age 45-65 years old

 -  male and female

 -  single- or multi-vessel CAD with flow-limiting lesions

 -  no indications for coronary artery bypass surgery (CABG)

 -  stable angina with indications for percutaneous coronary interventions (PCI)

 -  NYHA (New York Heart Association) I-III functional class of heart failure (HF)

 -  treated hypertension (in supine position: systole >140 mm Hg, diastole >90 mm Hg)

 -  de novo treated.

 Exclusion Criteria:

 -  non-compliance,

 -  angiographic SYNTAX score ≥23

 -  history of myocardial infarction (MI), unstable angina, PCI or CABG, atrial
 fibrillation or other dysrhythmias, stroke

 -  presence of indications for CABG

 -  presence of contraindications for PCI or CABG

 -  NYHA IV functional class of HF

 -  diabetes mellitus (in case of fasting glucose >7.0 mM/L or random glucose >11.0 mM/L)

 -  untreated hypertension

 -  asthma

 -  known hypersensitivity or contraindications to anti-platelet drugs

 -  contrast sensitivity

 -  participation to any drug- or intervention-investigation during the previous 60 days