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Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
Asian Journal of
Pharmacodynamics and
Pharmacokinetics
ISSN
1608-2281
Copyright by Hong Kong Medical Publisher
Publisher Homepage: www.hktmc.com
Attention on research of pharmacology and toxicology of
nanomedicines
Tie-Feng Cheng1, 2, Yong-Da Sun3,4,, Duan-Yun Si2,3，Chang-Xiao Liu2,3
1
Key Laboratory for Special Functional Materials, Henan University, Kaifeng, 475001, China
2
Research Center of New Drug Evaluation, The State Key Laboratories of Pharmacodynamics and
Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
3
Research Center of Biological Evaluation of Nanopharmaceuticals, China National Academy of
Nanotechnology and Engineering, Tianjin, 300457, China
4.
Tianjin Crystec Pharmaceutical technology Ltd, Tianjin, 300457, China
Abstract
In the 21st century, nanoscience and nanotechnology obtains the world attention due to this
revolutionary theory and technical features. Nanoscience and nanotechnology cover the theory
and technology of physics, chemistry, medicine, material science, biomedical engineering and
biology, therefore, they have no less contribution to science and technology as biotechnology
and information technology. Recent years have witnessed the rapid development of China’s
nanoscience and nanotechnology with widespread influence. It was attended by scientists of the
world. Research, development and application of nanotechnology research in China can be
summed up in three characteristics: the first, China government in support of sustainable
development; the second, significant academic achievements, and the third, a clear consensus on
sustainable development for nanoscience and nanotechnology research and development. In this
review paper, we discussed the pharmacology and toxicology of nanomedicines, and presented
some issues on research and development and application of nanomedicines in the future.
Key words
Nanoscience; nanotechnology; nanomedicines; pharmacology; toxicology; China; sustainable
development; academic achievements
Article history
Received 26 December 2008;
Publication data
Pages: 23;
Corresponding author
Tables: 2;
Accepted 27 February 2009
Figures: 1;
References: 47;
Paper ID: 1608-2281-2009-0901027-23
Professor Chang-Xiao Liu, Tianjin Institute of Pharmaceutical Research, 308 An-Shan West Road, Tianjin,
300193, China.
E-mail: [email protected].
and nanotechnology, as a newly emerging leading-edge
Introduction
discipline, cover many fields such as physics, chemistry,
Nanoscience and nanotechnology has attracted
medicine, material science, biomedical engineering and
full attention of scientists around the world due to the
biology, therefore, the rapid development of nanoscience
breakthrough theory and technical feature. Nanoscience
and nanotechnology has contributed more and more deep
27
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
Frederick, National Institutes of Health, USA, and
Professor Michael M. Gottesman (National Cancer
Institute, National Institutes of Health, USA), as
co-chairmen of this meeting, lead scientists from
China and USA to discussed nanoscience,
nanotechnology and nanomedicines for cancer
treatment. An emerging field that takes full
advantage of expertise and research approaches
from such academic disciplines as nanotechnology,
biology,
chemistry,
physics,
medicine,
pharmaceutics and public health. No single
discipline can deal with the new field characterized
with a lot of interdisciplinary and comprehensive
studies. It is both a topic at the cutting-edge of
science development and an important social issue
closely related to people’s health and environment,
offering unlimited opportunities for innovation. The
meeting was focused on nanomedicines and
nanotechnology for cancer treatment, environmental
health of nanotechnology and its safety, and the
strategy
and
policy
for
nanotechnology
development. Central topics: (1) Molecular Basis of
Nanomedicine, (2) Development of “Smart”
Nanoparticles, biomarker and targeted delivery for
cancer therapy and imaging, (3) Nanotechnology :
Path to the clinic promises and hurdles and (4) The
molecular basis for engineered nanomaterial
interactions with human health and the environment.
The 4 topics provided exciting information for
nanomedicine researches in basis and clinical
research strategy for further development of
nanomedicines.[3]
knowledge to other discipline as biotechnology and
information technology information technology.[1]
Recently, nanotechnology proves its diverse
applications to take up the international market in
areas of biomedicine, informatics, energy resource,
astronautics, oceanography and national defense,
and so on. These applications offer huge economic
and technological potentialities. Current advances in
nanoscience and nanotechnology have led to the
development of the new field of nanomedicine,
which includes many applications of nanomaterials
and nanodevices for diagnostic and therapeutic
purposes. At the Third Annual Meeting of the
American Academy of Nanomedicine held at the
University of California San Diego, in San Diego,
USA, during September 7-8, 2007. The discussion
was
focused
on
successful
translational
nanomedicine: from bench to bedside. There were
four keynote lectures and eight scientific
symposiums in this meeting. The researchers and
investigators reported the results and process of
current nanomedicine research and approaches to
clinical applications. The meeting provided exciting
information for nanomedicine clinical-related
researches and strategy for further development of
nanomedicine research which will be benefits to
clinical practice.[2]
Recent years have witnessed the rapid
development of China’s nano-science and
technology with widespread influence. It was
attended by scientists of the world. On January
2008, a proposal to convene a Sino-US symposium
on nanomedicine and nanobiology was jointly made
by Dr. Elias Zerhouni (Director of the National
Institutes of Health, USA), Dr. John E. Niederhuber
(Director of the National Cancer Institute, USA and
Dr. Samuel Wilson (Director of the National
Institute of Environmental Health Sciences, USA).
To integrate outstanding research forces in China
and carry out exchanges with scholars of the world,
in particular US, the Xiangshan Science Conference
(the 331st Xiangshan Science Conference) on
nanotechnology and nanomedicine for cancer
treatment held from 21 to 24 October in Beijing,
China. Professor Zhao YL (Chinese National
Research Center of Nanosceince), Professor Robert
P. Blumenthal (Center for Cancer Research
Nanobiology Program，National Cancer Institute –
Research and development of nanoscience
and nanomedicines in China
Now
in
China,
nanoscience
and
nanotechnology become ever more consequential in
our lives, we in the scientific community need to
better inform and educate the public about the
transformations this new nano era is likely to bring.
