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Nanotechnology and nanomedicine in cardiovascular therapy
9 Nanotechnology and nanomedicine in cardiovascular therapy T. K H A N, R. S. V O H R A and S. H O M E RVA N N I A S I N K A M, Leeds General Infirmary, UK
Abstract: Cardiovascular diseases (CVDs) are the leading cause of death in the Western world. Nanotechnology and nanomedicine are being utilised in the diagnosis and therapy of CVD and show real promise in certain areas. This chapter explores the use of nanotechnology in the therapy of CVD, including the potential role of nanofibres. It also examines the use of nanomedicine in a variety of imaging modalities employed in CVD management including positron emission tomography, optical imaging, computed tomography, ultrasound, magnetic resonance imaging and dual mode imaging. The chapter concludes by scrutinising the challenges facing this novel technology and its future prospects. Key words: cardiovascular disease, vascular disease, nanotechnology, nanomedicine, imaging, nanofibres.
9.1
Introduction: nanomedicine in cardiovascular therapy
Atherosclerosis and neointimal hyperplasia both contribute to cardiovascular disease (CVD), with atherosclerosis resulting in initial native vessel stenosis and neointimal hyperplasia leading to recurrent stenosis after operative intervention. Atherosclerosis is a syndrome characterised by plaque (or less commonly aneurysm) formation in arteries as a result of inflammation leading to a systematic disease often presenting with a significant overlapping of disorders including coronary heart disease, peripheral arterial disease, and carotid arterial disease (Liapis et al., 2009). Neointimal hyperplasia is the foundation, between the endothelium and the inner elastic lamina or luminal surface of vascular grafts/endovascular stents, of a thickened fibrocellular layer (Wang et al., 2006). Modulation of the well-characterised risk factors is sometimes not enough to control the disease process and potential for the use of nanomedicine in the therapy of CVD is extensive.
9.1.1 Stenosis, restenosis and neointimal hyperplasia Advances in drug eluting stent (DES) technology have improved the management of coronary artery disease. They inhibit restenosis through the 251 © Woodhead Publishing Limited, 2010
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controlled release of an antiproliferative agent, e.g Paclitaxel, following deployment and so improve long-term patency rates (Saia et al., 2008). However, this technology has drawbacks including stent thrombosis, longterm anti-platelet therapy and expense. The delivery of Paclitaxel using nanoscaffolds may improve patency rates even further. Nab-paclitaxel, a novel form of albumin-bound paclitaxel has been shown to reduce restenosis in animals and its safety is currently being investigated in humans. Margolis et al. (2007) assessed 23 patients (mean age 66 ± 10 years, 74% men, 26% with diabetes) receiving various intravenous doses of nab-paclitaxel following stenting of a single de novo lesion. Interestingly no major adverse cardiac events were reported at two or six months and only four incidences of restenoses requiring interventions were seen. However, at the higher doses of Nab-paclitaxel side-effects including moderate neutropenia, sensory neuropathy and alopecia were noted. Invasive catheter-based delivery of paclitaxel-coated nanoparticles may allow concentrated drug administration. Nanoparticles, consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) combined with paclitaxel, when administered via a catheter placed in balloon-injured rabbit iliac arteries show a significant 50% reduction in neointimal area when compared with controls (0.80 ± 0.19 mm2 with paclitaxel nanoparticle treated segments vs. 1.58 ± 0.6 mm2 control) (Westedt et al., 2007). Subsequent studies have shown similar outcomes when using paclitaxel-loaded biodegradable scaffolds in animal models (Mei et al., 2007, 2009). Neointimal hyperplasia at venous anastomosis sites in renal access surgery for dialysis is another area where the use of Paclitaxel has been assessed. Paclitaxel coated expanded poly(tetrafluoroethylene) (ePTFE) has been shown to reduce stenosis rates. However, these stents release the agent immediately upon revascularisation rather than a delayed or controlled release, which may attenuate restenosis rates. To enable controlled drug release, pacliataxel loaded poly(lactic-co-glycolic acid) nanoparticles were coated onto the luminal surface of ePTFE grafts by micro-tube pumping and spin penetration techniques. This avoided the initial burst release of the drug following reconstitution of flow within the conduit (in vitro) and produced a controlled drug delivery system (Lim et al., 2007). The role of numerous other agents bound to nanoparticles has been investigated including nitiric oxide (NO). Gels consisting of peptide amphiphile, heparin, and a diazeniumdiolate nitric oxide donor (1-[N(3-aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate (DPTA/ NO) or disodium 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2diolate (PROLI/NO) were applied to the periadventitial region of a rat carotid artery during surgery after endovascular balloon injury. Gels released nitric oxide locally for four days and resulted in attenuation in the neointimal hyperplasia response by up to 77%. Importantly, in vivo studies
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suggest that this inhibition of proliferation had a minimal effect on apoptosis (Kapadia et al., 2008). Platelet-derived growth factor (PDGF) is a key component in vein graft failure as it promotes proliferating vascular smooth muscle cells proliferation and monocyte infiltration. Therefore, delivery of PDGF-receptor tyrosine kinase inhibitor may inhibit hyperplasia. Indeed, polyethyleneglycol-modified poly(dl-lactide-coglycolide) nanoparticles coated with a PDGF-receptor tyrosine kinase inhibitor have been investigated. These particles were infused into excised rabbit segments of jugular vein and subsequently interposed into the ipsilateral carotid. At 28 days, there was significant suppression of neointima formation when compared to controls (Kimura et al., 2008). Doxorubicin, an alternative antiproliferative drug, has also been coupled with polyethylene glycol (PEG)-based block copolymer to form a core– shell nanoparticle (NK911). Again, intravenous administration of NK911 significantly inhibited neointima formation in a rat carotid model 4 weeks post-injury. Intravenous doxorubicin alone did not produce such results. Again an important observation is that NK911 inhibition of vascular smooth muscle proliferation is not accompanied by apoptosis or inhibition of inflammatory cell recruitment. Furthermore, NK911 was well tolerated without any adverse systemic effects (Uwatoku et al., 2003). A balance between limiting vascular stenosis and promoting endothelial healing in these balloon injury models is critical. The ability of nanoparticles to achieve this balance is demonstrated by the use of αvβ3-integrin-targeted rapamycin. Injured rabbit femoral arteries using a balloon stretch model showed a 50% reduction in luminal plaque in the targeted rapamycin segments when compared with contralateral control vessels using magnetic resonance angiograms (MRA). Indeed endothelial healing was similar in the αvβ3-integrin-targeted rapamycin treated group as in controls (Cyrus et al., 2008). Other more commonly used agents have been combined with nanoscaffolds to investigate any improvement in bioavailability. Prednisolonephosphate incorporated in pegylated 3,5-dipentadecyloxybenzamidine hydrochloride (TRM-484) has been shown to significantly reduce in-stent neointimal growth in atherosclerotic rabbits (Joner et al., 2008). Lisinopril encapsulated in poly(lactide-co-glicolide) nanoparticles has shown a promising release profile suggesting that it may be suitable for site-specific delivery by catheters in the prevention of restenosis following balloon angioplasty (Varshosaz and Soheili, 2008). 2-(2-Aminopyrimidino) ethyldiene-1,1bisphosphonic acid incorporated into a polylactide/glycolidebased polymer again produces a significant attenuation of neointima : media ratio (40%) and stenosis (45%) in a rat carotid artery injury model in comparison with controls. Hyperplasia was also significantly reduced after
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subcutaneous and intraperitoneal injection (Cohen-sela et al., 2006a,b). These agents may provide a cost-effective alternative. In addition to improving drug delivery, advances in nanotechnology may also modify drug action. Superparamagnetic nanoparticles can render endothelial cells magnetically responsive and thereby guide them onto steel stent wires through a series of magnetic field gradients (Polyak et al., 2008). Nanoparticles as gene carriers have been implicated as possible therapeutic agents. A poly(lactic-co-glycolic acid) complex with an incorporated plasmid DNA shows reduced interactions with blood components when infused into a rabbit carotid artery. When these particles are loaded with antisense against monocyte chemotactic protein-1, an improvement in gene transfer into vascular lesions was observed with a reduction of the intima : media ratio (Yang et al., 2008).
