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Nanomedicine and the
Cardiovascular System
This page intentionally left blank
Nanomedicine and the
Cardiovascular System
Editors
Ross J. Hunter
Cardiology Research Fellow
St Bartholomew’s Hospital
London
UK
Victor R. Preedy
Professor of Nutritional Biochemistry
School of Biomedical & Health Sciences
King’s College London
and
Professor of Clinical Biochemistry
King’s College Hospital
UK
Science Publishers
Jersey, British Isles
Enfield, New Hampshire
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2012 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20111025
International Standard Book Number-13: 978-1-4398-7989-4 (eBook - PDF)
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Preface
The nanosciences are a rapidly expanding field of research with a wide
applicability to all areas of health. They encompass a variety of technologies
ranging from particles to networks and nanostructures. For example,
nanoparticles have been proposed to be suitable carriers of therapeutic
agents whilst nanostructures provide suitable platforms for sub-micro
bioengineering. However, understanding the importance of nanoscience
and technology is somewhat problematical as a great deal of text can be
rather technical in nature with little consideration to the novice. In this
series Nanosciences Applied to Health and Biomedical Sciences we aim to
disseminate the information in a readable way by having unique sections
for the novice and expert alike. This enables the reader to transfer their
knowledge base from one discipline to another or from one academic level
to another. Each chapter has an abstract, “key facts”, applications to other
areas of health and disease and a “mini-dictionary” of key terms and phrases
within each chapter. Finally, each chapter has a series of summary points.
In this book Nanomedicine and the Cardiovascular System we cover
nanoparticle contrast agents, cell sheet nanotechnology, nanowire field-
effect transistors, atomic force microscopy, transfusion medicine, nanoscale
topography, nano wire sensor arrays, nanowire transistors, nanospheres,
nanomonitor technology, nanospin probes, nanomatrices, vascular grafts,
gene transfer using nanomicelles, nanobubbles, biodegradable nanofibers,
cholesterol-lowering drugs, thromboses, nanorods, nitric oxide, iron oxide
nano particles and stem cells.
Contributors to Nanomedicine and the Cardiovascular System are all
either international or national experts, leading authorities or are carrying
out ground breaking and innovative work on their subject. The book is
essential reading for cardiologists, cardiovascular scientists, research
scientists, medical doctors, health care professionals, pathologists,
biologists, biochemists, chemists and physicists, general practitioners as
well as those interested in heart disease and nano sciences in general.
Nanomedicine and the Cardiovascular System is part of the Nanoscience
Applied to Health and Medicine series.
The Editors
This page intentionally left blank
Contents
Preface v
Section 1: General Methods and Applications
1. Nanoparticle Contrast Agents for Cardiovascular 3
Medical Imaging
David P. Cormode, Ahmed Klink, Zahi A. Fayad and
Willem J.M. Mulder
2. Cell Sheet Nano Technology: Engineering and 25
Applications to Cardiology
Yuji Haraguchi, Tatsuya Shimizu, Masayuki Yamato,
Ross J. Hunter and Teruo Okano
3. Nanowire Field-effect Transistors and Their 45
Applications to Cardiology
Chia-Chang Tsai, Colin R. Martin, Yen-Bin Liu,
Chien-Yuan Pan and Yit-Tsong Chen
4. Atomic Force Microscopy and the Detection of 58
Nanosized Blood Microparticles
Y. Yuana, M.E. Kuil, T.H. Oosterkamp, R.M. Bertina and
S. Osanto
5. Nanobiotechnology-based Blood Substitutes and the 77
Cardiovascular Systems in Transfusion Medicine
Thomas Ming Swi Chang
6. Collagen Scaffolds and Their Application to 99
Cardiology—the Importance of Matrix Interactions
and Nanoscale Topography
Lynn Donlon and Daniel Frankel
7. Cardiac Biomarker and Nanowire Sensor Arrays 121
Guo-Jun Zhang
viii Nanomedicine and the Cardiovascular System
8. Electrical Recording from Cardiac Cells and Tissue 141
Using Nanowire Transistors
Tzahi Cohen-Karni, Bozhi Tian and Charles M. Lieber
9. Nanospheres and Applications to Cardiology. 164
Multifunctionality: The Key to Future Success
Andrea Masotti
10. Nanomonitor Technology and Its Applicability to 179
Diagnosis of Cardiac Disease
Shalini Prasad, Manish Bothara, Ravikiran K. Reddy,
Thomas Barrett and John Carruthers
11. Nanospin Probes and Applications to Cardiology 200
Valery V. Khramtsov and Denis A. Komarov
12. Native Endothelium-mimicking Nanomatrices and 221
Applications
Adinarayana Andukuri, Chidinma P. Anakwenze,
Bryan A. Blakeney and Ho-Wook Jun
13. Nanofibre-based Vascular Grafts 239
Sarra de Valence, Beat H. Walpoth and Michael Möller
Section 2: Focused Areas, Treatments and Diseases
14. Nanoparticle Processing of Cholesterol-Lowering Drug 263
Toshiro Fukami, Toyofumi Suzuki, Ayyalusamy Ramamoorthy
and Kazuo Tomono
15. Intratracheal Gene Transfer Using Polyplex 284
Nanomicelles and Their Application to Cardiology
Noriyuki Iwamoto and Mariko Hrada-Shiba
16. Use of Microbubbles and Nanobubbles for Diagnostic 303