Among the fields that have enjoyed particularly
rapid development in China in the past decade are
nanoscience and nanotechnology. These terms refer
to the growing knowledge base and technical
framework for understanding and manipulating
matter on nanometer scale ranging from the atomic
to the cellular. Like many other countries, we in
28
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
From 1990 to 2005 alone, over 1200 projects were
implemented. In addition, during this period, NSFC
approved nearly 1000 grants for small-scale projects
in related areas. With so much going on in
nano-related R&D in so many different places in
China, we created in 2000 the National Steering
Committee for Nanoscience and Nanotechnology to
oversee national policy and planning in these
arenas.[4]
Moving forward in nanoscience and
nanotechnology requires a particularly wide
spectrum of skills and knowledge. The demand for
multidisciplinary
research
platforms
with
components assembled from academia and industry
and that also have educational functions has become
especially strong in recent years. According to
incomplete statistics, more than 50 universities, 50
institutes and over 300 industry enterprises in China
have engaged in nanoscience and nanotechnology
research and development, with the involvement of
more than 3000 researchers across China. To move
forward and become more competitive in
nanoscience and nanotechnology, China needs to
continue to expand its now-limited research
infrastructure. In some areas, such as nanoscale
devices with novel electronic and optoelectronic
features, efforts to consolidate resources to tackle
key technological issues are under way. Efforts
have also been made to pursue industrial-scale
production of nanomaterials, such as CNTs,
polymeric nanocomposites, and nanoparticle
materials, with the intention of opening up
opportunities for new businesses to sprout and grow.
The nanoscience and nanotechnology community in
China has made remarkable advances across the
research and development spectrum, from
fundamental scientific research to studies into the
potential
societal
implications
of
new
nanotechnologies. China still has a long way to go
to improve the overall competitiveness of its
nanoscience and nanotechnology enterprise.[4]
During the Ninth Five-year Plan period
China expect that the development of nanoscience
and nanotechnology will greatly affect many areas
of scientific research and industrial development,
and many aspects of everyday life.[4]
Research, development and application of
nanotechnology research in China can be summed
up in three characteristics: the first, the government
in support of sustainable development; the second,
significant academic achievements, and the third, a
clear consensus on nano-innovation.
The government in support of sustainable
development
When the concept of nanoscience and
nanotechnology was first introduced in the 1980s, it
was received favorably in China. The initial interest
was in part stimulated by the development of new
tools and techniques for observing materials on the
nanoscale, especially scanning probe microscopes
(SPMs). Soon after the concept began trickling
through the scientific ranks, the Chinese Academy
of Sciences (CAS), the National Natural Science
Foundation of China (NSFC), and the State Science
and Technology Commission (SSTC)/ the Ministry
of Science and Technology (MOST) began funding
nanoscience-related work and activities. China also
has helped those who work in nanoscience and
nanotechnology to develop their sense of being part
of a new research and development community.
Since 1990, for example, dozens of international
and domestic conferences in the field have been
held in China. These conferences addressed a wide
range of topics in nanoscience and nanotechnology
and attracted wide attention and public interest. In
the 1990s, support for the development of
nanoscience and nanotechnology increased
substantially, largely through several major
initiatives. In 1990, for example, SSTC launched
the nearly decade-long "Climbing Up" project on
nanomaterial science. In 1999, MOST started a
national basic research project (“973” Plan) entitled
"Nanomaterial and Nanostructure" and has been
funding basic research on nanomaterials, such as
nanotubes, ever since. China National High
Technology Plan(“863” Plan), which encompasses
many categories of technology, has included a
series of projects for nanomaterial applications.
(1996-2000), the national “863” Plan supported by
China government starts the projects of improving
nanobiotechnology; during the Tenth Five-year
period (2001-2005)， national “863” and “973”
Plans
29
and
National
Natural
science
made
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
nanoscience, nanotechnology, and nanomedicine
studies
as
priority
subjects
to
support
A clear consensus on nano-innovation
Facing on the arduous in nanoscience and
nanotechnology research, and the risks of
nanopharmaceutical industry, we think in this area
should pay attention on four-oriented development,
according to China's national conditions. The first is
the practice research-oriented, combining basic and
application. The second is to set up different
professional disciplines for the research bases and
to strengthen the efficacy, safety, and the
industrialization, and feasibility study of
nanomedicines in order to ensure sustainable
development. The third, focus on solving the
challenging problem of the difficult implementation,
and
breakthroughs
in
nanoscience
and
nanotechnology. The fourth, the complexity in
research and development of the new technologies
requires to support with long-term development,
and to know the risks for technological
transformation to industrialization.
by
government. During the Eleventh Five-year Plan
period (2006-2010), the state is increased support
for nanoscience and nanotechnology research, the
annual input on
research,
one
billions of funds to carry out
of
three
subjects
of
nanopharmaceuticals are listed of the research plan.
Significant academic achievements
The scientific output of Chinese nanoscientists
is becoming ever more significant. According to the
Scientific Citation Index, CAS ranked fourth in the
world in total number of citations among those
institutions and universities that published more
than 100 nanotechnology papers from 1992 to 2002.
Another recent analysis of nanoscience productivity
around the world ranked China at the top for the
first 8 months of 2004. This should not give the
Chinese research community reason to be overly
optimistic, however. The volume of published
papers and total number of citations is only one
indicator of the value of research. Another is the
impact, or the number of citations per paper. From
2001 to 2003, the number of citations per
nanotechnology paper published by scientists in the
United States, Germany, Japan, and China was
about 6.56, 4.54, 3.7, and 2.28, respectively.
