Nanomedicine in Health and Disease, 1st Edition
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Nanomedicine in
Health and Disease
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
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Published by Science Publishers, an imprint of Edenbridge Ltd.
• St. Helier, Jersey, British Channel Islands
• P.O. Box 699, Enfield, NH 03748, USA
E-mail:
[email protected] Website: www.scipub.net
Marketed and distributed by:
Copyright reserved © 2011
ISBN 978-1-57808-725-9
Cover Illustrations: Reproduced by kind courtesy of the undermentioned authors:
Figure No. 3 from Chapter 4 by Kerriann R. Greenhalgh
Figure No. 5 from Chapter 9 by Rehab Amin
Figure No. 4 from Chapter 12 by Moritz Beck-Broichsitter et al.
Library of Congress Cataloging-in-Publication Data
Nanomedicine in health and disease / editors, Ross J. Hunter, Victor
R. Preedy.
p. ; cm. -- (Nanoscience applied to health and medicine)
Includes bibliographical references and index.
ISBN 978-1-57808-725-9 (hardcover)
1. Nanomedicine. 2. Nanotechnology--Health aspects. I. Hunter,
Ross, 1977- II. Preedy, Victor R. III. Series: Nanoscience applied
to
health and medicine.
[DNLM: 1. Nanomedicine--methods. 2. Nanostructures--therapeutic
use. QT 36.5]
R857.N34N356 2011
610.28--dc23
2011016513
The views expressed in this book are those of the author(s) and the publisher does not assume responsibility
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Copyright reserved © 2011
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, while nanostructures provide suitable platforms for
sub micro bioengineering. However, understanding the importance of
the nanoscience and technology is somewhat problematic as much of the
literature on the subject is highly technical, written with little consideration
for 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 readers 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 used within that chapter. Finally, each chapter has a
series of summary points. In this book we focus on nanomedicine in health
and disease. We cover the regulation of nanomedicine, nanotubes, topical
applications of nanoparticles, nanocrystals, antioxidant nanoparticles,
lipid nanocapsules, nanotheragnostic colloids, nanotechnology in the
control of infectious disease, virus-based nanoparticles and the safety of
nanoparticles. We also cover nanomedicine in relation to pulmonary drug
delivery, the control of infectious disease, radiation protection, arthritis,
cancer nanomedicine, blood diseases, neurodegenerative disorders, and
tissue and implant engineering.
Contributors to Nanomedicine in Health and Disease are all international
or national experts or leading authorities or are carrying out ground-
breaking and innovative work on their subject. The book is essential
reading for research scientists, medical doctors, health care professionals,
pathologists, biologists, biochemists, chemists and physicists, and general
practitioners as well as those interested in disease and nano sciences in
general.
The Editors
Copyright reserved © 2011
Contents
Preface v
Section 1: Introduction and Technology
1. Nanomedicine: An Introduction 3
Lajos P. Balogh
2. The Regulation of Nanomedicine 20
Joel D’Silva and Diana Bowman
3. Nanotubes and Their Application to Nanomedicine 43
Gianni Ciofani
4. Nanoparticles for Topical Application 64
Kerriann R. Greenhalgh
5. Nanocrystal Formulations for improved Delivery 79
of Poorly Soluble Drugs
Jan Möschwitzer and Rainer H. Müller
6. Antioxidant Nanoparticles 100
Beverly A. Rzigalinski, Kathleen Meehan, Mark D. Whiting,
Candace E. Dillon, Kevin Hockey and Michael Brewer
7. Lipid Nanocapsules in Nanomedicine 122
Marie Morille, Patrick Saulnier, Jean-Pierre Benoit
and Catherine Passirani
8. Nanotheragnostic Colloids in Disease 146
José L. Arias
9. Nanotechnology in Controlling Infectious Disease 167
Rehab Amin
10. Virus-based Nanoparticles as Tools for Biomedicine 184
Stefan Franzen, Steven A. Lommel and Bruce Oberhardt
11. Safety of Nanoparticles in Medicine 203
Maria Dusinska, Lise Marie Fjellsbø, Zuzana Magdolenova,
