Atherosclerosis Targeting Using Nanotechnology 2013

7/21/2019 Atherosclerosis Targeting Using Nanotechnology 2013

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BIOTECHNOLOGY, MOLECULAR BIOLOGY AND NANOMEDICINE VOL.1 NO.1 OCTOBER 2013ISSN:2330-9318 (Print) ISSN:2330-9326 (Online) http://www.researchpub.org/journal/bmbn/bmbn.html

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AbstractCoronary artery disease (CAD) emerges from

atherosclerosis and is the most common myocardial

infarction-induced death in the western world. Most

research data suggest that nanotechnologies could play a

major role in the development of novel imagistic and

therapeutic methods against atherosclerotic plaque. Here

we present the latest achievements in atheroscleroticplaque targeting, imaging and treatment using

nanotechnologies.

Keywordsatherosclerosis, targeting, imaging, nanoparticles,

plaque, therapy

I. INTRODUCTION

ardiovascular diseases (CVDs) include a broad variety

of disorders that affect the heart, the blood vessels or

both. These diseases include angina, arrhythmia,

atherosclerosis, cardiomyopathy, stroke, hypertension,myocarditis, and pericarditis.[1] Yearly, almost $0.5 trillion

dollars are spent on treatments for cardiovascular diseases.

Coronary artery disease (CAD) emerges from atherosclerosis

and is the most common myocardial infarction-induced death

in the western world. In the United States, CAD is responsible

for about one-third of total deaths.[2] Most patients die because

of rapidly developing thrombi that completely congest vessels

after rupture of atherosclerotic plaques.[3] In many cases,

plaques that rupture are nonstenotic (most cause less than 50%

luminal narrowing) and escape detection by conventional

imaging techniques (X-ray angiography, intravascular

ultrasound).[4]

Even if the therapeutic molecular scale potential of many new

agents is beyond doubt, several limitations can restrict their

clinical performance. These include unfavorable

Department of Cardiology, Centre Hospitaller Meaux, France, 2ndDepartment of Internal Medicine, Iuliu Hatieganu University of Medicine

and Pharmacy, Cluj-Napoca, RomaniaAddress for corespondence: 2nd Medical Clinic, University of Medicine and

Pharmacy, 2-4 Clinicilor Street, 400006 Cluj-Napoca, Romania, tel: +40 264593355, fax: +40 264 593355,

*Correspondence to Lucia Agoston Coldea (e-mail:[email protected]).

physico-chemical properties (such as water insolubility) and a

multitude of biological obstacles preventing therapeutic and

diagnostic contrast agents from reaching their destinations.

Currently, there are two targeting concepts: passive targeting

and active targeting. (Fig. 1)

Therefore, the uptake of molecularly targeted agents inside the

diseased tissue following intravenous administration is

extremely low (0.01% to 0.001% of the injected dose).[5] Anincreased dose of agents will result in a satisfactory therapeutic

response, creating a narrow efficiency/toxicity therapeutic

window. In conclusion, the perfect agent should be endowed

with some crucial characteristics, including stability in

biological environment, proper solubility and preferential

uptake at the disease site. However, no single molecule can

simultaneously accomplish all these functions.[6]. Most data

suggest that nanotechnologies could play a major role in the

development of new therapies.[7, 8] Here we present the latest

achievements in atherosclerotic plaque targeting, imaging and

treatment using nanotechnologies.

Atherosclerotic plaque imaging

Several imaging techniques can be employed to assess the in

vivo biodistribution of cell subpopulations loaded with

nanoscale contrast agents (QD or iron oxide

nanoparticles)[9-11].

Simultaneous ex vivo imaging of white blood cell subsets

inside lesions, with high signal-to-background ratios, has been

allowed by quantum dots (QD)-[12, 13] maurocalcine

bioconjugates. Flow cytometric analysis of QD-maurocalcine

nanoparticle labeling of both cell types exhibited high

efficiency and low cytotoxicity. Moreover, by employing

cytokine release and endothelial adhesion assays, QDbioconjugates proved not to damage native cell functions. En

faceoptical imaging helped detect ex vivo QD-labeled cells

within one month inside oil red O-positive aortic lesions in

mice.[14]

Nanomedicine-based approaches have been developed to

examine circulating cells that are able to attach to

atherosclerotic plaques or to sites of arterial

inflammation.[15-19]

Nanoscale particles, better known as nanoparticles, may consist

of various organic and inorganic materials.[20-22]

Advances in Atherosclerotic Plaque Targeting,Imaging and Treatment Using Nanotechnology

and Stem Cells ResearchLucia Agoston-Coldea,MD, PhD,

C


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Important examples of nanocarrier matrices involve

liposomes,[23] micelles[23, 24] and block copolymer

nanoparticles.[25-29] When developing therapeutic

nanocarriers, drugs can be encapsulated inside carriers based on

similar building blocks.[30-33] When it comes to polylactide

co-glycolide (PLGA) nanoparticles, they show controlled

degradation rates for tunable drug release profiles.[30]