Since 2006, Chinese basic research papers on
nanoscience and nanotechnology and total number
of citations have become the world's second largest,
behind only the United States. According to
statistical data from www.cnki.net (2004-2008),
Chinese scholars published a large number of
nano-page research thesis in Chinese academic
journals (as shown in Table 1).
Nanotoxilogy and Nanopharmacology
Nanotechnology is a newly fashionable field
but in the world of drug development it is certainly
not new. Nanotechnology has a vital role to play in
realizing cost-effective diagnostic, therapeutic and
prevent tools. The applications of nanotechnology
for treatment, diagnosis, monitoring and control of
biological systems have recently been referred to as
nanomedicine. The nanocarriers have been made of
safe materials, including synthetic biodegradable
polymers, lipids and polysaccharides. Nanomedicines (nanopharmaceuticals) are the convergence of nanotechnology and biotechnology and an
important
component
of
nanotechnology.
Application of nanotechnology is just started in
traditional Chinese medicines.
Nanopharmaceuticals or "Nanomedicines" can
be developed either as drug delivery systems or
biologically active drug products. They comprise
nanometre size scale complex systems, consisting
of at least two components, one of which being the
active ingredient. Drug delivery is an
interdisciplinary area of research that aims at
making the administration of complex new drugs
feasible, as well as adding critical value to the drugs
that are currently in the market. At present, one of
Table 1. Papers published in Chinese journals from
2004 to 2008
Year
Nanoscience and
nanotechnology
Nanomedicine
2004
2005
2006
2007
2008
179
226
280
169
235
11
22
41
18
7
30
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
staff safety and waste management in environment.
The development of in vitro models of testicular
toxicity may provide important tools for
investigating specific mechanisms of toxicity in the
testis. Although various systems have been reported,
their application in toxicological studies has been
limited by the poor ability to replicate the complex
biochemical, molecular, and functional interactions
observed in the testis. In vitro models have been
established, and some of them have tried to
reproduce the complex interactions that take place
between the different germ cells. These models are
limited by the poor viability of freshly isolated germ
cells. So the development of a germ-line stem cell is
of great interest. After previous studies to develop
an immortalized cell line[6-8] with promising
application in the study of testis toxicity. In vivo
system for evaluation on safety and toxicology is
very importance. This evidence of physiologically
significant histopathological changes clearly
indicates the potential of these nanomaterials for
human toxicity at realistic doses.
Nanoscale materials are seeming application in
direct interventions to improve public health both
through therapeutic strategies and environmental
remediation. Recent years have seen the emergence
of nano-engineered drug delivery strategies.
Approval of abraxane, a nano-formulation of taxol
for the treatment of breast cancer, was received by
Food and Drug Administration (FDA), USA. This
protein nano-bead conjugated pharmaceutical has
increased water solubility allowing for elimination
of the toxicity associated with the solvent vehicle
and improved therapeutic index. The benefit of
abraxane relies on the nanoscale formulation rather
than on the emergent properties of the
nanomaterials as a therapeutic modality.[9] Powers et
al pointed
out
that basis nanoparticle
characterization techniques are discussed, along
with some of the issues and implications associated
with measuring nanoparticle properties and their
interactions with biological systems. Recommendations
regarding
how
to
approach
nanomaterial characterization include using proper
sampling and measurement techniques, forming
multidisciplinary teams, and making measurements
as close to the biological action point as possible.[10]
The science of toxicology has provided the
the most attractive areas of research in drug delivery
is the design of nanomedicines consisting of
nanosystems that are able to deliver drugs to the
right place, at appropriate times. The goal of the
present article is to review the advances we have
made in the development and characterization of
nanosystems intended to be used as drug carriers for
mucosal administration. These nanocarriers are able
to protect the associated drug against degradation
and facilitate its transport across critical and
specific barriers. Some are further able to release
the associated drug to the target tissue in a
controlled manner. These nanocarriers have been
made of safe materials, including synthetic
biodegradable polymers, lipids and polysaccharides.
The change in the physicochemical and structural
properties of engineered nanosized materials with a
decrease in size could be responsible for a number
of material interactions that could lead to
toxicological effects. At present, scientists must
accept that it is still very early in the toxicological
evaluation for nanomaterials and nanomedicines,
and few data on the safety and toxicity. The safety
evaluation of nanomedicines includes workforce
exposure limits in manufacturing process,
environment impact with general impact and to
patients after administration and safety for human
use, such as depends on route of administration,
dose and dosing frequency, as well as safety in drug
delivery relates to toxicity of drug payload. The
biomedical evaluation of nanomedicines includes
biodistribution, metabolic fate, Persistance of
non-degradable systems, Specific therapeutic issues
and immunogenicity. We must pay an attention on
the relative issues of nanomedicines with human
health and safety and toxicity to develop the
evaluation methods of nanoproducts and make
nanotechnology play a great role in the progress in
nanotechnology and medicines and medicine
engineering.[5]
Evaluation on safety and toxicology of
nanomedicines
The toxicology of nanomedicines used in
device manufacture should be considered during
their entire life cycle at stages of manufacture and
preclinical and clinical development, consumer and
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Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
directed toward understanding and creating
improved materials, devices, and systems that
exploit these properties. In a review, Thomas et al
reviewed that a limited subset of products that
contain nanoscale materials, assess the available
data for evaluating the consume exposures and
potential hazard associated with these products, and
discuss the capacity of US regulatory agencies to
address the potential risks associated with these
products.[11] Some of the potential impacts of
dermal exposure to nanoscale materials include the
following: (1) enhanced amount and depth of
penetration of active ingredients in cosmetic into
the skin resulting in increased activity, (2)
ingredients that are chemically unstable in air and
light (as retinal and vitamin E) may be more readily
used in topical products following encapsulation in
nanoparticles, and (3) and timed release of
ingredients may become more feasible in topical
products and could allow for improved
effectiveness equivalent to current controlled
release orally administered drugs.
foundation for understanding and studying the
interactions between chemical drugs and biology.