Solveig Ravnum, Alessandra Rinna and Elise Rundén-Pran
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viii Nanomedicine in Health and Disease
Section 2: Applications to Health
12. Pulmonary Drug Delivery with Nanoparticles 229
Moritz Beck-Broichsitter, Thomas Schmehl, Werner Seeger
and Tobias Gessler
13. Carbon Nanotubes and Infectious Diseases 249
Yitzhak Rosen, Brandon Mattix, Apparao Rao and Frank Alexis
14. Radiation Protection with Nanoparticles 268
Cheryl H. Baker
15. Nanoparticle Therapy in Arthritis 293
José L. Arias
16. Phospholipid-based Nanomicelles in Cancer 314
Nanomedicine
Hayat Onyuksel and Amrita Banerjee
17. Tumor-specific Liposomal Nanomedicines: Antitumor 336
Antibody-modified Doxorubicin-loaded Liposomes
Tamer Elbayoumi and Vladimir Torchilin
18. Nanomedicine in Blood Diseases 356
Denis B. Buxton
19. Nanomedicine and Neurodegenerative Disorders 377
Ari Nowacek, Gang Zhang, JoEllyn McMillan, Tomomi Kiyota,
Elena Batrakova and Howard E. Gendelman
20. Nanotechnological Applications in Tissue and Implant 398
Engineering
Viswanathan S. Saji and Han-Cheol Choe
Index 415
About the Editors 421
Color Plate Section 423
Copyright reserved © 2011
Section 1: Introduction and Technology
Copyright reserved © 2011
1
Nanomedicine: An Introduction
Lajos P. Balogh
ABSTRACT
Nanoscience and nanotechnology is closing the gap in our
knowledge between molecular and bulk properties. This process
has enormous significance in understanding and changing our
world. It is expected that this field will expand greatly as advances
are being made in using nanoscience and nanotechnology for
basic, translational, and clinical medical research. In the next
decade, nanomedicine will forever change how we diagnose and
treat patients.
The general relationship between science, technology, medicine,
business and society is always the same, whether it is “nano”
or not “nano”. However, the emergence of nanomedicine has a
significant practical future in medicine and human health. The
market for life sciences and health care products can currently
be measured in hundreds of billions of U.S. dollars. A market of
many billions more is predicted within ten years, primarily in
medical devices, implants, imaging and diagnostics enabled by
nanoscience and nanotechnology. As a consequence, the quality
of life is expected to improve considerably.
Nanomedicine research is reforming our understanding of biological
processes, it will transform clinical medicine, and it will change the
way pharmaceutical commercialization and business is done.
364 Ocean Ave, Ocean Shores Tower, Suite 702, Revere, MA 02151; Email: [email protected];
[email protected]
Copyright reserved © 2011
4 Nanomedicine in Health and Disease
A strategy to accelerate nanoscience and nanoengineering
for medicine and health reflects increasing societal need and
technology pull, as well as basic science push. Apart from the great
promises of the relevant sciences and developing technologies,
there are several challenges present for this paradigm-changing
field, especially in the areas of communication, commercialization,
safety, regulations, standardization, education, and public policies.
The success of nanomedicine ultimately will depend on whether or
not we can transform and harmonize commercialization processes
to allow personalized medicine, whether nanoscience becomes
a successful “nanobusiness,” and whether these new tools and
devices will reach the clinic and improve public health. In reality,
at the clinical level, the practitioner does not have to know that
it is nanotechnology at work—only that the new procedure or
“medicine” works better, and it is more affordable.
INTRODUCTION
A few terms are defined at the outset.
A nanometer (nm) is 1x10–9 m; 1000 nm equals 1 µm.
Science is the study of the physical world and its manifestations, aimed
at discovering ruling principles of the phenomenal world by employing
scientific methods, especially systematic observation and experiment.
(See also: http://encarta.msn.com/encnet/features/dictionary/
dictionaryhome.aspx.)