Vascular Molecular Imaging and Therapeutic Applications
Chih-Hsien Lee, Cheng-An J. Lin, Rajkumar Rajendram and
Walter H. Chang
17. Multifunctional Nanoagents for the Detection and 324
Treatment of Thromboses
S. Sibel Erdem and Jason R. McCarthy
18. Biodegradable Nanofibers in Cardiovascular Medicine: 345
Drug Delivery Application
Masato Mutsuga, Aika Yamawaki-Ogata, Yuji Narita,
Makoto Satake, Hiroaki Kaneko and Yuichi Ueda
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Contents ix
19. Europium Hydroxide Nanorods and Angiogenic 370
Processes
Chitta Ranjan Patra
20. Iron Oxide Nanoparticles and Cardiac Stem Cells 391
K.W. Au, April M. Chow, Ed X. Wu and H.F. Tse
21. Nitric Oxide from Nanoparticles and Applications to 407
Cardiovascular Health
Pedro Cabrales, Adam J. Friedman and Joel M. Friedman
Index 427
About the Editors 433
Color Plate Section 435
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Section 1: General Methods and
Applications
This page intentionally left blank
1
Nanoparticle Contrast Agents for
Cardiovascular Medical Imaging
David P. Cormode,1,a,* Ahmed Klink,1,b Zahi A. Fayad1,c and
Willem J.M. Mulder1,d
ABSTRACT
Over the last ten years, nanoparticles have become increasingly
studied as contrast agents for medical imaging. This is due to their
unique contrast-generating properties as well as their potentially
long circulation half-lives, their high payload and the ease of
integrating multiple properties. In particular, they are highly
effective for molecular imaging, the non-invasive visualization
of the levels of molecules or cell types. Cardiovascular diseases
are particularly interesting to study with molecular imaging
because of the multiple processes and stages involved and
therefore the many cell types and molecules that are important
in these diseases. Nanoparticle contrast agents that have been
used in conjunction with cardiovascular magnetic resonance
1
Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, One
Gustave L. Levy Place, Box 1234, New York, NY 10029.
a
E-mail: [email protected]
b
E-mail: [email protected]
c
E-mail: [email protected]
d
E-mail: [email protected]
*Corresponding author
List of abbreviations after the text.
4 Nanomedicine and the Cardiovascular System
imaging, computed tomography, nuclear imaging techniques or
ultrasound include iron oxides, micelles, liposomes, emulsions,
gold nanoparticles, quantum dots and lipoproteins. In addition to
the above-mentioned technological aspects we highlight several
examples of the use of nanoparticles in cardiovascular imaging as
case studies at the end of this chapter.
INTRODUCTION
There has been a tremendous focus of research effort on nanotechnology
in general and nanoparticles specifically in the past twenty years. Part
of the reason for these efforts is that materials confined to nano-sizes (in
the range of 1–100 nm in one or more dimensions) can exhibit unusual
properties, be it optical, electronic, magnetic, fluorescent or catalytic. A
pertinent example of this is quantum dots, semiconductor-based colloids
that, when in the size range 1–10 nm, possess extraordinary fluorescent
properties. Nanoparticles can be formed from a wide variety of materials,
including inorganic materials such as gold, silver, platinum, iron oxide,
bismuth and cadmium selenide. Such inorganic materials invariably
possess some kind of organic coating, but nanoparticles can also be entirely
composed of organic materials such as polymers, amphiphiles, sugars or
proteins. Some of these coatings, such as polyethylene glycol, have been
found to make nanoparticles highly biocompatible and non-toxic both in
vitro and in vivo. Nanoparticles are now being explored in the biomedical
field for drug delivery, gene therapy and medical imaging, among other
applications.
Medical imaging is a highly important field, allowing for advanced
diagnosis, monitoring of therapy and surgical planning. X-ray imaging
is the oldest medical imaging technique, but it is still very widely used.
Newer techniques include magnetic resonance imaging (MRI), positron
emission tomography (PET) and X-ray computed tomography (CT). These
techniques provide three-dimensional datasets of images of patients, as
opposed to the two-dimensional images produced by X-ray imaging.
Additionally, ultrasound is a widely used technique and fluorescence
imaging systems are starting to become available. The details of these
different systems are described in a subsequent section. A crucial aspect
of all medical imaging systems is image contrast, i.e., visual differences
between structures and tissues. There are many ways of generating image
contrast, but one way is the use of contrast agents, substances used to
enhance the contrast of structures or fluids within the body in medical
imaging. This allows, for example, visualization of the vasculature or
detection of liver tumors. Contrast agents are either small molecules or
Nanoparticle Contrast Agents for Cardiovascular Medical Imaging 5
nanoparticles that incorporate some substance that produces contrast for
the relevant imaging technique; for example, gadolinium is included in
both small molecule contrast agents and nanoparticle formulations to
produce contrast in MRI.