While the use of nanomaterials, nanomedicines/
nanopharmaceuticals is rather new in the
commercial products, the philosophical basis for
performing the toxicological evaluation of these
products is not expected to be different form other
chemical drugs.
At present, scientists must accept that it is still
very early in the toxicological evaluation for
nanomaterials, nanomedicines/nanopharmaceuticals,
and few data on the safety and toxicity. The basic
tenet of study designed to develop a study system of
toxic effects of nanomaterials, nanomedicines/
nanopharmaceuticals on biological systems is to
understand the physico-chemical characteristics of
nanomaterials, nanomedicines. Therefore, the
approach to addressing the safety and toxicity of
these products will best be conducted via
multidisciplinary terms. Many traditional methods
and approaches will likely be applicable to study of
nanomaterials,nanomedicines/nanopharmaceuticals.
Nanotechnology research and development is
Table 2. The biomedical evaluation of nanomedicines
Evaluation terms
Evaluation contents
Biodistribution
Metabolic fate
Immunogenicity
Persistance of non-degradable systems
Biocompatibility
Whole organism, cellular level
Absorption, distribution, metabolism and excretion
IgG/IgM production, cytokine induction
Possibility of lysosomal storage disease
Biological environment and toxicology and adverse
effect to patients
Therapeutic index of nanomedicines and its delivery
systems in drug delivery relates to toxicity pf drug
payload
Specific therapeutic issues
play a significant role. It should be realized that the
animal bioassays presently used in toxicity testing
are model systems for the prediction of toxicity in
humans or the environment. In the last few decades
new technologies and new knowledge have become
available. This development is the result of
intensive fundamental toxicological research and the
implementation of new methods and technologies.[12]
The biomedical evaluation of nanomedicines
includes biodistribution, metabolic fate, persistance
Due to the nanotechnology combines with
biotechnology, a newly emerging cross-disciplinary
field nanobiotechnology, this becomes the new
developing area. As the research and application of
nanotechnology, studying and understanding the
complex relationship between nanomaterials/
nanomedicines and biological system will show
special important to environmental, human health
and safety. Criticism of the use of laboratory
animals for the safety testing of chemicals is
increasing, in society as a whole and also in the
scientific world. This criticism is not only limited to
ethical concerns, but scientific considerations also
of non-degradable systems, Specific therapeutic issues
and immunogenicity (Table 2).[1]
32
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
delivery vehicles, and other useful biological tools.
The unprecedented freedom to design and modify
nanomaterials to target cells, chaperone drugs,
image biomolecular processes, sense and signal
molecular responses to therapeutic agents, and guide
surgical procedures is the fundamental capability
offered by nanotechnology, which promises to
impact drug development, medical diagnostics, and
clinical applications profoundly (Fig 1).[14]
Intraperitoneal injection of [Gd@C82(OH)22]n
nanoparticles decreased activities of enzymes
associated with the metabolism of reactive oxygen
species (ROS) in the tumor-bearing mice. Several
physiologically relevant ROS were directly
scavenged by nanoparticles, and lipid peroxidation
was inhibited in this study. [Gd@C82(OH)22]n
nanoparticles significantly reduced the electron spin
resonance
(ESR)
signal
of
the
stable
2,2-diphenyl-1-picryhydrazyl radical measured by
ESR spectroscopy. Like-wise, studies using ESR
with
spin-trapping
demonstrated
efficient
scavenging of superoxide radical anion, hydroxyl
radical,
and
singlet
oxygen
(1O2)
by
[Gd@C82(OH)22]n nanoparticles. In vitro studies
using liposomes prepared from bovine liver
phosphatidylcholine revealed that nanoparticles also
had a strong inhibitory effect on lipid peroxidation.
Consistent with their ability to scavenge ROS and
inhibit lipid peroxidation, we determined that
[Gd@C82(OH)22]n nanoparticles also protected cells
subjected in vitro to oxidative stress. Studies using
human lung adenocarcinoma cells or rat brain
capillary endothelial cells demonstrated that
[Gd@C82(OH)22]n nanoparticles reduced H2O2induced ROS formation and mitochondrial damage.
[Gd@C82(OH)22]n nanoparticles efficiently inhibited the growth of malignant tumors in vivo. In
summary, the results obtained in this study reveal
antitumor
activities
of
[Gd@C82(OH)22]n
nanoparticles in vitro and in vivo. Because ROS are
known to be implicated in the etiology of a wide
range of human diseases, including cancer, the
present findings demonstrate that the potent
inhibition of [Gd@C82(OH)22]n nanoparticles on
tumor growth likely relates with typical capacity of
scavenging reactive oxygen species.[13]
Fig 1. Medical applications of nanotechnology. The
size and tailorability of nanoparticles may lea
to their widespread use in a variety of medical
applications.[14]
Engineered nanomaterials are at the leading
edge of the rapidly developing nanosciences and are
founding an important class of new materials with
specific physicochemical properties different from
bulk materials with the same compositions. The
potential for nanomaterials is rapidly expanding
with novel applications constantly being explored in
different areas. The unique size-dependent
properties of nanomaterials make them very
attractive
for
pharmaceutical
applications.
Investigations of physical, chemical and biological
properties of engineered nanomaterials have yielded
valuable information. Cytotoxic effects of certain
engineered nanomaterials towards malignant cells
form the basis for one aspect of nanomedicine. It is
inferred that size, three dimensional shape,
hydrophobicity and electronic configurations make
them an appealing subject in medicinal chemistry.