9.1.2 Angiogenesis Angiogenesis is the foundation of new blood vessels and may be due to vasculogenesis (spontaneous blood formation) or intussusception (growth of new blood vessels by branching from existing ones) (Burri et al., 2004). Therapeutic angiogenesis is used to promote healing in conditions which were traditionally difficult to treat, such as ischemic ulceration. Vascular endothelial cell growth factor (VEGF) is a key component in promoting angiogenesis, but intravenous administration alone is ineffective and localised delivery is required. This was originally described using a peripherally inserted catheter which is invasive. VEGF bound to dextran sulphate at its heparin binding site and encapsulated by selected polycations (chitosan, polyethylenimine, or poly-l-lysine) can produce controlled local release of VEGF for approximately 10 days (Huang et al., 2007). VEGF incorporated into a hydrogel is stable for up to a month (Matsusaki et al., 2007). VEGF-gene delivery when combined with nanoparticles is an alternative to protein delivery. When injected into rabbit myocardium the enhanced gene transfection produces a significant increase in the number of capillaries (Yi et al., 2006). In addition a similar agent injected into a rat ischaemic limb model demonstrated a significant improvement in neovascularisation in comparison to plasmid DNA at 12 days following therapy (Kang et al., 2008). Furthermore, magnetic nanoparticles containing VEGF plasmid can be localised to a specific area when in a magnetic field producing enhanced VEGF delivery and a subsequent doubling of the capillary density and capillary-to-muscle fibre ratio when compared with controls (Jiang et al., 2005). In addition, local expression of VEGF can be induced by targeting hypoxia inducible factors such as hypoxia inducible factor-1α. When nanoparticles containing the hypoxia inducible factor-1α gene are applied
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to full-thickness dermal wounds, angiogenesis was significantly higher along with the level of maturity when compared to that induced by the application of VEGF (Trentin et al., 2006). Therapy of CVD has become a highlight of nanomedicine research and may play a central role in disease prevention and treatment.
9.2
Nanomedicine in cardiovascular imaging
There has been a significant improvement in platform technology for imaging modalities for magnetic resonance imaging (MRI), nuclearcomputed tomography imaging, and optical and ultrasound imaging. In addition our increased understanding of specific cellular markers has provided novel targets for these modalities over the past 10 years. Added to this the potential of nanotechnology, the area of CVD imaging is an extremely exciting one.
9.2.1 Nuclear/positron emission tomography imaging The general approach of nuclear (gamma/SPECT (single photon emission computed tomography)) imaging and positron emission tomography (PET), for example, has been to utilise very small tracer quantities of contrast agents (e.g. radionuclide-labelled antibodies, peptides or small molecules) rather than large payload particles. For example, folate receptor-targeted polymeric shell cross-linked nanoparticles containing 64Cu have been recently used for PET imaging of tumours. Other approaches for characterising atherosclerosis include imaging of apoptosis by annexinphosphatidyl serine targeting, unstable carotid plaque imaging with metabolic (fluorodeoxyglucose) readouts, and macrophage chemotaxis imaging (Blankenberg et al., 2002; Rudd et al., 2002; Britz-Cunningham and Adelstein, 2003; Rossin et al., 2005).
9.2.2 Optical imaging Quantum dots are small (<10 nm) fluorescent semiconductor nanocrystals which possess unique luminescent properties compared with more established organic dyes and fluorescent proteins. Their fluorescence emission is stable and dependent on particle size. Cadmium selenium–zinc sulphide quantum dots have been used to visualise capillaries hundreds of micrometres deep through the skin of living mice. Cadmium-based quantum dots have also be used to image cerebral vasculature. Methoxy-PEGylated quantum dots were used to visualise arterioles and capillary networks in mouse hind limb skeletal muscle (Akerman et al., 2002; Larson et al., 2003; Bateman et al., 2007; J.D. Smith et al., 2007).
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Viral nanoparticles can also be fluorescently labelled to high densities. An example of this is the use of the cowpea mosaic virus (in living mouse and chick embryos) as a probe which allows dynamic imaging of the vascular endothelium for up to 72 hours and to a depth of 500 μm (Lewis et al., 2006).
9.2.3 Computed tomography imaging The most widely used contrast agents for computed tomography (CT) over the past 25 years are iodine based (on a platform of tri-iodobenzene). These molecules are limited in CVD by their non-specific distribution, brief imaging times, extravasation and unsuitability in those with renal impairment (Hainfeld et al., 2006; Rabin et al., 2006; Kong et al., 2007). Gold nanoparticles coated with PEG have nearly a five times higher attenuation level than that of Ultravist (a commonly used current CT contrast agent). Intravenous infusion, of these nanoparticles, into a rat model revealed a significantly longer intravascular time at four hours when compared to 10 minutes for Ultravist. In addition the cardiac ventricles and great vessels could be clearly delineated. However there was significant accumulation of these particles within the liver and spleen; the significance and fate of this is unclear (Kim et al., 2007). However, smaller particles (1.9 ± 0.1 nm) integrated with gold (obtained from Nanoprobes, Inc.) when injected intravenously into mice displayed lower retention levels in the liver and spleen. Futhermore blood vessels with diameters of approximately 100 μm along with regions of angiogenesis were visible. There was no evidence of toxicity up to 30 days after injection nor any alteration in mouse behaviour (Hainfeld et al., 2006). Gold nanoparticles have also been used to visualise tumour vasculature in a mouse model with a stable imaging window up to 24 hours post-injection (Cai et al., 2007). Nanoparticles used in CT imaging also include a polymer coated bismuth sulphide unit and a Lipiodol-based agent. In a mouse model, the Bismuthbased nanoparticle has demonstrated a five-fold improved X-ray absorption compared with iodine, a circulation time of two hours and a safety profile comparable to iodine-based imaging agents (Rabin et al., 2006). On the other hand Lipiodol, a naturally occurring iodinated compound, can be modified with Pluronic F127 (copolymer poloxamer 407) to deliver a nanostructure with a longer circulation time than commercial iodinated preparations while maintaining a similar safety profile (Kong et al., 2007).
