Plasmonic Nanophotothermal Therapy of Atherosclerosis
Condition: Stable Angina; Heart Failure; Atherosclerosis; Multivessel Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Atherosclerosis; Angina, Stable
Study type: Interventional

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Transplantation of nanoparticles; Transplantation of iron-bearing nanoparticles; Stenting
Intervention type(s): Procedure; Procedure; Device
Intervention description(s): 60 patients into nanogroup with the use of 60/15-70/40 nm silica-gold nanoparticles (NPs) transplanted by endoscopic cardiac surgery in the composition of bioengineered on-artery patch grown on the basis of biopolymeric scaffold and host circulating CD45-CD34-CD73+CD105+ progenitor cells; 60 - into ferro-magnetic group with 60/15-70/40 nm silica-gold iron-bearing NPs with delivery in hand of magnetic navigation system; 60 - in sirolimus-eluting stenting control
Other intervention name(s): XIENCE V
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: nanoparticles; mesenchymal stem cell; plasmonics; atherosclerosis; IVUS; stenting