Their unique structure coupled with immense scope
for derivatization forms a base for exciting
developments in therapeutics. This review article
addresses the fate of absorption, distribution,
metabolism and excretion (ADME) of engineered
nanoparticles in vitro and in vivo. It updates the
distinctive methodology used for studying the
biopharmaceutics of nanoparticles. This review
addresses the future potential and safety concerns
and genotoxicity of nanoparticle formulations in
Evaluation on pharmacology of
nanomedicines
Nanotechnology manifests itself in a wide
range of materials that can be useful to medical
application. Virtually all of these materials have
been designed with chemically modifiable surfaces
to attach a variety of legends that can turn these
nanomaterials into biosensors, molecular-scale
fluorescent tags, imaging agents, targeted molecular
33
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
dendrimers (in various sizes, surface substituents,
and net charges) and inorganic nanoparticles,
properties of both of which can be individually
modified and optimized. In this study we examine
effects of size and surface charge on the behavior of
Au-dendrimer CNDs in mouse tumor models.
Quantitative biodistribution and excretion analyses
including 5-nm and 22-nm positive surface, 5-nm
and 11-nm negative surface, and a 5-nm neutral
surface CNDs were carried out in the B16 mouse
melanoma tumor model system. Results seen with
the 22-nm CND in the B16 melanoma model were
corroborated in a prostate cancer mouse tumor
model system. Quantitative in vivo studies confirm
the importance of charge and show for the first time
the importance of size in affecting CND
biodistribution and excretion. Interestingly, CNDs
of different size and/or surface charge had high
levels of uptake (“selective targeting”) to certain
organs without specific targeting moieties placed on
their surfaces. Researchers conclude that size and
charge greatly affect biodistribution of CNDs.
These findings have significance for the design of
all particle-based nanodevices for medical uses. The
observed organ selectivity may make these
nanodevices exciting for several targeted medical
applications.[17]
general. It particularly emphasizes the effects of
nanoparticles on metabolic enzymes as well as the
parenteral or inhalation administration routes of
nanoparticle formulations. This paper illustrates the
potential of nanomedicine by discussing
biopharmaceutics of fullerene derivatives and their
suitability for diagnostic and therapeutic purposes.
Future direction is discussed as well.[15]
With the rapid development of quantum dot
(QD) technology, water-soluble QDs have the
prospect of being used as a biological probe for
specific diagnoses, but their biological behaviors in
vivo are little known. Our recent in vivo studies
concentrated on the bio-kinetics of QDs coated by
hydroxyl group modified silica networks (the QDs
are 21.3±2.0 nm in diameter and have maximal
emission at 570 nm). Male ICR mice were
intravenously given the water-soluble QDs with a
single dose of 5 nmol/mouse. Inductively coupled
plasma-mass spectrometry was used to measure the
(111)Cd content to indicate the concentration of
QDs in plasma, organs, and excretion samples
collected at predetermined time intervals.
Meanwhile, the distribution and aggregation state of
QDs in tissues were also investigated by
pathological
examination
and
differential
centrifugation. The plasma half-life and clearance
of QDs were 19.8±3.2 h and 57.3±9.2 ml·h-1·kg-1,
respectively. The liver and kidney were the main
target organs for QDs. The QDs metabolized in
three paths depending on their distinct aggregated
states in vivo. A fraction of free QDs, maintaining
their original form, could be filtered by glomerular
capillaries and excreted via urine as small
molecules within five days. Most QDs bound to
protein and aggregated into larger particles that
were metabolized in the liver and excreted via feces
in vivo. After five days, 8.6% of the injected dose of
aggregated QDs still remained in hepatic tissue and
it was difficult for this fraction to clear.[16]
There is growing interest in developing
tissue-specific multifunctional drug delivery
systems with the ability to diagnose or treat several
diseases. One class of such agents, composite
nanodevices
(CNDs),
is
multifunctional
nanomaterials with several potential medical uses,
including cancer imaging and therapy. Nanosized
metal-dendrimer CNDs consist of poly(amidoamine)
Study on responses of Ferric oxide
nanoparticles:
Ferric oxide (Fe2O3) nanoparticles are of
considerable
interest
for
application
in
nanotechnology related fields. However, as iron
being a highly redox-active transition metal, the
safety of iron nanomaterials need to be further
studied. In this study, the size, dose and time
dependent of Fe2O3 nanoparticle on pulmonary and
coagulation system have been studied after
intratracheal instillation. The Fe2O3 nanoparticles
with mean diameters of 22 and 280 nm, respectively,
were intratracheally instilled to male Sprague
Dawley rats at low (0.8 mg·kg-1) and high (20
mg/kg) doses. The toxic effects were monitored in
the post-instilled 1, 7 and 30 days. Our results
showed that the Fe2O3 nanoparticle exposure could
induce oxidative stress in lung. Alveolar
macrophage (AM) over-loading of phagocytosed
nanoparticle by high dose treatment had occurred,
34
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
Misfolding and self-assembly of proteins in
nanoaggregates of different sizes and morphologies
(nanoensembles, primarily nanofilaments and
nanorings) is a complex phenomenon that can be
facilitated, impeded, or prevented by interactions
with various intracellular metabolites, intracellular
nanomachines controlling protein folding, and
interactions with other proteins. A fundamental
understanding of molecular processes leading to
misfolding and self-aggregation of proteins
involved in various neurodegenerative diseases will
provide important information to help identify
appropriate therapeutic routes to control these
processes. An elevated propensity of misfolded
protein conformation in solution to aggregate with
the formation of various morphologies impedes the
use of traditional physiochemical approaches for
studies of misfolded conformations of proteins.
Kransnoslobodtsev et al tethered the protein
molecules to surfaces to prevent aggregation and,
with force spectroscopy using an atomic force
microscopy, probed the interaction between protein
molecules depending on their conformations.