Engineering is the process of designing and making tools, machines,
apparatus, and systems to exploit phenomena for practical human purposes.
It translates basic and applied science into technology. Mathematics and
predictive models are distinct components of engineering, which is always
quantitative.
Technology is the study, development, and application of engineered
devices, machines, and techniques for manufacturing and productive
processes; a method or methodology that applies technical knowledge
or tools; and the sum of a society’s or culture’s practical knowledge,
especially with reference to its material culture. Technology has to satisfy
additional requirements such as utility, usability and safety. (See also:
http://en.wikipedia.org/wiki/Technology#cite_note-12.)
Medicine is the study and the cycle of diagnosis, treatment, monitoring,
prediction, and prevention of diseases. Following up with patients,
collecting and evaluating data, and other tasks are also considered part
of medicine. The term “medicine” itself could also mean a substance that
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Nanomedicine: An Introduction 5
promotes healing. Potential sub-categories of medicine may include
diagnostics, therapeutics, regenerative medicine, prosthetics, public
health, toxicology, point-of-care monitoring, nutrition, medical devices,
prosthetics, biomimetics, and bioinformatics.
Medical research together with monitoring and follow-up of patients
improves our health-related knowledge, which is realized in education
and practiced through our public health systems. Knowing the cause
and mechanism of an illness may lead to its temporary or permanent
prevention.
Science, engineering, technology, commercialization, business and society are in a
special relationship with each other. Successful new products have to pass
the whole sequence from science through business to serve society’s needs.
These fields are vertically interrelated and embedded in each other (Fig. 1)
and are connected by communication and dynamic interactions. Science
generates new knowledge, engineering creates new tools, and technology
develops processes to manufacture goods. When fundamental business
requirements are met, technologies can be commercialized. Standards and
appropriate regulations are prerequisites to successful commercialization.
Commercialization requires sufficient scientific knowledge (in the form of
intellectual property secured by patents) and needs creative engineering,
a technology that is competitive on the market; the product must also
satisfy society’s needs.
Fig. 1. The {{{{Science}Engineering}Technology}Business} hierarchy. Progress on these fields
could be driven by hypothesis, need, and/or opportunity. Efficient communication between
these layers is of utmost importance for successful commercialization.
Color image of this figure appears in the color plate section at the end of the book.
Copyright reserved © 2011
6 Nanomedicine in Health and Disease
Nanoscience is the study of nanoscale substances, objects, structures, and
materials applying scientific methods to understand and control matter at
the nanoscale (Fig. 2). As such, it is part of all disciplines of natural science.
Nanomaterials are not new materials with magical properties; rather,
nanoscale materials are made of well-known materials and building
blocks that display properties that do not exist outside the nanorange.
Measurements performed at that level to understand how things work are
also considered part of nanoscience.
Nanotechnology is the “application of scientific knowledge to manipulate
and control matter in the nanoscale in order to make use of size- and
structure-dependent properties and phenomena, as distinct from those
associated with individual atoms or molecules or with bulk materials.
Manipulation and control includes material synthesis” (ISO/TS 80004-
1:2010, http://db.iso.org).
Nanomedicine exploits and builds upon novel research findings in
nanoscience, nanotechnology, biology, and medicine; it unifies the
efforts of scientists, engineers, and physicians determined to apply their
latest research results to translational and clinical medicine, ultimately
developing novel and better approaches and paradigm-changing solutions
to health-related issues, ultimately improving the quality of life (Balogh
2009).
Nanoscience, nano-engineering and nanotechnology are the science, engineering,
and technology of nanoscale materials and nanosized systems.
Although there are ongoing discussions whether “nanoscale” is 1–100
nm (where most of the novel “nano” properties are usually observed), or
1–1000 nm (in agreement with the original meaning of “nano” (10–9), there
is a general consensus that the term “nanosized” means that the structure
of a material is on the nanometer scale, at least in one dimension. The
nanoscopic range lies between the atomic “angstrom” (10–10 m) range and
the bulk state (the “micro” and “macro” world). It connects “molecular”
and “bulk” regimes, where atomic/molecular, “nano”, and materials
characteristics are simultaneously present (Balogh 2010a) (Fig. 2).