9.2.4 Ultrasound imaging Ultrasound with its advantages of good patient tolerance, low cost and benign compression waves is established as an indispensable radiological
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tool. Its use has become widespread in most healthcare settings, leading to increasing interest in improving ultrasound efficacy through the introduction of micro- and nanoparticle-based agents. Microbubbles have been used in cardiovascular imaging as they produce an acoustic signal in an ultrasound field, thereby allowing assessment of perfusion. Smaller particles such as liquid-filled nanodroplets may have an important role. These nanoparticless have shown promising results in imaging microvasculature (to 100 μm). However, ultrasound imaging is less sensitive to liquid-filled nanoparticles due to their size and relative incompressibility when compared with microbubbles (Dayton et al., 2006). As microbubbles and nanodroplets have their own specific advantages, parallel development of both particle families continues. For example, gas-filled microspheres and liquid-filled nanoparticles may be employed in ultrasound molecular imaging by the incorporation of surface receptor-specific ligands. Such particles may be used in microvascular imaging to detect upregulated leukocyte adhesion molecules as in ischaemia reperfusion (Weber and Lemor, 2004; Kaufmann and Lindner, 2007; Kaufmann et al., 2007; Villanueva and Wagner, 2008).
9.2.5 Magnetic resonance imaging The non-invasive nature, high resolution and contrast of magnetic resonance imaging (MRI) along with lack of ionising radiation have led to its wide use in the clinical setting. Therefore considerable interest has been generated in investigating the feasibility of utilising nanoparticles to improve MRI (Cyrus et al., 2005; Mulder and Fayad, 2008). Magnetic particles have the ability to respond to variations in magnetic fields and this characteristic makes them ideal candidates in the development of nanostructures in MRI. Superparamagnetic iron oxide particles have several possible clinical applications including the detection of metastases and in inflammatory diseases. Superparamagnetic iron oxide particles have been combined with Annexin V (which recognises apoptotic cells via phosphatidyl serine) to create a targeted nanoparticle which has been successfully used to identify high grade atherosclerotic regions. In a rabbit model of atherosclerosis this nanoparticle displayed negative MRI contrast at atheromatous lesions but not at healthy arterial sites nor in healthy controls. The dose of targeted nanoparticle required was in the order of a thousand times less than for untargeted superparamagnetic nanoparticles with recognisable differences between occlusive and mural plaques. Plaque contrast is maintained for two months; however, this is undesirable in patients requiring regular repeat MRI to assess disease progression (Smith et al., 2007). It is postulated that iron oxide nanoprobes may also be used to label macrophages which can then be tracked to sites of atherosclerosis.
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The resulting accumulation of these particles may then be detected by MRI (Zhang et al., 2008). While lacking the advantages of targeted nanoparticles, non-targeted nanoparticles can be easier to produce and may still be of benefit in MRI. They can be combined with other novel techniques such as inversion recovery with on resonant water suppression (IRON). IRON causes dispersion of the resonant frequency of the protons in proximity to the contrast agents. Since contrast agents are localised in the blood this leads to higher intravascular contrast (Riederer, 2008). Employing IRON with the long circulating monocrystalline iron oxide particle (MION)-47, in a rabbit model, led to an increase in intravascular contrast whilst suppressing background tissue (mean contrast to noise ratio after injection was 61.9 ± 12.4 vs. a baseline of 1.1 ± 0.4 p < 0.001) and was also higher when compared with conventional magnetic resonance angiograms. The combination of these two technologies may result in an improvement in clinical MRI use (Korosoglou et al., 2008). There are other applications of nanotechnology in tissue engineering. Human aortic smooth muscle cells loaded with ultra-small superparamagnetic iron oxide nanoparticles were seeded into tissue engineered vascular grafts and subsequently implanted as aortic interposition grafts in mice. The nanoparticles were retained for three weeks during which MRI was used for real time non-invasive monitoring of smooth muscle cell retention (Nelson et al., 2008). This technology could be used to improve current tissue engineering of vascular conduits and validate engineered grafts in the future. Nanoparticles have also been used to improve experimental techniques. In the laboratory setting iron oxide nanoparticle-loaded vascular smooth muscle cells were delivered endovascularly to abdominal aortic aneurysms in a rat model. The presence of these nanoparticles could be confirmed on MRI (Corot et al., 2006; Deux et al., 2008). Non-iron-based magnetic nanoparticles are being developed. These include magnetoliposomes, which are magnetite cores encapsulated in a phospholipid bilayer. Such phospholipid vesicles containing phosphatidylethanolamine-diethylenetriaminepentaacetic acid can be complexed with gadolinium ions (Gd3+) to produce an agent which may have potential in MRI contrast, though in vivo data are awaited (Ito et al., 2005b; De Cuyper et al., 2007). Another family of nanoparticles showing promise in MRI are dendrimers. Different generations of gadolinium (Gd3+) diethylenetriaminepentaacetic acid (DTPA)-terminated poly(propylene) dendrimers have been developed as contrast agents in MRI. These Gd3+-based complexes provided prolonged intravascular duration with improved contrast. Each generation is defined according to the number of Gd3+ ions per molecule (G1 – 4 ions per molecule, G3 – 16 ions per molecule, G5 – 64 ions per molecule, etc.).
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The generations with higher Gd3+ content (G3 and G5) show prolonged enhancement of tissue vasculature and are suited for non-tissue specific imaging of sub-millimetre sized blood vessels (Yan et al., 2005; Langereis et al., 2006). In a study comparing G1, G2 and G3 contrast agents, G3 agents provided prolonged contrast enhancement in the heart and vasculature and did so at a lower dose (Kaneshiro et al., 2008). The creation of Gd3+ dendrimers has been followed by intra-generational modifications. Two different G4 agents, bearing either an isothiocyanate or succimidyl ester moiety, displayed equivalent organ vasculature enhancement although with different clearance rates. This may allow greater flexibility in contrast dose and imaging time while using almost identical agents (Xu et al., 2007). The role of nanotechnology in MRI continues to be a rapidly expanding field as is exemplified by the recent use of a gold and copper nanoshell in an in vivo mouse model where it enhanced vascular contrast, but with a dose-dependent toxic effect, indicating the need for more detailed investigation (Su et al., 2007).
9.2.6 Dual-mode imaging Dual-mode imaging yields greater information than either method alone by allowing the clinician to employ different imaging modalities (each with its own advantages) highlighting different areas of interest while using a single contrast agent. To aid this, nanostructures capable of functioning with different imaging modalities settings would be very valuable in the clinical setting. In light of the advantages of MRI, most of the dual-mode nanoparticles have been developed for use with MRI and another modality. Table 9.1 gives examples of such nanoparticles. Other nanoparticles, not dependent on the use of MRI, are also being investigated. They include an amine-functionalised quantum dot consisting of three components: a VEGF protein, a macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for VEGF receptor recognition and 64Cu labelling for PET imaging. This nanoparticle has shown potential for dual PET and near-infrared fluorescence imaging of VEGF receptor recognition in a mouse model (Chen et al., 2008).
