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Nanomedicine
A Soft Matter Perspective

Edited by
Dipanjan Pan
University of Illinois
Urbana-Champaign

Boca Raton London New York

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Dedicated to my beloved wife, Angana
Contents
Preface.......................................................................................................................ix
The Editor..................................................................................................................xi
Contributors............................................................................................................ xiii

Chapter 1 Introduction........................................................................................... 1

Chapter 2 Nuclear Imaging with Nanoparticles.................................................. 31

Ali Azhdarinia and Sukhen C. Ghosh

Chapter 3 Molecular Imaging at Nanoscale with Magnetic Resonance

Imaging............................................................................................... 75
Patrick M. Winter

Chapter 4 Optical Imaging with Nanoparticles................................................. 103

Walter J. Akers

Chapter 5 Contrast Agents for Computed Tomographic Imaging..................... 131

Dipanjan Pan, Santosh K. Misra, and Sumin Kim

Chapter 6 Nanomedicine: Perspective and Promises........................................ 151

Dipanjan Pan

vii
Preface
The capability to monitor disease biosignatures for early and noninvasive detec-
tion in combination with targeted therapy is a pressing clinical need and the basis
for nanomedicine. This multidisciplinary field is evolving fast and presenting new
clinically relevant promises as the science of molecular biology, genomics, chem-
istry, and nanotechnology contribute greatly. In this book we discuss the unique
opportunities presented by biomaterials at the nanoscale. Nanoparticle-­based ther-
anostic approaches have emerged as an interdisciplinary area, which shows promise
to understand the components, processes, dynamics, and therapies of a disease at a
molecular level. The unprecedented potential of nanotechnology for early detection,
diagnosis, and personalized treatment of diseases has found application in every bio-
medical imaging modality. However, with the increasing concern about the ethical
and toxicity issues associated with some “nanoplatforms,” the biomedical research-
ers are in pursuit of safer, more precise, and effective ways to practice nanomedicine.
This book provides a broad introduction to matters for nanomedicinal applica-
tion. It covers comprehensive information regarding “soft” nanoscopic objects with
prerequisite features for different imaging modalities. The book also offers a gen-
eral introduction to the various drug delivery systems and their opportunities from
chemistry, materials, biology, and nanomedical standpoints. The book provides a
broad introduction to the field and the subfield, with a deeper discussion on the indi-
vidual modalities for molecular imaging, expanded in four chapters. The theranos-
tic approach is introduced to the readers in the first chapter with discussion about
the potential of drug delivery in conjunction with molecular imaging. In Chapter 2,
Dr. Ali Azhdarinia and Dr. Sukhen C. Ghosh, from the University of Texas Health
Science Center, discuss the potential of nuclear medicine and describe relevant
chemical strategies for the design and syntheses of agents suitable for these tech-
niques. In Chapter 3, Dr. Patrick M. Winter, from the Cincinnati Children’s Hospital,
emphasizes nanomedicine strategies with magnetic resonance imaging. In Chapter 4,
Dr. Walter J. Akers, from the Washington University School of Medicine, illustrates
various possibilities with optical-­based techniques. In Chapter 5, Dr. Dipanjan Pan,
Dr. Santosh Misra, and Sumin Kim, from the University of Illinois at Urbana–­
Champaign, discuss the unique potential for imaging molecular signatures with
computed tomography. In Chapter 6, Dr. Dipanjan Pan critically reviews the status
of various nanomedicine platforms in clinical trials. This concluding chapter also
tries to capture potential pitfalls and challenges faced by the field.
It is anticipated that the book will garner interest across disciplines—within the
related areas of chemistry, biochemistry, molecular biology, physiology, and experi-
mental and pharmaceutical sciences. For advanced readers, we expect that it may
stimulate experimentation to progress and tune the existing nanomedicine technolo-
gies for translational and clinical applications.