People interact and behave differently when they are alone, are in
groups, or form an audience. Nanoscale objects, atoms and molecules,
also behave differently when they are separate from the others, or are
held together in small groups, or are present in bulk. In general, “nano”
properties are due to the direct interactions of small numbers of atoms
and/or molecules keeping them together in a given environment.
Emergence of “nano” properties may be due to quantum effects between
the atoms or molecules (Brus 1984; Alivisatos 1998), the increased role
of surface interactions (Nel et al. 2006), and the collective properties of the
particles formed from more than one primary object. Figure 3 depicts the
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Nanomedicine: An Introduction 7
Fig. 2. The nanoscopic range is between “molecular” and “bulk” regimes, where molecular,
“nano”, and materials characteristics are present simultaneously.
Color image of this figure appears in the color plate section at the end of the book.
Fig. 3. Change of relative differences in mass as nanoparticles (NP) during transition towards
bulk materials. There is no sharp limit towards the bulk phase (Balogh 2010b, Fig. 2., with
permission).
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8 Nanomedicine in Health and Disease
relative change in mass of particles formed by adding one more unit to an
atom or molecule as a function of the number of original objects. It is clear
that as the particle becomes bigger its average diameter increases, and the
measurable property differences gradually diminish until the differences
become unmeasurable (Balogh 2010b). Scientifically it is impossible to
point out the precise length limits of “nanoscale properties”, because there
is no sharp limit on the “bulk” side. For different substances and materials
and even for different (e.g., optical or electromagnetic) properties of the
same material, the nanorange (transitional properties between molecular
and bulk behavior) may lie somewhere else on the nanometer length-
scale.
Size is the most obvious independent variable of nanoparticles
that can be measured and nanoscale properties are often attributed to
changes in size only. However, size is just one of the factors determining
properties, and composition, shape, and architecture also play a definitive
role. In principle, “nano” characteristics of materials are determined by
the individual properties of the participating constituents (composition)
and the means by which they interact with each other and with their
immediate environment. Size (i.e., L linear parameter) is directly related
to surface (which is proportional to L2), and increase of the surface area
increases everything related to surface interactions (e.g., surface forces,
solubility, penetration/scattering of light, biodistribution, degree of
opsonization). Similarly, surface/volume ratio (~L2/~L3) increases with
decreasing size, and more and more atoms and molecules will be on the
surface of a particle (Nel 2006).
For medical nanodevices combining inorganic, organic and biological
materials the picture is much more complex. Here the primary components
comprising a single nanodevice may be objects of different nature (e.g.,
organic or inorganic molecules, synthetic macromolecules, peptides,
proteins, antibodies, nanoparticles). This complexity is unavoidable to
successfully address complicated biological processes. We believe that
better understanding of nanoparticles, nanoscale materials, and nanoscale
laws will lead to a seamless integration of theory and models, which
sooner or later will enable the design of better nanodevices and a priori
prediction of their actions and biological properties.
In summary, “nano” properties are due to the following:
• quantum effects,
• the increased role of surface interactions, and
• collective properties of the objects, which depend on architecture.
“Nano” properties of materials are determined by the individual
properties of the constituents and the way primary components interact
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Nanomedicine: An Introduction 9
with each other and with their environment. Properties of individual
nanoparticles in a nanomaterial may differ slightly; therefore, properties
of nanomaterials have a distribution around an average value for every
distinct property (the only exception is chemical composition).
Size is just one of the factors determining properties of nanoscale
materials. It is impossible to point out the precise length limits of the
range of “nanoscale properties” without specifying the material system
itself first. Nanoscale properties (transitional between molecular and bulk
state) could be different for different properties of the same material. Either
way, the resulting novel “nano” properties can effectively be used to
create innovative tools and design new processes that lead to technologies
offering better solutions to medical problems (Balogh 2010a).