9.2.7 Nanotechnology-based imaging for atherosclerosis Atherosclerotic plaque formation and rupture accounts for approximately a third of deaths each year in the UK, through myocardial infarction, ischaemic strokes, renal disease and limb loss. Early changes in vascular architecture during atherosclerosis cannot be detected by current imaging techniques. However it is possible that using the nanotechnology strategy
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Table 9.1 Bimodal nanoparticles
Nanoparticle
Imaging modality (as well as MRI)
Gold core encapsulated in a shell of gadolinium chelates
CT
Aliphatic amine polystyrene bead Iron oxide nanostructure Amine terminated cross-linked superparamagnetic iron oxide (CLIO)-Cy5.5 Silica shell quantum dot with gadolinum
PET
Gadolinium oxide embedded in a polysiloxane shell
PET Fluorescence
Fluorescence
Fluorescence
Current state of development Mouse and rat model study – these nanoparticles are suitable for dual modality imaging of blood vessels without undesirable accumulation in the lungs, spleen and liver (Alric et al., 2008) In vitro development (Jarrett et al., 2008) In vitro development (Jarrett et al., 2008) In a mouse model, MRI and fluorescence confirmed accumulation in infarcted regions of the myocardium (Sosnovik et al., 2007) In a rat model, there was no alteration in physiological parameters after nanoparticle injection (Bakalova et al., 2008) In a mouse model, this nanoparticle is suitable for imaging of blood vessels without undesirable accumulation in the lungs and liver (Bridot et al., 2007)
may fill this void. αvβ3-Integrin is a receptor expressed on platelets for vitronectin which is found in the extracellular matrix. αvβ3-Integrin targeted paramagnetic nanoparticles injected intravenously into a rabbit model of atherosclerosis localised to areas of angiogenesis (a feature of plaque development) could be detected by MRI as 47 ± 5% enhancement in signal (Winter et al., 2003). High density lipoprotein-based nanoparticles can localise to areas of atherosclerosis in a mouse model (Frias et al., 2006). Similarly, a nanoprobe consisting of a hydrophobically modified glycosol chitosan nanoparticle conjugated with an atherosclerotic plaque-recognising peptide (AP peptide) and labelled with Cy5.5 appears to aggregate in atherosclerotic regions in mice (Park et al., 2008). Interestingly a trimodal imaging (PET, MRI and fluorescence) nanoparticle consisting of a magnetofluorescent nanoparticle labelled with 64Cu when injected into a mouse model of atherosclerosis accumulated at sites of atherogenesis at amounts two to three times higher than controls (Nahrendorf et al., 2008).
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These studies highlight the role that nanotechnology could potentially play in the management of cardiovascular disease in the coming years.
9.3
Nanofibres
The first synthetic graft to be used clinically was Vinyon N in the early 1950s (Voorhees et al., 1952). Since then numerous synthetic grafts are available but their thrombogenicity makes them unsuitable for low-flow conditions, e.g. when the luminal diameter is less than 6 mm. Again the nanotechnology strategy using nanofibres with tissue engineering is attempting to tackle this problem (Hoenig et al., 2006). Electrospinning employs an electric field and the principle of mutual charge repulsion to produce a jet of the polymeric solution onto a collector which then solidifies to produce fibres. If the collector is static the fibres will be randomly distributed and if the collector is rotating then they are aligned. Co-axial electrospinning, a more recent development, allows the integration of two components into one conduit to produce core–shell structured nanofibres (Venugopal et al., 2008). Examples of materials used in electropsun nanofibres include poly(caprolactone), collagen blended poly(l-lactic acid)-co-poly(epsiloncaprolactone), and silk (He et al., 2005b; Ma et al., 2005; Soffer et al., 2008). These products have shown significant potential especially when coelectrospun with the tri-n-buytlamine salt of heparin. This results in a heparin-releasing nanofibre whose surface content of heparin could be increased by raising the heparin content in the fabrics (Kwon and Matsuda, 2005). Electrospun nanofibres could also potentially be modified to present nanostructured surfaces which encourage endothelial cell adhesion. This was demonstrated by higher human umbilical vein endothelial cell adherence to a poly(ethylene terephthalate) fabric covalently linked to nano-scaled sintered hydroxyapatite compared with the absence of hydroxyapatite (Furuzono et al., 2006; Igarashi et al., 2007). Electrospun fibres can also be biodegradable (Xu et al., 2004). Endothelialisation of nanofibres may prevent intimal hyperplasia, which is a significant problem in small diameter vascular grafts. A nanofibre fabricated by electrospinning collagen-coated poly(l-lactic acid)-copoly(epsilon-caprolactone) can attach human coronary artery endothelial cells, possibly due to its collagen coat, which subsequently proliferate (He et al., 2005a). Self-assembling nanoparticles offer an alternative to electrospun nanofibres. These nanoparticles form molecular coatings 1–10 nm in depth. Self-assembled monolayers of 11-mercaptoundecanoic acid and 11mercapto-1-undecanol on stainless steel can be aids to drug delivery in
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coronary artery stents (Mahapatro et al., 2006). Similarly thrombin coated magnetic microbeads positioned (using a magnetic field) in fibrin gels to produce scaffolds show adhesion and proliferation of human endothelial cells (Alsberg et al., 2006). Nanofibre technology has diversified considerably since its inception. Under exploration is ‘magnetic force-based tissue engineering’ which employs the labelling of sheets of endothelial cells, smooth muscle cells and fibroblasts using magnetite cationic liposomes. Using a magnetic field these sheets are rolled to form a tube (Ito et al., 2005a). Also being investigated are porous micropatterned poly-caprolactone scaffolds (in an attempt to maintain adequate nutrient diffusion) and ‘pressure assisted cell spinning’ (a possible rival process to electrospinning) (Sarkar et al., 2006; Arumuganathar et al., 2007).
9.4
Future trends
9.4.1 Challenges Nanomedicine has displayed great potential in cardiovascular disease. However, as with any novel agent it is important to be aware of the risks involved. Human endothelial cells exposed to alumina nanoparticles have increased adhesion of activated monocytes and expression of VCAM-1, ICAM-1 and ELAM-1. This proinflammatory response of the endothelium together with increased expression of such adhesion molecules may promote atherosclerosis (Oesterling et al., 2008). In some cases nanoparticles may have a prothrombotic effect, such as carbon nanotubes which stimulate platelet aggregation with an accelerated rate of vascular thrombosis in rat carotid arteries (Radomski et al., 2005). Increased platelet aggregation has also been displayed with the use of carbon black and water-soluble fullerenes (Niwa and Iwai, 2007). Water-soluble fullerenes have also exhibited the ability to inhibit endothelial cell growth (Yamawaki and Iwai, 2006). Systemically, nanoparticles may be nephrotoxic. The respiratory system may also be at risk from systemic administration especially if nanoparticles are delivered as aerosols (Card et al., 2008).
9.4.2 Nanomedicine and cardiovascular disease in the future In conclusion, the future of nanoparticles in the treatment of cardiovascular disease lies in their ability to fulfil complementary roles by combining both diagnostic (i.e. imaging) and therapeutic functions. The progress of multifunctional nanoparticle research has been dominated by the treatment of
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tumours, for example by the incorporation of doxorubicin and paclitaxel into magnetic nanoparticles which can be imaged by MRI and have demonstrated antiproliferative activity in MCF-7 cells (a breast cancer cell line with characteristics of differentiated mammary epithelium). (Jain et al., 2008) Despite the time lag in their development, there is huge potential in investing in nanotechnology in cardiovascular disease (Lanza et al., 2002).