Research results show that formation of filamentous
aggregates is facilitated at pH values corresponding
to the maximum of rupture forces. They report here
on development of a novel surface chemistry for
anchoring of amyloid β (Aβ) peptides at their
N-terminal moieties. The use of the site-specific
immobilization procedure allowed us to measure the
rupture of Aβ-Aβ contacts at the single-molecule
level. The rupture of these contacts is accompanied
by the extension of the peptide chain detected by a
characteristic elastomechanical component of the
force-distance curves. Potential applications of
nanomechanical studies for understanding the
mechanisms of development of protein misfolding
diseases are discussed.[20]
while the non-phagocytosed particles were found
entering into alveolar epithelial in day 1 after
exposure. Several inflammatory reactions including
inflammatory and immune cells increase, clinical
pathological changes: follicular hyperplasia, protein
effusion, pulmonary capillary vessel hyperaemia
and alveolar lipoproteinosis in lung were observed.
The sustain burden of particles in AM and
epithelium cells has caused lung emphysema and
pro-sign of lung fibrosis. At the post-instilled day
30, the typical coagulation parameters, prothrombin
time (PT) and activated partial thromboplastin time
(APTT) in blood of low dose 22 nm-Fe2O3 treated
rats were significantly longer than the controls. We
concluded that both of the two-sized Fe2O3 particle
intratracheal exposure could induce lung injury.
Comparing with the submicron-sized Fe2O3 particle,
the nano-sized Fe2O3 particle may increase
microvascular permeability and cell lysis in lung
epitheliums and disturb blood coagulation
parameters significantly.[18]
Superparamagnetic iron oxide nanoparticles
(SPIONs) are applied in stem cell labeling because
of their high magnetic susceptibility as compared
with ordinary paramagnetic species, their low
toxicity, and their ease of magnetic manipulation.
The present work is the study of CD133+ stem cell
labeling by SPIONs coupled to a specific antibody
(AC133), resulting in the antigenic labeling of the
CD133+ stem cell, and a method was developed for
the quantification of the SPION content per cell,
necessary for molecular imaging optimization. Flow
cytometry analysis established the efficiency of the
selection process and helped determine that the
CD133 cells selected by chromatographic affinity
express the transmembrane glycoprotein CD133.
The presence of antibodies coupled to the SPION,
expressed in the cell membrane, was observed by
transmission electron microscopy. Quantification of
the SPION concentration in the marked cells using
the ferromagnetic resonance technique resulted in a
value of 1.70 × 10–13 mol iron (9.5 pg) or 7.0 × 106
nanoparticles per cell (the measurement was carried
out in a volume of 2 µL containing about 6.16 × 105
pg iron, equivalent to 4.5 × 1011 SPIONs).[19]
Research and Application of Carbon
Nanotubes
A good representative of this fast-moving field
is the family of nanomaterials known as carbon
nanotubes (CNTs). These all-carbon tubes are just a
few nanometers in diameter, which makes them
comparable in girth to DNA molecules, and come in
either singlewalled varieties or multiwalled varieties
with a nesting of carbon shells resembling the
Mechanisms of development of protein
misfolding diseases
35
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
angiotensin II type 1 receptor by AFM with
functionalized tip is introduced in this article. Some
prospective methods to improve the imaging
resolution are also discussed.[22]
CNTs are nanodevices with important potential
applications in biomedicine such as drug and gene
delivery. Brain diseases with no current therapy
could be candidates for CNT-based therapies. Little
is known about toxicity of CNTs and of their
dispersion factors in the brain. Reaearchers show
that multiwall CNTs (MWCNTs) coated with
Pluronic F127 (PF127) surfactant can be injected in
the mouse cerebral cortex without causing
degeneration of the neurons surrounding the site of
injection. They also show that, contrary to previous
reports on lack of PF127 toxicity on cultured cell
lines, concentrations of PF127 as low as 0.01% can
induce apoptosis of mouse primary cortical neurons
in vitro within 24 hours. However, the presence of
MWCNTs can avoid PF127-induced apoptosis.
These results suggest that PF127-coated MWCNTs
do not induce apoptosis of cortical neurons.
Moreover, the presence of MWCNTs can reduce
PF127 toxicity.[23]
Interactions of multiwalled carbon nanotubes
(MWCNTs) with human epidermal keratinocytes
(HEKs) were studied with respect to the effect of
surfactant on dispersion of MWCNT aggregates and
cytotoxicity. Our earlier studies had shown that the
unmodified MWCNTs were localized within the
cytoplasmic vacuoles of HEKs and elicited an
inflammatory response. However, MWCNTs in
solution tend to aggregate and, therefore, cells are
exposed to large MWCNT aggregates. The purpose
of this study was to find a surfactant that prevents
the formation of large aggregates of MWCNTs
without being toxic to the HEKs. HEKs were
exposed to serial dilutions (10% to 0.1%) of L61,
L92, and F127 Pluronic and 20 or 60 Tween for 24
hours. HEK viability, proportional to surfactant
concentration, ranged from 27.1% to 98.5% with
Pluronic F127; viability with the other surfactants
was less than 10%. Surfactants dispersed and
reduced MWCNT aggregation in medium.
MWCNTs at 0.4 mg·ml-1 in 5% or 1% Pluronic
F127 were incubated with HEKs and assayed for
interleukin 8 (IL-8). MWCNTs were cytotoxic to
HEKs independent of surfactant exposure. In
structure of a retractable antenna. CNTs are
nanodevices with important potential applications in
biomedicine such as drug and gene delivery.
Recognition
of
functionalization
of
nanotubes
Current advances in nanotechnology have led
to the development of the new field of
nanomedicine, which includes many applications of
nanomaterials and nanodevices for diagnostic and
therapeutic purposes. The same unique physical and
chemical properties that make nanomaterials so
attractive may be associated with their potentially
calamitous effects on cells and tissues. The recent
study on nanomedicine and nanotoxicology
published by Kagan et al demonstrated that
aspiration of single-walled CNTs elicited an
unusual inflammatory response in the lungs of
exposed mice with a very early switch from the
acute inflammatory phase to fibrogenic events
resulting in pulmonary deposition of collagen and
elastin. This was accompanied by a characteristic
change in the production and release of
proinflammatory to anti-inflammatory profibrogenic cytokines, decline in pulmonary function, and
enhanced susceptibility to infection. Chemically
unmodified (nonfunctionalized) CNTs are not
effectively
recognized
by
macrophages.