THE NEED FOR NEW SOLUTIONS IN HEALTH CARE
The world longs for better health care. In the U.S. the cost of health care
is skyrocketing and threatens to bankrupt the health care system. As an
example, the direct medical cost in the U.S. was about $90 billion for cancer
and about $116 billion for diabetes in 2007. The annual medical care cost
for spinal cord injury in the U.S. is about $1.5 billion; the full annual costs
are estimated at about $10 billion. In order to remain physically active,
approximately 200,000 people receive hip implants and 300,000 people
receive knee implants in the U.S. The average lifetime of current orthopedic
implants is only 10–15 years, and revision surgeries and their recoveries
are not as successful as the first operation. The cost of an implant varies,
but is roughly $20,000.
At the same time, in developing countries, especially in Africa,
thousands are dying every day because they cannot afford medication.
Asian countries are looking at traditional cures as alternatives to western-
style pharmaceutics. People are hopeful for change, but they also naturally
fear the unknown.
Everybody is looking for new solutions, and most of these new
approaches may be offered by nanomedicine.
Nanomedicine connects chemistry, materials science, physics, biology,
and engineering to basic and preclinical medical research as well as
clinical medicine. While the most developed areas for nanoscale materials
are chemistry, materials science, and physics, the last few years have
seen unprecedented advances in the field of biology. The decoding of the
human genome coupled with gene transfection technologies offer great
opportunities for treating illnesses. It has long been recognized by health
care practitioners that individual patients respond differently to the same
drug, in terms of both efficacy and safety. Drug pharmacological response
Copyright reserved © 2011
10 Nanomedicine in Health and Disease
is underlined by two interrelated dynamic processes: physiologically based
pharmacodynamics is associated with what the drug does to the body
(i.e., drug-receptor interactions), whereas pharmacokinetics describes
what an organism does to the drug (i.e., the processes of drug absorption,
distribution, metabolism and elimination) (Viziriakis 2010).
Pharmacogenomic testing and individualized adjustment of drug
selection and dosage schemes will also improve treatments and eliminate
adverse response effects caused by the differential pharmacological
response of different patients to the same drug(s). Understanding the
genetic origin and molecular mechanism of diseases will significantly
improve the outcome of clinical treatments (Balogh 2009).
There are many reasons to consider nanosized substances for
medicine. Decreasing particle size results in increased surface interactions
for both nanocrystals and emulsions, which may result in increased
solubility for both hydrophilic and hydrophobic drugs. Liposomes,
polymers, surface compatibilized nanoparticles, dendrimers and
other vesicles are usually able to deliver larger payloads, and chemical
modifications of surfaces can accommodate to receptor-specific targeting
moieties. Interactions of nanodevices with cells are different from those
of small molecules: pinocytosis and receptor-mediated endocytosis are
the major uptake mechanisms (Fahmy 2005). Nanoscale devices have
different biodistribution, pharmacodynamic and pharmacokinetic
behavior compared to traditional drugs (Li 2010) and offer unusual
pharmacodynamics and pharmacokinetics that are not accessible for small
molecules and traditional substances. Functional and multifunctional
nanodevices are assembled from various nanosized components that carry
out the various desired functions. For medical nanodevices, there are a
few critical basic requirements to meet: they must be stabile in body fluids,
lack toxicity, have appropriate biodistribution, and have predictable and
ideal pharmacokinetic behavior without significant immunogenicity. In
addition to functional interactions such as binding to receptors, blocking
or internalization, initiating signaling events and so on, all of these
requirements need to be considered in their design. These are typical
steps in nanomedical engineering to design, analyze, and manufacture
nanodevices.
For example, an ideal anticancer drug must have a low level of
systemic toxicity, it should target the appropriate cells at the desired sites
of action, its location and effects should be observable by existing imaging
techniques, and it should deliver the correct dose of therapeutic agents
for the desired length of time. In addition, it may use a non-invasive
external trigger to release therapeutic molecules and document response
to therapy by identifying residual cells. In this case, seven different actions
would be needed to accomplish this task. Although modern drugs can
Copyright reserved © 2011