In the field of medical imaging, there are several reasons that
nanoparticles are attractive for use as contrast agents, as opposed to small
molecules. First, nanoparticles may provide unique contrast properties,
such as the aforementioned fluorescence of quantum dots or the intense
MRI contrast produced by iron oxide nanoparticles. Second, small
molecules have a half-life of only a few minutes and the contrast they
produce can therefore swiftly dissipate. Nanoparticles, on the other hand,
can be designed to have extended half-lives, which can be valuable in cases
of image-guided surgery, such as stent emplacement. The extended half-life
of nanoparticles would avoid the need to repeatedly inject a small molecule
contrast agent. Third, nanoparticles can deliver very high payloads, with as
many as millions of contrast-generating atoms per nanoparticle as opposed
to normally only one such atom for a small molecule. Last, it is relatively
straightforward to include multiple components in nanoparticles, such as
additional forms of contrast, targeting molecules or therapeutic materials.
Inclusion of targeting molecules allows imaging of specific cell types,
molecules (e.g., cell surface receptors) or biological processes. This field of
targeted imaging is known as molecular imaging. Molecular imaging can
allow advanced diagnoses, analysis of therapeutic efficacy and improved
information on diseases.
Cardiovascular diseases are the primary cause of mortality in the
Western world and consequently their study via imaging is of crucial
importance for better understanding of fundamental disease processes,
improved diagnoses and the evaluation of (new) therapies. The majority
of the work that has been done in nanoparticle-based imaging of
cardiovascular disease has focused on molecular imaging. Cardiovascular
diseases are also often rather interesting to study, with many different
cells and molecules involved and several stages of progression that have
distinct levels of expression of cell types and molecular markers. For
example, atherosclerosis is a progressive inflammatory disease in which
there is a gradual buildup of fatty molecules in the arteries, recruitment
of macrophages and other cell types to form tissue deposits known as
atherosclerotic plaques (Fig. 1). Eventually, lipid-rich, necrotic or calcified
cores develop in these plaques. These plaques sometimes rupture,
whereupon a thrombus forms that may occlude the artery and block the
blood flow. Ruptures of plaques in the coronary arteries cause 70% of
heart attacks. The cell types, molecules and processes of interest include
macrophages, endothelial cells, foam cells, smooth muscle cells, vascular
cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1,
6 Nanomedicine and the Cardiovascular System
Fig. 1. A simplified depiction of the progression over time of an atherosclerotic lesion,
indicating the different processes that occur and receptors expressed at different stages of
lesion development. Reproduced with permission from Sanz and Fayad (2008).
Color image of this figure appears in the color plate section at the end of the book.
selectins, collagen, the αvβ3-integrin, matrix metalloproteinases, cathepsins,
fibrin, angiogenesis, inflammation, apoptosis and thrombosis (Sanz et
al. 2008). Imaging thromboses is discussed in depth in Chapter 17 on
multifunctional nanoagents for the detection and treatment of thromboses.
From a molecular imaging perspective, it is an interesting challenge to
develop contrast agents for these widely differing species, which occur in
different locations in the arteries. An additional challenge is the different
locations of the vascular beds, i.e., the coronaries in the heart, the aorta
and other arteries in the abdomen and the peripheral arteries. An imaging
modality-nanoparticle combination that works well in the carotid arteries
may not work so well for the coronary arteries, because of the motion
of the heart and chest and differences in the surrounding tissue. For
these reasons, cardiovascular diseases (e.g., atherosclerosis, myocardial
infarction and abdominal aortic aneurysms) have drawn a great deal of
interest in the molecular imaging field with many nanoparticles designed
to investigate them.
Nanoparticle Contrast Agents for Cardiovascular Medical Imaging 7
In this chapter we discuss the different types of nanoparticles used as
contrast agents in cardiovascular imaging. Subsequently, we discuss how
the different imaging techniques work. Last, we give a series of examples
of nanoparticles used in cardiovascular disease.
NANOPARTICLES
In this section we describe the different types of nanoparticles that have
been used in cardiovascular imaging and highlight some of their most
important features.
Nanoparticles can be synthesized from a wide variety of materials and
have widely varying structures. Before covering nanoparticle types in
depth, first we will discuss a generalized design of nanoparticles for
molecular imaging (Fig. 2). These nanoparticles usually have a core and
one or more layers of coating materials. The coatings are used to make
the nanoparticle hydrophilic and biocompatible. Contrast-generating
materials can be located within the core, in the coating or at the coating
surface. In the case of gadolinium, for example, contrast is generated with
these ions mainly via contact with water, so gadolinium is usually located
at the nanoparticle surface, whereas fluorophores do not require contact
with water and therefore can be located anywhere within the nanoparticle
structure. The availability of different locations in which to load contrast-
generating materials or other substances is often exploited to include two
or even three types of contrast-generating material in the nanoparticle. In
some cases, contrast-generating materials and therapeutics are combined
Fig. 2. Schematic depiction of a nanoparticle for use in cardiovascular molecular imaging,
indicating the important components. Reproduced with permission from Cormode et al.
(2009).
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