9.5
References
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Abstract: Cardiovascular diseases (CVDs) are the leading cause of death in the Western world. Nanotechnology and nanomedicine are being utilised in the diagnosis and therapy of CVD and show real promise in certain areas. This chapter explores the use of nanotechnology in the therapy of CVD, including the potential role of nanofibres. It also examines the use of nanomedicine in a variety of imaging modalities employed in CVD management including positron emission tomography, optical imaging, computed tomography, ultrasound, magnetic resonance imaging and dual mode imaging. The chapter concludes by scrutinising the challenges facing this novel technology and its future prospects. Key words: cardiovascular disease, vascular disease, nanotechnology, nanomedicine, imaging, nanofibres.
9.1
Introduction: nanomedicine in cardiovascular therapy
Atherosclerosis and neointimal hyperplasia both contribute to cardiovascular disease (CVD), with atherosclerosis resulting in initial native vessel stenosis and neointimal hyperplasia leading to recurrent stenosis after operative intervention. Atherosclerosis is a syndrome characterised by plaque (or less commonly aneurysm) formation in arteries as a result of inflammation leading to a systematic disease often presenting with a significant overlapping of disorders including coronary heart disease, peripheral arterial disease, and carotid arterial disease (Liapis et al., 2009). Neointimal hyperplasia is the foundation, between the endothelium and the inner elastic lamina or luminal surface of vascular grafts/endovascular stents, of a thickened fibrocellular layer (Wang et al., 2006). Modulation of the well-characterised risk factors is sometimes not enough to control the disease process and potential for the use of nanomedicine in the therapy of CVD is extensive.
9.1.1 Stenosis, restenosis and neointimal hyperplasia Advances in drug eluting stent (DES) technology have improved the management of coronary artery disease. They inhibit restenosis through the 251 © Woodhead Publishing Limited, 2010
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controlled release of an antiproliferative agent, e.g Paclitaxel, following deployment and so improve long-term patency rates (Saia et al., 2008). However, this technology has drawbacks including stent thrombosis, longterm anti-platelet therapy and expense. The delivery of Paclitaxel using nanoscaffolds may improve patency rates even further. Nab-paclitaxel, a novel form of albumin-bound paclitaxel has been shown to reduce restenosis in animals and its safety is currently being investigated in humans. Margolis et al. (2007) assessed 23 patients (mean age 66 ± 10 years, 74% men, 26% with diabetes) receiving various intravenous doses of nab-paclitaxel following stenting of a single de novo lesion. Interestingly no major adverse cardiac events were reported at two or six months and only four incidences of restenoses requiring interventions were seen. However, at the higher doses of Nab-paclitaxel side-effects including moderate neutropenia, sensory neuropathy and alopecia were noted. Invasive catheter-based delivery of paclitaxel-coated nanoparticles may allow concentrated drug administration. Nanoparticles, consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) combined with paclitaxel, when administered via a catheter placed in balloon-injured rabbit iliac arteries show a significant 50% reduction in neointimal area when compared with controls (0.80 ± 0.19 mm2 with paclitaxel nanoparticle treated segments vs. 1.58 ± 0.6 mm2 control) (Westedt et al., 2007). Subsequent studies have shown similar outcomes when using paclitaxel-loaded biodegradable scaffolds in animal models (Mei et al., 2007, 2009). Neointimal hyperplasia at venous anastomosis sites in renal access surgery for dialysis is another area where the use of Paclitaxel has been assessed. Paclitaxel coated expanded poly(tetrafluoroethylene) (ePTFE) has been shown to reduce stenosis rates. However, these stents release the agent immediately upon revascularisation rather than a delayed or controlled release, which may attenuate restenosis rates. To enable controlled drug release, pacliataxel loaded poly(lactic-co-glycolic acid) nanoparticles were coated onto the luminal surface of ePTFE grafts by micro-tube pumping and spin penetration techniques. This avoided the initial burst release of the drug following reconstitution of flow within the conduit (in vitro) and produced a controlled drug delivery system (Lim et al., 2007). The role of numerous other agents bound to nanoparticles has been investigated including nitiric oxide (NO). Gels consisting of peptide amphiphile, heparin, and a diazeniumdiolate nitric oxide donor (1-[N(3-aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate (DPTA/ NO) or disodium 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2diolate (PROLI/NO) were applied to the periadventitial region of a rat carotid artery during surgery after endovascular balloon injury. Gels released nitric oxide locally for four days and resulted in attenuation in the neointimal hyperplasia response by up to 77%. Importantly, in vivo studies
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suggest that this inhibition of proliferation had a minimal effect on apoptosis (Kapadia et al., 2008). Platelet-derived growth factor (PDGF) is a key component in vein graft failure as it promotes proliferating vascular smooth muscle cells proliferation and monocyte infiltration. Therefore, delivery of PDGF-receptor tyrosine kinase inhibitor may inhibit hyperplasia. Indeed, polyethyleneglycol-modified poly(dl-lactide-coglycolide) nanoparticles coated with a PDGF-receptor tyrosine kinase inhibitor have been investigated. These particles were infused into excised rabbit segments of jugular vein and subsequently interposed into the ipsilateral carotid. At 28 days, there was significant suppression of neointima formation when compared to controls (Kimura et al., 2008). Doxorubicin, an alternative antiproliferative drug, has also been coupled with polyethylene glycol (PEG)-based block copolymer to form a core– shell nanoparticle (NK911). Again, intravenous administration of NK911 significantly inhibited neointima formation in a rat carotid model 4 weeks post-injury. Intravenous doxorubicin alone did not produce such results. Again an important observation is that NK911 inhibition of vascular smooth muscle proliferation is not accompanied by apoptosis or inhibition of inflammatory cell recruitment. Furthermore, NK911 was well tolerated without any adverse systemic effects (Uwatoku et al., 2003). A balance between limiting vascular stenosis and promoting endothelial healing in these balloon injury models is critical. The ability of nanoparticles to achieve this balance is demonstrated by the use of αvβ3-integrin-targeted rapamycin. Injured rabbit femoral arteries using a balloon stretch model showed a 50% reduction in luminal plaque in the targeted rapamycin segments when compared with contralateral control vessels using magnetic resonance angiograms (MRA). Indeed endothelial healing was similar in the αvβ3-integrin-targeted rapamycin treated group as in controls (Cyrus et al., 2008). Other more commonly used agents have been combined with nanoscaffolds to investigate any improvement in bioavailability. Prednisolonephosphate incorporated in pegylated 3,5-dipentadecyloxybenzamidine hydrochloride (TRM-484) has been shown to significantly reduce in-stent neointimal growth in atherosclerotic rabbits (Joner et al., 2008). Lisinopril encapsulated in poly(lactide-co-glicolide) nanoparticles has shown a promising release profile suggesting that it may be suitable for site-specific delivery by catheters in the prevention of restenosis following balloon angioplasty (Varshosaz and Soheili, 2008). 2-(2-Aminopyrimidino) ethyldiene-1,1bisphosphonic acid incorporated into a polylactide/glycolidebased polymer again produces a significant attenuation of neointima : media ratio (40%) and stenosis (45%) in a rat carotid artery injury model in comparison with controls. Hyperplasia was also significantly reduced after
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subcutaneous and intraperitoneal injection (Cohen-sela et al., 2006a,b). These agents may provide a cost-effective alternative. In addition to improving drug delivery, advances in nanotechnology may also modify drug action. Superparamagnetic nanoparticles can render endothelial cells magnetically responsive and thereby guide them onto steel stent wires through a series of magnetic field gradients (Polyak et al., 2008). Nanoparticles as gene carriers have been implicated as possible therapeutic agents. A poly(lactic-co-glycolic acid) complex with an incorporated plasmid DNA shows reduced interactions with blood components when infused into a rabbit carotid artery. When these particles are loaded with antisense against monocyte chemotactic protein-1, an improvement in gene transfer into vascular lesions was observed with a reduction of the intima : media ratio (Yang et al., 2008).