ix
The Editor
Prof. Dipanjan Pan joined the University
of Illinois in 2013. Previously, he was an
assistant professor of medicine, research
at the Division of Cardiology, Washington
University in St. Louis. He also served as a
full faculty member of Siteman Cancer Center
at Washington University. After receiving his
PhD in chemistry, he pursued a postdoctoral
career in polymer science and nanotechnology
at the Department of Chemistry, Washington
University, in St. Louis. Soon, after a brief stint
in the industry (General Electric biosciences/­
healthcare), Dr. Pan joined the Washington
University faculty in 2007.
Prof. Pan’s research is broadly aimed at
developing clinically translatable defined
nanoparticle platforms for molecular imag-
ing, drug delivery, and nonviral gene delivery
applications. His research is highly multidisciplinary, which brings skills from syn-
thetic chemistry, nanoengineering, molecular biology, and preclinical animal mod-
els. Prof. Pan is a co-­inventor of several engineered nanoplatforms for molecular
imaging and therapeutic application. His research covers several imaging modali-
ties, including MRI, CT, optical, PET/­SPECT, and photoacoustic imaging. His work
has been commercialized for preclinical application and externally supported by
federal agencies such as NIH, AHA, as well as the Children’s Discovery Institute.

xi
Contributors
Walter J. Akers, DVM, PhD Sumin Kim, BS
Mallinckrodt Institute of Radiology Department of Bioengineering and
Washington University School of Beckman Institute
Medicine University of Illinois,
St. Louis, Missouri Urbana–­Champaign
Urbana, Illinois
Ali Azhdarinia, PhD
Center for Molecular Imaging,
Santosh K. Misra, PhD
The Brown Foundation Institute
Department of Bioengineering and
of Molecular Medicine
Beckman Institute
The University of Texas Health Science
University of Illinois,
Center at Houston
Urbana–­Champaign
Houston, Texas
Urbana, Illinois
Sukhen C. Ghosh, PhD
Center for Molecular Imaging, Dipanjan Pan, PhD
The Brown Foundation Institute Department of Bioengineering and
of Molecular Medicine Beckman Institute
The University of Texas Health Science University of Illinois,
Center at Houston Urbana–­Champaign
Houston, Texas Urbana, Illinois

Patrick M. Winter, PhD

Department of Radiology
Cincinnati Children’s Hospital
Cincinnati, Ohio

xiii
 1 Introduction

CONTENTS
1.1 Introduction....................................................................................................... 1
1.2 Biological Barriers............................................................................................. 2
1.3 Rational Design of Nanoparticles...................................................................... 3
1.3.1 Contrast Materials and Targeting Agents..............................................3
1.3.2 Targeting Strategies and Homing Agents.............................................. 5
1.3.3 Nanoparticle Platforms.......................................................................... 6
1.3.4 Surface Chemistries...............................................................................7
1.4 Specific Examples of Targeted Molecular Imaging and Therapy.....................8
1.4.1 Opportunities with Ultrasound Imaging............................................. 10
1.4.2 Opportunities with MR Imaging......................................................... 11
1.4.3 Opportunities with Emerging Imaging Technologies......................... 16
1.5 Conclusions...................................................................................................... 18
References................................................................................................................. 18

1.1 INTRODUCTION
Nanotechnology is the science of manipulating matter on an atomic and molecular
scale. Over the past decade, this field has seen enormous growth in terms of precisely
manipulating matter at the “nano” scale. At scales on the order of hundreds of nano-
meters, novel materials properties emerge, enabling the development of new classes
of materials. The unique properties experienced at that scale have been utilized to
create many new materials with a vast range of applications, such as in electron-
ics, energy production, and, very recently, human health. It can create opportuni-
ties for paradigm shifting results, creating preventive, diagnostic, and therapeutic
approaches to human diseases such as cancer, neurological, and cardiovascular [1–7]
diseases. The strategy for uniting diagnostics and/­or therapeutics on the nanoscale
is defined popularly as nanomedicine, which offers benefits due to the high degree
of equivalent transport and distribution of the active agents within the biological
systems for the diagnosis and treatment of diseases.
The biological transport routes, functionally and at the cellular and subcellular
levels, are heavily influenced by the physical attributes of the nanoagents. These
physical attributes include their size (extra- or intravascular), shape/­morphology
(e.g., spherical vs. rod), and flexibility (“soft” vs. “hard”), as well as their chemical
identities, including surfaces presenting homing agents for specific recognition by
and triggering of biological receptors, cell penetrating peptides (CPPs), etc. It is of
critical significance to gain understanding of these parameters in details that govern
their uniformity with control over their physical and chemical characters.

