Nanotechnology for the treatment of coronary in stent restenosis: a clinical perspective
Vascular Cell. 2011;
Received: 19 July 2010 | Accepted: 18 April 2011 | Published: 18 April 2011
Vascular Cell ISSN: 2045-824X
Coronary in stent restenosis remains a significant limitation to the long term efficacy of coronary artery stent placement. In this review the authors review the pathophysiology of coronary in stent restenosis, together with an overview of the current treatment modalities. The potential clinical utility of nanotechnology is also reviewed.
The first human safety trial of systemic nanoparticle paclitaxel (nab-paclitaxel) for in stent restenosis (SNAPIST-I) is discussed. The results showed no significant adverse advents attributable to the nab-paclitaxel at 10 or 30 mg/m2, although moderate neutropenia, sensory neuropathy and mild to moderate reversible alopecia occurred at higher doses. No major adverse cardiac events were recorded at 2 months, whilst at 6 months, 4 target lesions required revascularisation. The investigators concluded therefore that systemic nab-paclitaxel was well tolerated at a dose of <70 mg/m2. To date however, no formal clinical evaluation has been reported as to the clinical utility of nab-paclitaxel, or any of the nano preparations discussed, for the suppression of coronary in stent restenosis.
1. Introduction: Overview of Nanomedicine Applications in Cardiology
Cardiovascular disease, including acute coronary syndromes and cerebrovascular events continue to be a major source of mortality and morbidity. Current medical screening and diagnosis is limited and many of the symptoms and signs of cardiovascular and cerebrovascular disease are non-specific.
Nanomedicine provides a unique opportunity to explore at a cellular or organ level the various pathophysiologies of the cardiovascular system. Nanomolecules have been used in:
Assessing and treating atherosclerosis in asymptomatic patients Coronary revasculariation Thrombolytic therapy Treatment of coronary in stent restenosis.
2. The use of Nanotechnology for the Treatment of Coronary In Stent Restenosis
There is still a significant requirement for a novel drug delivery mechanism for the treatment of coronary in stent restenosis, due to the limitations of the current modalities including late stent thrombosis.
A nanoparticle based approach is ideal for the treatment of restenosis since targeted delivery of nanoparticles is feasible and much lower concentrations of the active drug can be used hence reducing systemic toxicity.
The size of particle however is critical in the distribution of nanoparticles in the blood vessel wall. Westedt
Some examples of nanoparticles used in the treatment of in stent restenosis are reviewed below.
3.1 Lipid Based Nanoparticles
Liposomes are small and have a spherical shape and are formed from natural and non-toxic phospholipids and cholesterol. As liposomes are small and posses hydrophobic and hydrophilic characteristics there are ideally suited to the development of novel drug delivery systems . Liposome surfaces can be modified to increase circulating half-life and conjugated to antibodies or ligands for enhanced tissue specificity.
Lipid based nanoparticles have been utilised to deliver a number of different classes of drug to the arterial endothelium.
Clodronate, a bisphonsphonate, has been delivered using liposome nanoparticle of 1:3 distearoyl phosphatidylglycerol, 1, 2 distearoly-sn-gylcero-3-phosphcholine . Lyposomal choldronate inhibited neointimal growth in the balloon injured rabbit carotid artery after systemic administration. Other members of the bisphosphonate class of drugs including pamidronate and alendronate have been utilised as antirestenotic agents in balloon injured rat carotid artery model . It is noteworthy, however, that these experiments were performed in a carotid artery model and whether the results are relevant to coronary restenosis after PCI remains unknown.
TRM 484 consists of nanoparticles of prednisolone with high infinity to chrondroitin suphate proteoglycans and at a dose of 1 mg/kg significantly reduced neo intimal growth in atherosclaratic New Zealand White Rabbits implanted with bare metal stents .
3.2 Polymeric based nanoparticles
These are solid, colloidal particles of macromolecules that range in size from 10-1000 nm . They are idea drug delivery systems , where the compound of interest may be dissolved, entrapped, adsorbed, attached or encapsulated into the nanoparticle matrix [8, 9].