Functionalization of nanotubes results in their
increased recognition by macrophages and is thus
used for the delivery of nanoparticles to
macrophages and other immune cells to improve the
quality of diagnostic and imaging techniques as
well as for enhancement of the therapeutic
effectiveness of drugs. These observations on
differences in recognition of nanoparticles by
macrophages have important implications in the
relationship between the potentially toxic health
effects of nanomaterials and their applications in the
field of nanomedicine.[21] Although membrane
proteins consist of a substantial amount of the
human genome and are the main drug targets, the
study of cell membrane proteins in situ is
complicated by the technical limitations. The recent
development of atomic force microscopy (AFM)
opens a new way to study the functions of cell
membrane proteins in situ at the single-molecule
level. A detailed procedure for investigation of
36
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
opportunities for treating both skin and systemic
infections.[26]
contrast, MWCNT-induced IL-8 release was
reduced when exposed to 1% or 5% Pluronic F127
(P <0 .05). However, both MWCNTs and surfactant,
alone or in combination, increased IL-8 release
compared with control exposures at 12 and 24 hours.
These results suggest that the surfactant- MWCNT
interaction is more complex than simple dispersion
alone and should be investigated to determine the
mode of interaction.[24]
Tsuneo Urisu et al have developed two basic
technologies for fabrication of supported planar
lipid bilayer membrane ion channel biosensors: a
defect-free lipid bilayer formation on the substrate
surface with electrode pores and a patterning
technique for the hydrophobic self-assembledmonolayer to form the guard ring that reduces the
lipid bilayer edge-leak current. The importance of
the supported-membrane structure to achieve low
noise and high-speed performance is suggested on
the basis of the observed relation between the
single-ion-channel current noise and the pore
size.[25]
Pegylated liposomal doxorubicin
According to the American Cancer Society in
2006, an estimated 20180 new cases of ovarian
cancer will be diagnosed in the US in 2006.
Approximately 15310 of these women will die of
this disease. The vast majority will present with
advanced disease and will require chemotherapy,
and the majority of these will relapse. Safe,
effective cancer treatments are needed for relapsed
ovarian cancer. Goals include improving symptoms,
enhancing quality of life, and prolonging survival.
Currently, in the USA, the initial treatment consists
of maximal surgical debulking followed by
carboplatin and taxane chemotherapy. When the
disease recurs, the patient and physician are
presented with a host of chemotherapy options. One
drug that is increasingly being used is pegylated
liposomal doxorubicin.[27].
Encapsulation in polyethylene glycol-coated
(pegylated; Stealth) liposomes alters the
pharmacokinetic characteristics, and hence the
safety and tolerability profile, of doxorubicin.
Pegylated liposomal doxorubicin administered as a
single agent is generally well tolerated. Grade III/IV
leucopenia,
stomatitis
and
palmar-plantar
erythrodysaesthesia affected 16, 6 and 18% of solid
tumour patients, respectively. Other adverse effects
included nausea and vomiting and alopecia. Acute
hypersensitivity infusion reactions have been
reported in up to 9% of patients in some studies.
Recently published data from a phase II trial in
patients with refractory ovarian cancer showed no
alopecia or cardiotoxicity and little nausea and
vomiting after pegylated liposomal doxorubicin.
Unlike free doxorubicin, pegylated liposomal
doxorubicin is not a vesicant. Preliminary data, not
yet confirmed in comparative studies, suggest that
the pegylated liposomal formulation may be less
cardiotoxic than free doxorubicin. Mucositis,
however, appears to be increased. Studies to
determine optimal dosing schedules and safety of
pegylated liposomal doxorubicin in combination
with other agents are ongoing.[28]
Polyacrylate nanoparticle emulsions
Greenhalgh et al have recently reported on a
new nanomedicine containing antibiotic-conjugated
polyacrylate nanoparticles, which has shown
activity against methicillin-resistant Staphylococcus
aureus (MRSA) in vitro and no cytotoxicity toward
human dermal cells. The water-based nanoparticle
emulsion is capable of solubilizing lipophilic
antibiotics for systemic administration, and the
nanoparticle drug delivery vehicle has shown
protective properties for antibiotics from hydrolytic
cleavage by bacterial penicillinases, thus
rejuvenating the drug's activity against resistant
microbes such as MRSA. In Greenhalgh et al report,
the first in vivo study of this penicillin-conjugated
nanoparticle emulsion in determining toxicological
responses initiated upon systemic and topical
application in a murine model. Favorable results
were observed in vivo upon both routes of
administration and, when topically applied to a
dermal abrasion model, the emulsion enhanced
wound healing by an average of 3 to 5 days. This
study suggests that polyacrylate nanoparticlecontaining emulsions may afford promising
37
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
preferential uptake and decreased clearance of the
drug delivery system, increasing the exposure of the
tumor to the drug. When the liposome does leave
the intravascular compartment, in normal tissues it
is Phase II single-agent studies In a subsequent
Phase II study, evaluated 79 better-defined patients
all of whom were platinum and taxane refractory.
Eighty-five percent of the patients had received
more than 2 prior chemotherapy regimens. These
“doubly refractory” patients were treated with 50
mg/m2 of pegylated liposomal doxorubicin every 4
weeks. Fourteen partial responses and 1 complete
response were reported for an overall response rate
of 16.9%. The median time to response was 15
weeks. The median progression-free survival for all
patients treated in this study was 19.3 weeks (range
0.7–86 weeks). In addition, 36 patients (57%) were
classified as having stable disease, and achieved a
median progression-free survival of 21.9 weeks.