1
2 Nanomedicine: A Soft Matter Perspective

A subtopic of nanomedicine research is molecular imaging. Emerging trends in

molecular imaging (MI) bring promises to recognize the components, progressions,
dynamics, and therapies of a disease at a molecular level. MI unites new agents
with biomedical imaging tools to identify cellular events visually and depict specific
molecular trails in vivo that are key targets in disease progression. The recognition
of the existing prospect to detect preclinical pathology has seen myriad progress in
this area to synchronous development of sensitive, high-­resolution imaging modali-
ties and specific molecular probes.
The most commonly used noninvasive cellular and molecular imaging techniques
include clinical modalities—that is, ultrasound (US), positron emission tomogra-
phy (PET), computed tomography (CT), and magnetic resonance imaging (MRI)
and experimental imaging techniques (e.g., optical, photoacoustic imaging [PAI],
etc.). Nanoarchitectures for medicinal application can be designed from various pre-
cursor materials (e.g., lipids, polymers, metals, etc.). They can act as a reservoir
material to encapsulate a wide range of active constituents, including contrast agents,
therapeutics, and homing moieties. Soft nanomaterials (e.g., well-defined polymers,
lipids, etc.) are excellent examples for their versatility in terms of modifying their
structures for high payload and delivery to the disease site. Some of the materials
are also known to respond to environmental factors (e.g., physiological or external
stimuli). The physiological factors include pH, enzymatic, oxidative, and reductive
conditions. The external stimuli can be exemplified as temperature, ultraviolet (UV)-
visible (vis) light, near-­IR (infrared), stimulation with magnetic fields or ultrasonic
vibrations, etc.
The physicochemical properties of these nanoparticles influence their shelf-­life
and in vivo stability, biodegradability, biocompatibility, biodistribution, and bioelim-
ination. Therefore, the strategy for generating particles for nanomedicine application
depends on the target disease, intended site of delivery (organs, tissues, cellular or
subcellular organelles), route of administration, and the technique used for imaging.
In most cases, intravenous injection is the primary route of administration, but there
are other, nonconventional ways of administration (e.g., intradermal/­transdermal,
oral, and mucosal delivery).

1.2 BIOLOGICAL BARRIERS
For cell- or tissue-­specific delivery, drugs are encapsulated into nanoparticles and
are modified in a defined way so that they reach their destinations (i.e., sites of action),
typically on the cellular or molecular levels. The hurdles of the delivery of these
drugs (also their carrier nanoparticles) can be classified into pathway barriers and
cellular barriers (the limited cellular uptake, endosomal or lysosomal degradation,
and the inefficient translocation to the targeted subcellular organelles). Pathway
barriers (“en route” barriers) can be exemplified as the obstacles that nanoparticles
experience once they are in blood and extracellular matrix. The behavior of the
nanoparticles following intravenous administration is complex. Once in the blood,
they are exposed to renal and hepatic clearance, disruption, clumping, opsonization,
and clearance by the reticuloendothelial system (RES). RES is now referred to as the
mononuclear phagocytic system (MPS). Nanoparticles can extravasate or allocate
Introduction 3