Nanoscale imaging agents may contain[34-37] gadolinium oriron oxide for magnetic resonance contrast, gold colloids or

radiotracer-based nanoassemblies for x-ray contrast[38-40],

gas-filled microbubbles for ultrasound imaging[40-43], and

infrared stains and quantum dot nanocrystals (QD) for optical

imaging.[44-46]

Fig.1 Schematic illustration of therapeutic options in

targeting atherosclerotic plaque

Polyethyleneimine (PEI), which a cationic polymer, has been

widely employed in gene therapy applications, mainly in the

branched form.[47-49] Phospholipid liposomes attached to

polyethylene glycol have been developed to postpone clearance

from the circulation for the extension of the in vivo persistence

of the therapeutic agent.[50-52] Imaging, as well as therapeutic

nanocarriers, are normally surface coated with biorecognition

moieties (peptides or antibodies) to allow in vivo delivery of

the imaging or therapeutic agent to the targeted site inside the

plaque (e.g. macrophage), to support image-guided plaque

staging.[1, 53]

Stem cell therapy

The protective, restorating and regenerative role of stem cell

therapy in CVDs has become quite disputed in the last

years.[54-57] Multiple cell types have been thought to be good

candidates.[58] Delivery pathways of progenitor cells to the

heart available today include intravenous (IV), intracoronary

(IC) or direct epicardial injection and, more recently, injection

in the coronary sinus, are ineffective due to low cell retention

and a lack of targeted localization. Even if intravenous delivery

of cells is the least invasive of these methods, most of the

delivered cells get blocked in the lungs, with less than 1%

reaching the infarcted heart.[59] Angioplasty allows cell

delivery by intracoronary infusion directly to the target site.The design of well-controlled, engineered nanodimensional

constructs and nanoarchitectures hold great potential for an

effort to imitate the natural physical and biological

environment that boosts tissue reconstruction and growth

through enhanced cell differentiation and functionality. [60-61]

The matrix represent an imitation of the ECM found inside the

body and offers a framework for interactions between cells and

the limited space that modifies and systematizes cells into 3D

tissues and organs.[60] Nutrient transport inside the scaffold is

primarily a matter of dispersion and it is of crucial importance

as it manages cell proliferation and differentiation.[62]

Traditional polymer-processing techniques find it hard to

produce fibers smaller than 10 m in diameter, which areseveral classes of magnitude larger than the innate ECM

topography (50500 nm). [60][63]

Atheroma-Specific Biosensors

Molecular components of the atheroma can generate

nanoscale devices to optimize disease-customized approaches.

This concept is reported to be based on contrast agents that can

be generated so as to aggregate when excited by proteolytic

activity. Magnetic resonance signal contrast can be enhanced

by examining the aggregation of contrast agents, as for exampleiron oxide nanoparticles. A similar strategy has been employed

in order to achieve protease-induced plaque absorption of

nanoparticles via surface incorporation of polymers that restrict

nanoparticle accumulation into the plaque but are cleavable by

specific enzymes. The design of nanoscale biosensors aims at

detecting circulating biomarkers which hold good potential to

predict atherosclerosis and treatment response, such as those

able to assess the characteristics of blood-borne lipoproteins.

Nanoscale device engineering allows enhanced biological

interactions within these systems, leading to a higher sensitivity


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than that achieved by traditional approaches.[60] Targeting

vascular epitopes

The vascular endothelium, lining blood vessels and creating

a natural barrier that separates blood from surrounding tissue,

has emerged as an attractive target for both drug delivery and

imaging due to its proximity to intravenously administered

therapy.[64, 65] Moreover, the unique markers expressed by

endothelial cells during CAD development enable the design ofmolecular imaging probes and targeted nanovectors for

localized therapies.[66] Proinflammatory markers, such as

selectins, VCAM-1 and ICAM-1, expressed during chronic

inflammation, prominent in most CVDs, are prime objectives

for targeted nanovectors.[67] Nanovectors may also be directed

to CAD by targeting fibrin clots formed at the site of

atherosclerosis when blood comes into contact with the

exposed tissue inside the plaque.[68] Even if nanovectors may

be targeted to biomarkers expressed by the endothelium, the

endothelial cells themselves may not be the target of the

therapy. For example, cells such as monocytes, T cells and

foam cells recruited into atherosclerotic plaques or theunderlying tissue have been employed as targets.[69] When the

vascular endothelium is not the final destination of imaging and

drug carriers, this role being played by the underlying

tissue/organ, particle uptake and/or transcytosis of the

nanovector must be regarded.[70] Another possible approach in

the treatment for atherosclerosis could be based on targeting

neovascularization of the vasa vasorum (network of small

arteries in the vascular wall) which is strongly related to plaque

growth and rupture.[71]