9.1.2 Angiogenesis Angiogenesis is the foundation of new blood vessels and may be due to vasculogenesis (spontaneous blood formation) or intussusception (growth of new blood vessels by branching from existing ones) (Burri et al., 2004). Therapeutic angiogenesis is used to promote healing in conditions which were traditionally difficult to treat, such as ischemic ulceration. Vascular endothelial cell growth factor (VEGF) is a key component in promoting angiogenesis, but intravenous administration alone is ineffective and localised delivery is required. This was originally described using a peripherally inserted catheter which is invasive. VEGF bound to dextran sulphate at its heparin binding site and encapsulated by selected polycations (chitosan, polyethylenimine, or poly-l-lysine) can produce controlled local release of VEGF for approximately 10 days (Huang et al., 2007). VEGF incorporated into a hydrogel is stable for up to a month (Matsusaki et al., 2007). VEGF-gene delivery when combined with nanoparticles is an alternative to protein delivery. When injected into rabbit myocardium the enhanced gene transfection produces a significant increase in the number of capillaries (Yi et al., 2006). In addition a similar agent injected into a rat ischaemic limb model demonstrated a significant improvement in neovascularisation in comparison to plasmid DNA at 12 days following therapy (Kang et al., 2008). Furthermore, magnetic nanoparticles containing VEGF plasmid can be localised to a specific area when in a magnetic field producing enhanced VEGF delivery and a subsequent doubling of the capillary density and capillary-to-muscle fibre ratio when compared with controls (Jiang et al., 2005). In addition, local expression of VEGF can be induced by targeting hypoxia inducible factors such as hypoxia inducible factor-1α. When nanoparticles containing the hypoxia inducible factor-1α gene are applied
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to full-thickness dermal wounds, angiogenesis was significantly higher along with the level of maturity when compared to that induced by the application of VEGF (Trentin et al., 2006). Therapy of CVD has become a highlight of nanomedicine research and may play a central role in disease prevention and treatment.
9.2
Nanomedicine in cardiovascular imaging
There has been a significant improvement in platform technology for imaging modalities for magnetic resonance imaging (MRI), nuclearcomputed tomography imaging, and optical and ultrasound imaging. In addition our increased understanding of specific cellular markers has provided novel targets for these modalities over the past 10 years. Added to this the potential of nanotechnology, the area of CVD imaging is an extremely exciting one.
9.2.1 Nuclear/positron emission tomography imaging The general approach of nuclear (gamma/SPECT (single photon emission computed tomography)) imaging and positron emission tomography (PET), for example, has been to utilise very small tracer quantities of contrast agents (e.g. radionuclide-labelled antibodies, peptides or small molecules) rather than large payload particles. For example, folate receptor-targeted polymeric shell cross-linked nanoparticles containing 64Cu have been recently used for PET imaging of tumours. Other approaches for characterising atherosclerosis include imaging of apoptosis by annexinphosphatidyl serine targeting, unstable carotid plaque imaging with metabolic (fluorodeoxyglucose) readouts, and macrophage chemotaxis imaging (Blankenberg et al., 2002; Rudd et al., 2002; Britz-Cunningham and Adelstein, 2003; Rossin et al., 2005).
9.2.2 Optical imaging Quantum dots are small (<10 nm) fluorescent semiconductor nanocrystals which possess unique luminescent properties compared with more established organic dyes and fluorescent proteins. Their fluorescence emission is stable and dependent on particle size. Cadmium selenium–zinc sulphide quantum dots have been used to visualise capillaries hundreds of micrometres deep through the skin of living mice. Cadmium-based quantum dots have also be used to image cerebral vasculature. Methoxy-PEGylated quantum dots were used to visualise arterioles and capillary networks in mouse hind limb skeletal muscle (Akerman et al., 2002; Larson et al., 2003; Bateman et al., 2007; J.D. Smith et al., 2007).
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Viral nanoparticles can also be fluorescently labelled to high densities. An example of this is the use of the cowpea mosaic virus (in living mouse and chick embryos) as a probe which allows dynamic imaging of the vascular endothelium for up to 72 hours and to a depth of 500 μm (Lewis et al., 2006).
9.2.3 Computed tomography imaging The most widely used contrast agents for computed tomography (CT) over the past 25 years are iodine based (on a platform of tri-iodobenzene). These molecules are limited in CVD by their non-specific distribution, brief imaging times, extravasation and unsuitability in those with renal impairment (Hainfeld et al., 2006; Rabin et al., 2006; Kong et al., 2007). Gold nanoparticles coated with PEG have nearly a five times higher attenuation level than that of Ultravist (a commonly used current CT contrast agent). Intravenous infusion, of these nanoparticles, into a rat model revealed a significantly longer intravascular time at four hours when compared to 10 minutes for Ultravist. In addition the cardiac ventricles and great vessels could be clearly delineated. However there was significant accumulation of these particles within the liver and spleen; the significance and fate of this is unclear (Kim et al., 2007). However, smaller particles (1.9 ± 0.1 nm) integrated with gold (obtained from Nanoprobes, Inc.) when injected intravenously into mice displayed lower retention levels in the liver and spleen. Futhermore blood vessels with diameters of approximately 100 μm along with regions of angiogenesis were visible. There was no evidence of toxicity up to 30 days after injection nor any alteration in mouse behaviour (Hainfeld et al., 2006). Gold nanoparticles have also been used to visualise tumour vasculature in a mouse model with a stable imaging window up to 24 hours post-injection (Cai et al., 2007). Nanoparticles used in CT imaging also include a polymer coated bismuth sulphide unit and a Lipiodol-based agent. In a mouse model, the Bismuthbased nanoparticle has demonstrated a five-fold improved X-ray absorption compared with iodine, a circulation time of two hours and a safety profile comparable to iodine-based imaging agents (Rabin et al., 2006). On the other hand Lipiodol, a naturally occurring iodinated compound, can be modified with Pluronic F127 (copolymer poloxamer 407) to deliver a nanostructure with a longer circulation time than commercial iodinated preparations while maintaining a similar safety profile (Kong et al., 2007).