Early work on polymeric nanoparticles began with a comparison of probucol delivery by polymeric and liposomal nanoparticles. Probucol has been shown to reduce restenosis after angioplasty provided oral administration is commenced one month before the procedure . Klughertz and colleagues prepared 35S-probucol incapsulated in either liposomal or polylactic-coglycolic acid (PLGA) nanoparticles, which were delivered using an infusion catheter after balloon angioplasty of rabbit iliac arteries. Iliac arteries, perivascular fat and downstream tissues were harvested and the radioactivity measured from animals euthanized on day 0,3 and 7 after dosing. The results showed after delivery efficiency was superior with PLGA . It should be noted however that these experiments were conducted outside the coronary circulation.
Paclitaxel is a member of the taxane family of drugs. Paclitaxel loaded nanoparticles have been prepared from oil-water emulsion using biodegradable PLGA and surface modified with the cationic surfactant didoceylmethylammonium bromide (DMAB) to enhance arterial retention.
Work from another group has demonstrated that the antiproliferative effects of paclitaxel can be significantly improved by co-administration of other agents . C6-ceramide is an apoptotic signalling molecule and has been combined with paclitaxel in polymeric nanoparticles consisting of poly(ethylene oxide) - modified poly (episilon caprolactone). Combination of paclitaxel with cereamide when administered in nanoparticle formulation significantly augmented the antiproliferative effect of either agent alone .
The angiotensin-converting-enzyme inhibitor, lisinopril, has also been encapsulated in nanoparticles of PLGA for site specific delivery by catheters for the prevention of coronary in stent restenosis , although to date
Further work from Cohen-Sela's group  incorporated the antiproliferative agent mitramycin into PLGA nanoparticles using a nanoparticipation technique. Unfortunately
Work to increase the bioadhesive properties of nanoparticles has been suggested to improve retention and arterial uptake of nanoparticles into the arterial wall . Zou
Recent research has focused on the administration of drugs using biodegradable polymer nanoparticles capable of prolonged drug release. Sustained drug release of dexamethasone or rapamycin from nanoparticles based on poly (ethylene oxide) and poly (d.L-lactic-co-glycolic acid) block copolymers has been investigated . The investigators found that treating the nanoparticles with gelatine or albumin after drug loading resulted in a linear drug release, the rate of release being related to the amount of protein associated with the nanoparticles . Release of dexamethasone and rapamycin was sustained for 17 and 50 days respectively .
The tryphostins are a class of platelet derived growth factor (PDGF) receptor β tyrosine kinase blockers [22, 23]. Preclinical investigations have reported results with the experimental compound AG-1295 incorporated in polylactide nanoparticles. PLA AG-1295 nanoparticles were delivered via an infusion catheter in a balloon injured swine model, resulting in inhibition of smooth muscle cell (SMC) growth. Further, another tyrphostin AGL-2043 encapsulated in in PLA nanoparticles inhibited restenosis in both balloon injured rat carotid artery and stented porcine artery models .
3.3 Gel like Nanoparticles
Previous research  has demonstrated that nanosized (100 nm) hydrogel spheres made of poly (N-isopropylacrylamide) are internalised by endothelial cells and VSMC more than microspheres (1 μm), although cellular uptake was dependant on the incubation time, sphere concentration and introduced shear stress levels of the medium. In contrast, microspheres were rapidly taken up by phagocytes, especially at high concentration . These findings lead the authors to suggest that hydrogel nanospheres are more effective as an intravascular delivery system in terms of vascular uptake and biocompatibility .
Since significant number of VSMC undergo rapid apoptosis following balloon angioplasty Reddy and colleagues  tested the hypothesis that preventing VSMC from apoptosis could prevent intimal hyperplasia. They used rapamycin (which has anti-apoptotic and antiproliferative actions) loaded gel nanoparticles of mean diameter 54 nm. When infused into a rat carotid artery model of vascular injury the authors report significant inhibition of hyperplasia and re-endothelialisation of the injured artery. Further, the group report inhibition of activation of caspase 3/7 enzyme systems in the treated artery, preventing VSMC from undergoing apoptosis 
3.4 Miscellaneous Studies
Moreover, further preclinical work has demonstrated the utility of tissue factor targeted nanoparticles containing doxorubicin or paclitaxel to inhibit VSMC proliferation in culture .
In addition, intra mural delivery of αVβ3-targeted rapamycin loaded nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury .
3.5 Clinical Study
To date only one human study has been reported in the literature. In 2007, Margolis
Much work therefore has been undertaken to evaluate the potential clinical utility of nanoparticles for the targeted and non-targeted delivery of various agents with antiproliferative and anti-restenostic actions. To date most of these investigations have been conducted either
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