Polymeric nanoparticles are broadly suggested as vectors for

targeted drug delivery based on their variety of materials, sizes

and shapes.[72] Typical formulations include [73]solid matrix,

polymersomes and dendrimers, and accessible biodegradablepolymers include polylactic acid, polyglycolic acid, their

copolymer poly(lactide-co-glycolide), poly(caprolactone) and

poly(ethylene glycol). Solid matrix particles come in a multiple

shapes and sizes and may be coated with various targeting

ligands.[74] One of the drawbacks of solid matrix particles

made from biodegradable polymers, including polylactic acid,

polyglycolic acid and their copolymers, is the acidic

degradation environment that may damage certain loaded

therapeutics, especially proteins.[75] This acidity can be

diminished through the incorporation of trehalose or poorly

soluble bases together with the encapsulated drug, as this

proved to increase the stability of encapsulated proteins. [76]

Polymersomes are composed of bilayer membranes ofamphiphilic block-copolymers and resemble lipid-based

liposomes in their membrane flexibility, while maintaining

better structural integrity and enabling greater PEGylation.[77]

Dendrimers are very small, repetitively branched polymers that

enable the attachment of targeting ligands, imaging markers

and therapeutics. Therefore, they can be beneficial for

theranostic applicationsthe combination of therapeutics and

diagnostics in a single-carrier system.[78] Nevertheless, high

concentrations of dendrimers can be toxic (depending on their

surface characteristics) and they often exhibit poor loading

capacity. Additionally, covalent bonding of therapeutics to

dendrimer surface is usually employed when physical

entrapment is not possible, which potentially diminishes their

effectiveness as drug carriers.[79] In conclusion, similar to

soluble carriers, dendrimers may be more appropriate for gene

delivery and imaging applications.[80] The polylysine

dendrimer Gadomer-17, complexed with 24 Gd-DOTA

(gadolinium-tetraazacyclododecane tetraacetic acid), has beenexamined for use as MRI contrast agent, demonstrating

promising in vivo efficiency with minimal toxicity.[81]

Micelles, colloidal particles which are in equilibrium with

the molecules or ions in their solution of origin, are limited to

the entrapment of hydrophobic drugs, but when smaller, they

might infiltrate tissue from the bloodstream. They may

combine multifunctional complexes with polymers and couple

with targeting ligands/contrast agents for imaging.[82]

Lipoproteins are also limited to hydrophobic drugs, their

loading and release not being as tunable as that of other

materials. Synthetic high-density lipoproteins (HDL) may be

coated with contrast agents such as gadolinium and target HDLreceptors of macrophages.[83, 84] Alternatively, synthetic

HDL can be combined with inorganic compounds, such as iron

oxide, to make iron oxide core HDL nanoparticles that employ

the natural HDL trafficking pathway, with magnetic resonance

contrast enhancement offered by iron oxide.[85, 86]

Particles made of inorganic materials such as gold, silver,

silicon, iron oxides and carbon have been examined for their

potential in drug delivery. One issue regarding the design of

these particles is the loading and release profiles of therapeutics,

requiring pore tuning in order to achieve the desired release.

Iron oxide and polymer-coated iron oxide particles have been

investigated for MRI imaging of cardiovascular systems based

on their paramagnetic properties[86, 87]. Iron oxide particlesmight be employed as contrast agents for both magnetic

resonance and X-ray imaging techniques, enabling overlaying

images from two sources and thus ensuring a more detailed

analysis of diseased tissues.[88]

Microspheres with diameters ranging from 2 to 5 microns

have been noted to exhibit much better localization and binding

to infected endothelial cell monolayers from bulk human blood

flow than nanospheres with diameters from 100 to 500 nm.[89]

This may be the result of particle size impact on the interactions

with red blood cells (RBCs). Larger particles (>2 m in

diameter) are preferentially excluded from the blood flow and

pushed aside, but nanospheres are small enough to easily fit in

the pocket between RBCs.[89] Smaller nanoparticles,especially those within a few tens of nanometers, might

distribute into plasma and exhibit enhanced localization to the

wall in bulk blood flow. Nevertheless, the small size restricts

their usefulness for drug delivery because of their low drug

transport ability.[90, 91]

Several authors loaded nanoscale gadolinium-based contrast

agents into porous silicon microparticles, demonstrating an

enhanced contrast due to their geometrical restrictions.[92] For

drug delivery, microcarriers would attach to the endothelial

wall and release their nanocarrier cargo at the vessel wall,


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where they might transmigrate through the endothelium. The

development of microcarriers is needed in order to release their

cargo over an appropriate time frame, possibly involving

fast-degrading polymers as a shell for the rapid release of

nanocarriers. CVDs, such as atherosclerosis, that damage larger

arteries, may use the vasa vasorum that feed the wall of these

arteries for the effective delivery of nanoparticles without a

microcarrier system.Nanotechnology implies the design of materials and

functional structures with at least one characteristic nanometric

dimension. The use of nanotechnology in stem cell research

and development is currently a new interdisciplinary borderline

in materials science and regenerative medicine.[60]

Nevertheless, further investigations are also required for the

careful assessment of unexpected toxicities and biological

interactions of the nanoparticles with therapeutic properties

inside the living organism [8, 22, 31, 93].

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Atherosclerosis Targeting Using Nanotechnology 2013