9.2.4 Ultrasound imaging Ultrasound with its advantages of good patient tolerance, low cost and benign compression waves is established as an indispensable radiological
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tool. Its use has become widespread in most healthcare settings, leading to increasing interest in improving ultrasound efficacy through the introduction of micro- and nanoparticle-based agents. Microbubbles have been used in cardiovascular imaging as they produce an acoustic signal in an ultrasound field, thereby allowing assessment of perfusion. Smaller particles such as liquid-filled nanodroplets may have an important role. These nanoparticless have shown promising results in imaging microvasculature (to 100 μm). However, ultrasound imaging is less sensitive to liquid-filled nanoparticles due to their size and relative incompressibility when compared with microbubbles (Dayton et al., 2006). As microbubbles and nanodroplets have their own specific advantages, parallel development of both particle families continues. For example, gas-filled microspheres and liquid-filled nanoparticles may be employed in ultrasound molecular imaging by the incorporation of surface receptor-specific ligands. Such particles may be used in microvascular imaging to detect upregulated leukocyte adhesion molecules as in ischaemia reperfusion (Weber and Lemor, 2004; Kaufmann and Lindner, 2007; Kaufmann et al., 2007; Villanueva and Wagner, 2008).
9.2.5 Magnetic resonance imaging The non-invasive nature, high resolution and contrast of magnetic resonance imaging (MRI) along with lack of ionising radiation have led to its wide use in the clinical setting. Therefore considerable interest has been generated in investigating the feasibility of utilising nanoparticles to improve MRI (Cyrus et al., 2005; Mulder and Fayad, 2008). Magnetic particles have the ability to respond to variations in magnetic fields and this characteristic makes them ideal candidates in the development of nanostructures in MRI. Superparamagnetic iron oxide particles have several possible clinical applications including the detection of metastases and in inflammatory diseases. Superparamagnetic iron oxide particles have been combined with Annexin V (which recognises apoptotic cells via phosphatidyl serine) to create a targeted nanoparticle which has been successfully used to identify high grade atherosclerotic regions. In a rabbit model of atherosclerosis this nanoparticle displayed negative MRI contrast at atheromatous lesions but not at healthy arterial sites nor in healthy controls. The dose of targeted nanoparticle required was in the order of a thousand times less than for untargeted superparamagnetic nanoparticles with recognisable differences between occlusive and mural plaques. Plaque contrast is maintained for two months; however, this is undesirable in patients requiring regular repeat MRI to assess disease progression (Smith et al., 2007). It is postulated that iron oxide nanoprobes may also be used to label macrophages which can then be tracked to sites of atherosclerosis.
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The resulting accumulation of these particles may then be detected by MRI (Zhang et al., 2008). While lacking the advantages of targeted nanoparticles, non-targeted nanoparticles can be easier to produce and may still be of benefit in MRI. They can be combined with other novel techniques such as inversion recovery with on resonant water suppression (IRON). IRON causes dispersion of the resonant frequency of the protons in proximity to the contrast agents. Since contrast agents are localised in the blood this leads to higher intravascular contrast (Riederer, 2008). Employing IRON with the long circulating monocrystalline iron oxide particle (MION)-47, in a rabbit model, led to an increase in intravascular contrast whilst suppressing background tissue (mean contrast to noise ratio after injection was 61.9 ± 12.4 vs. a baseline of 1.1 ± 0.4 p < 0.001) and was also higher when compared with conventional magnetic resonance angiograms. The combination of these two technologies may result in an improvement in clinical MRI use (Korosoglou et al., 2008). There are other applications of nanotechnology in tissue engineering. Human aortic smooth muscle cells loaded with ultra-small superparamagnetic iron oxide nanoparticles were seeded into tissue engineered vascular grafts and subsequently implanted as aortic interposition grafts in mice. The nanoparticles were retained for three weeks during which MRI was used for real time non-invasive monitoring of smooth muscle cell retention (Nelson et al., 2008). This technology could be used to improve current tissue engineering of vascular conduits and validate engineered grafts in the future. Nanoparticles have also been used to improve experimental techniques. In the laboratory setting iron oxide nanoparticle-loaded vascular smooth muscle cells were delivered endovascularly to abdominal aortic aneurysms in a rat model. The presence of these nanoparticles could be confirmed on MRI (Corot et al., 2006; Deux et al., 2008). Non-iron-based magnetic nanoparticles are being developed. These include magnetoliposomes, which are magnetite cores encapsulated in a phospholipid bilayer. Such phospholipid vesicles containing phosphatidylethanolamine-diethylenetriaminepentaacetic acid can be complexed with gadolinium ions (Gd3+) to produce an agent which may have potential in MRI contrast, though in vivo data are awaited (Ito et al., 2005b; De Cuyper et al., 2007). Another family of nanoparticles showing promise in MRI are dendrimers. Different generations of gadolinium (Gd3+) diethylenetriaminepentaacetic acid (DTPA)-terminated poly(propylene) dendrimers have been developed as contrast agents in MRI. These Gd3+-based complexes provided prolonged intravascular duration with improved contrast. Each generation is defined according to the number of Gd3+ ions per molecule (G1 – 4 ions per molecule, G3 – 16 ions per molecule, G5 – 64 ions per molecule, etc.).
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The generations with higher Gd3+ content (G3 and G5) show prolonged enhancement of tissue vasculature and are suited for non-tissue specific imaging of sub-millimetre sized blood vessels (Yan et al., 2005; Langereis et al., 2006). In a study comparing G1, G2 and G3 contrast agents, G3 agents provided prolonged contrast enhancement in the heart and vasculature and did so at a lower dose (Kaneshiro et al., 2008). The creation of Gd3+ dendrimers has been followed by intra-generational modifications. Two different G4 agents, bearing either an isothiocyanate or succimidyl ester moiety, displayed equivalent organ vasculature enhancement although with different clearance rates. This may allow greater flexibility in contrast dose and imaging time while using almost identical agents (Xu et al., 2007). The role of nanotechnology in MRI continues to be a rapidly expanding field as is exemplified by the recent use of a gold and copper nanoshell in an in vivo mouse model where it enhanced vascular contrast, but with a dose-dependent toxic effect, indicating the need for more detailed investigation (Su et al., 2007).
9.2.6 Dual-mode imaging Dual-mode imaging yields greater information than either method alone by allowing the clinician to employ different imaging modalities (each with its own advantages) highlighting different areas of interest while using a single contrast agent. To aid this, nanostructures capable of functioning with different imaging modalities settings would be very valuable in the clinical setting. In light of the advantages of MRI, most of the dual-mode nanoparticles have been developed for use with MRI and another modality. Table 9.1 gives examples of such nanoparticles. Other nanoparticles, not dependent on the use of MRI, are also being investigated. They include an amine-functionalised quantum dot consisting of three components: a VEGF protein, a macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for VEGF receptor recognition and 64Cu labelling for PET imaging. This nanoparticle has shown potential for dual PET and near-infrared fluorescence imaging of VEGF receptor recognition in a mouse model (Chen et al., 2008).