into the various body tissues and organs, which is highly dependent on their char-
acteristics, size, shape, and composition. The excretion of nanoparticles through the
renal pathway is dependent on nanoparticle size. It is believed that a typical renal
cutoff is 10 nm or approximately 50 kDa. Hepatic clearance of nanoparticles into bile
and feces is another path of excretion from the body. Opsonization is considered one
of the major barriers to particle stability in vivo. The examples of opsonins are com-
plement proteins, immunoglobulins, albumin, and fibrinogen. These proteins adsorb
on the surface of nanoparticles and label them for attack by the RES. The RES (or
MPS) is a part of the human immune system that entails phagocytic cells (e.g., blood
monocytes and macrophages accumulated in lymph nodes), spleen, liver (Kupffer
cells), and other tissues. These cells scavenge and consume foreign particles when
they are identified by the appropriate opsonin. The opsonization of nanoparticles
can generate immunological reactions and other in vivo instability to destabilize the
particles, leading to the premature release of their payloads.
The mode of cellular uptake is critical for delivering drugs. Nanoparticles may
interact with the lipid bilayer of the outer surface of cells and cellular membranes
followed by internalization through a process called endocytosis. In this process,
the nanoparticles are engulfed into different sizes of vesicles by the plasma mem-
brane. Contingent on the internalization pathway, nanomaterial compositions (lipid
vs. polymeric), size, morphology, and surface chemistry, they can create vesicles
of different kinds (e.g., endosomes, phagosomes, or macropinosomes). Some of the
most commonly documented mechanisms for the uptake of nanoparticles are phago-
cytosis, lipid-­fusion/­contact-­facilitated, clathrin-­mediated, caveolin-­mediated, and
clathrin/­caveolin-­independent endocytosis. Translocation to nucleus or mitochon-
dria is another challenging issue due to the physiological nature of these organelles.
Recycling (exocytosis) of the vesicle contents is also a possible pathway for the excre-
tion of nanoparticles from cells. Direct translocation of nanoparticles is possible by
using a category of peptides called cell-­penetrating peptides (e.g., HIV-­TAT1). CPPs
have been applied for the transport of nanoparticles and cargoes to get a direct access
to the cytoplasm after crossing the membrane.

1.3 RATIONAL DESIGN OF NANOPARTICLES

1.3.1 Contrast Materials and Targeting Agents
The term “nano” comes from the ancient Greek νάνος, nanos, which refers to “dwarf.”
It is a unit of measurement and can be denoted as 1 × 10 –9 m, or equal to 10 ang-
stroms. At the nanometric scale, due to the size and high surface area, these par-
ticles show unique properties. In real-­world scenarios, humans are 107 times smaller
than the Earth, whereas 100 nm sized particles are 107 times smaller than humans
(Figure 1.1).
These properties are exploited in wide-­ranging biomedical applications including
imaging and targeted drug delivery. There has been a surge of developing molecular
assemblies at the nanometric scale in anticipation that unique chemical and biologi-
cal properties will be achieved based on their interaction at their increased functional
area. The high surface area to volume ratio allows multiple alterations to introduce
4 Nanomedicine: A Soft Matter Perspective

• Humans are 10,000,000 times smaller than the Earth.

• A 100 nm sized particle, is 10,000,000 times smaller than a human.

Height of 100 m
a child 1m
10–1 m

Size of an
10–2 m
insect 1 cm

10–3 m
1 mm

Hair
10–4 m
diameter
Scaling
down
Bacteria
10–6 m
1 micron
10–7 m
Viruses

10–8 m

DNA Nanotechnology
10–9 m
100 nm
Hydrogen
10–10 m
atom

FIGURE 1.1 (See color insert.) Size scales in nanotechnology.

homing agents, contrast agents, and drug payloads internally or on the surface. Thus,
the number of ligands per nanoparticle is increased, which in turn improves their
binding affinity and decreases the rate of dissociation. This “stick-­and-­stay” effect is
frequently referred to as avidity of a nanoparticle.
Toward this goal, well-­defined nanoscale materials are being developed involving
conventional and advanced chemical strategies to carry contrast materials (e.g., radio
isotopes 99mTc, paramagnetic/­superparamagnetic metals, fluorophores, heavy met-
als, etc.). Other constructs are, themselves, the image-­able agent, but are specifically
tuned for targeting (e.g., dextran-­coated iron oxides).
For developing clinically translatable nanomedicine agents, the materials must
possess a tolerable toxicity (acute, systemic, immune response, cellular), long circu-
lating half-­life, excellent contrast-­to-­noise ratio enhancement, high binding efficacy,
and compatibility with commonly used commercial imaging modalities.