9.2.7 Nanotechnology-based imaging for atherosclerosis Atherosclerotic plaque formation and rupture accounts for approximately a third of deaths each year in the UK, through myocardial infarction, ischaemic strokes, renal disease and limb loss. Early changes in vascular architecture during atherosclerosis cannot be detected by current imaging techniques. However it is possible that using the nanotechnology strategy
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Table 9.1 Bimodal nanoparticles
Nanoparticle
Imaging modality (as well as MRI)
Gold core encapsulated in a shell of gadolinium chelates
CT
Aliphatic amine polystyrene bead Iron oxide nanostructure Amine terminated cross-linked superparamagnetic iron oxide (CLIO)-Cy5.5 Silica shell quantum dot with gadolinum
PET
Gadolinium oxide embedded in a polysiloxane shell
PET Fluorescence
Fluorescence
Fluorescence
Current state of development Mouse and rat model study – these nanoparticles are suitable for dual modality imaging of blood vessels without undesirable accumulation in the lungs, spleen and liver (Alric et al., 2008) In vitro development (Jarrett et al., 2008) In vitro development (Jarrett et al., 2008) In a mouse model, MRI and fluorescence confirmed accumulation in infarcted regions of the myocardium (Sosnovik et al., 2007) In a rat model, there was no alteration in physiological parameters after nanoparticle injection (Bakalova et al., 2008) In a mouse model, this nanoparticle is suitable for imaging of blood vessels without undesirable accumulation in the lungs and liver (Bridot et al., 2007)
may fill this void. αvβ3-Integrin is a receptor expressed on platelets for vitronectin which is found in the extracellular matrix. αvβ3-Integrin targeted paramagnetic nanoparticles injected intravenously into a rabbit model of atherosclerosis localised to areas of angiogenesis (a feature of plaque development) could be detected by MRI as 47 ± 5% enhancement in signal (Winter et al., 2003). High density lipoprotein-based nanoparticles can localise to areas of atherosclerosis in a mouse model (Frias et al., 2006). Similarly, a nanoprobe consisting of a hydrophobically modified glycosol chitosan nanoparticle conjugated with an atherosclerotic plaque-recognising peptide (AP peptide) and labelled with Cy5.5 appears to aggregate in atherosclerotic regions in mice (Park et al., 2008). Interestingly a trimodal imaging (PET, MRI and fluorescence) nanoparticle consisting of a magnetofluorescent nanoparticle labelled with 64Cu when injected into a mouse model of atherosclerosis accumulated at sites of atherogenesis at amounts two to three times higher than controls (Nahrendorf et al., 2008).
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These studies highlight the role that nanotechnology could potentially play in the management of cardiovascular disease in the coming years.
9.3
Nanofibres
The first synthetic graft to be used clinically was Vinyon N in the early 1950s (Voorhees et al., 1952). Since then numerous synthetic grafts are available but their thrombogenicity makes them unsuitable for low-flow conditions, e.g. when the luminal diameter is less than 6 mm. Again the nanotechnology strategy using nanofibres with tissue engineering is attempting to tackle this problem (Hoenig et al., 2006). Electrospinning employs an electric field and the principle of mutual charge repulsion to produce a jet of the polymeric solution onto a collector which then solidifies to produce fibres. If the collector is static the fibres will be randomly distributed and if the collector is rotating then they are aligned. Co-axial electrospinning, a more recent development, allows the integration of two components into one conduit to produce core–shell structured nanofibres (Venugopal et al., 2008). Examples of materials used in electropsun nanofibres include poly(caprolactone), collagen blended poly(l-lactic acid)-co-poly(epsiloncaprolactone), and silk (He et al., 2005b; Ma et al., 2005; Soffer et al., 2008). These products have shown significant potential especially when coelectrospun with the tri-n-buytlamine salt of heparin. This results in a heparin-releasing nanofibre whose surface content of heparin could be increased by raising the heparin content in the fabrics (Kwon and Matsuda, 2005). Electrospun nanofibres could also potentially be modified to present nanostructured surfaces which encourage endothelial cell adhesion. This was demonstrated by higher human umbilical vein endothelial cell adherence to a poly(ethylene terephthalate) fabric covalently linked to nano-scaled sintered hydroxyapatite compared with the absence of hydroxyapatite (Furuzono et al., 2006; Igarashi et al., 2007). Electrospun fibres can also be biodegradable (Xu et al., 2004). Endothelialisation of nanofibres may prevent intimal hyperplasia, which is a significant problem in small diameter vascular grafts. A nanofibre fabricated by electrospinning collagen-coated poly(l-lactic acid)-copoly(epsilon-caprolactone) can attach human coronary artery endothelial cells, possibly due to its collagen coat, which subsequently proliferate (He et al., 2005a). Self-assembling nanoparticles offer an alternative to electrospun nanofibres. These nanoparticles form molecular coatings 1–10 nm in depth. Self-assembled monolayers of 11-mercaptoundecanoic acid and 11mercapto-1-undecanol on stainless steel can be aids to drug delivery in
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coronary artery stents (Mahapatro et al., 2006). Similarly thrombin coated magnetic microbeads positioned (using a magnetic field) in fibrin gels to produce scaffolds show adhesion and proliferation of human endothelial cells (Alsberg et al., 2006). Nanofibre technology has diversified considerably since its inception. Under exploration is ‘magnetic force-based tissue engineering’ which employs the labelling of sheets of endothelial cells, smooth muscle cells and fibroblasts using magnetite cationic liposomes. Using a magnetic field these sheets are rolled to form a tube (Ito et al., 2005a). Also being investigated are porous micropatterned poly-caprolactone scaffolds (in an attempt to maintain adequate nutrient diffusion) and ‘pressure assisted cell spinning’ (a possible rival process to electrospinning) (Sarkar et al., 2006; Arumuganathar et al., 2007).
9.4
Future trends
9.4.1 Challenges Nanomedicine has displayed great potential in cardiovascular disease. However, as with any novel agent it is important to be aware of the risks involved. Human endothelial cells exposed to alumina nanoparticles have increased adhesion of activated monocytes and expression of VCAM-1, ICAM-1 and ELAM-1. This proinflammatory response of the endothelium together with increased expression of such adhesion molecules may promote atherosclerosis (Oesterling et al., 2008). In some cases nanoparticles may have a prothrombotic effect, such as carbon nanotubes which stimulate platelet aggregation with an accelerated rate of vascular thrombosis in rat carotid arteries (Radomski et al., 2005). Increased platelet aggregation has also been displayed with the use of carbon black and water-soluble fullerenes (Niwa and Iwai, 2007). Water-soluble fullerenes have also exhibited the ability to inhibit endothelial cell growth (Yamawaki and Iwai, 2006). Systemically, nanoparticles may be nephrotoxic. The respiratory system may also be at risk from systemic administration especially if nanoparticles are delivered as aerosols (Card et al., 2008).
9.4.2 Nanomedicine and cardiovascular disease in the future In conclusion, the future of nanoparticles in the treatment of cardiovascular disease lies in their ability to fulfil complementary roles by combining both diagnostic (i.e. imaging) and therapeutic functions. The progress of multifunctional nanoparticle research has been dominated by the treatment of
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tumours, for example by the incorporation of doxorubicin and paclitaxel into magnetic nanoparticles which can be imaged by MRI and have demonstrated antiproliferative activity in MCF-7 cells (a breast cancer cell line with characteristics of differentiated mammary epithelium). (Jain et al., 2008) Despite the time lag in their development, there is huge potential in investing in nanotechnology in cardiovascular disease (Lanza et al., 2002).
9.5
References
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