This was one of the first studies to show that disease
stabilization in recurrent ovarian cancer is of
clinical benefit. All patients reported at least 1
adverse event, but the majority were grade 1 or 2.
Asthenia and palmar-plantar erythrodysesthesia
(PPE) were seen in 41.6%. Only 1 patient
experienced any cardiac complications, and there
were no treatment-related deaths. This study
demonstrated that pegylated liposomal doxorubicin
was useful in this drug-resistant setting, and
associated with no life-threatening toxicities.
In China, Liang W et al research results on
doxorubicin- containing PEG-PE micelles are an
important
contribution
to
nanomedicine
development (which is called “nanoparticles carry
chemotherapy drug deeper into solid tumors”).
Editorial members, Dreher MR and Chilkoti A in J
Natl Cancer Inst get a high evaluation for their
research. Solid tumors account for more than 85%
of cancer mortality. To obtain nutrients for growth
and to metastasize, cancer cells in solid tumors must
grow around existing vessels or stimulate formation
of new blood vessels. These new vessels are
abnormal in structure and characterized by leakage,
tortuousness, dilation, and a haphazard pattern of
interconnection. Tumor structure and blood flow
hinder the treatment of solid tumors. To reach
cancer cells in optimal quantity, a therapeutic agent
must pass through an imperfect blood vasculature to
Pegylated liposomal doxorubicin is a
formulation of doxorubicin in which the molecule
itself is packaged in a liposome made of various
lipids with an outer coating of polyethylene glycol.
Liposomal technology is being used in increasing
amounts in the therapy of a variety of cancers,
including ovarian cancers. A reviews written by
Green et al on the mechanistic actions of this
formulation, the Phase II and Phase III data that
helped define the role of pegylated liposomal
doxorubicin in recurrent ovarian cancer, as well as a
discussion of some of the side-effects and their
management. [27] Pegylated liposomal doxorubicin
is one of a new class of drug formulations. The
doxorubicin molecules in pegylated liposomal
doxorubicin are encapsulated in a bilayer sphere of
lipids. This vesicle is then surrounded by a dense
layer of polyethylene glycol (PEG), hence the name
pegylated liposomal doxorubicin. The size of the
liposomes, approximately 100 nm, prevents them
from entering tissues with tight capillary junctions,
such as the heart and gastrointestinal tract, as well
as selectively depositing the liposome into the
tumor. In contrast to normal vessels, the vessels of
the
tumor
are
tortuous,
dilated,
have
morphologically abnormal endothelial cells, and are
leaky due to large spaces between pericytes. The
study on mechanism of action exhibited that these
physical characteristics allow more extravasation of
the vesicles into the tumor, thus encouraging more
deposition of the chemotherapy agent into the tumor.
The PEG coating on the liposome creates a
hydrophilic layer around the liposome that buffers
the liposome wall from the surrounding milieu. This
decreases proteins from binding to the lipid bilayer.
These proteins act as opsonins, attracting
foreign particles that in turn activate the
mononuclear phagocytic cells. This leads to break
down of the liposome and release of the drug.
Therefore, the PEG coating on the liposome
increases the longevity of the liposome. Pegylated
liposomal doxorubicin was cleared via the
lymphatic system and returned to the circulation. In
tumor tissue, however, there are no lymphatics.
Therefore, when the liposome is deposited it
remains for a longer time. This allows a higher dose
of doxorubicin to be released in the tumor, and a
lower dose in normal tissue. Collectively, there is
38
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
patient. In platinum-sensitive patients, pegylated
liposomal doxorubicin also produced a survival
advantage. Results from prospective and
retrospective studies further demonstrate the
improved cardiac safety of pegylated liposomal
doxorubicin
compared
to
conventional
anthracyclines. Based on survival and toxicity
advantages and a once-monthly administration
schedule, pegylated liposomal doxorubicin is the
first-choice nonplatinum agent for relapsed ovarian
cancer. Pegylated liposomal doxorubicin may also
have clinical application in combination regimens
for platinum-sensitive ovarian cancer, as
consolidation/maintenance therapy for ovarian
cancer, as a component of first-line therapy for
ovarian cancer, and in the treatment of other
gynecologic malignancies. Future clinical trials will
further define and maximize the role of pegylated
liposomal doxorubicin in the treatment of ovarian
cancer and other gynecologic malignancies.[32]
the tumor, cross vessel walls into the interstitium
and penetrate multiple layers of solid tumor cells.
Recent studies have demonstrated that poor
penetration and limited distribution of doxorubicin
in solid tumors are the main causes of its
inadequacy as a chemotherapeutic agent.
Encapsulation of doxorubicin into PEG-PE micelles
increased its accumulation and penetration in
tumors in terms of both the percentage of cells that
were reached by the drug and the intracellular levels
that were attained. This increased accumulation and
penetration can be attributed to the efficient
internalization of the drug-containing micelles by
the endocytotic cell uptake mechanism and
enhanced permeability and retention of tumors with
leaky vasculature. High intracellular retention is
especially important because doxorubicin must be
internalized to be effective in tumor therapy. The
doxorubicin- containing PEG-PE micelles had
greatly increased antitumor activity in both
subcutaneous and lung metastatic LLC tumor
models compared with free doxorubicin. However,
mice treated micelle- encapsulated doxorubicin
showed fewer signs of toxicity than those treated
with free doxorubicin. This drug packaging
technology may provide a new strategy for design
of cancer therapies.[29,30] At our laboratory, studied
nanoparticle of doxorubicin eliminate the
accumulation in tissues of tumor-bearing mice.
Compared with general doxorubicin preparation,
which is a marketed product, nanoparticle micelle
of doxorubicin has the similar pharmacokinetics in
the tissue, and the similar concentrations in the
tumor tissue. Howerever, the accumulation of
doxorubicin in the heart, spleen, kidney, lung,
tumor, muscle and skin decreased significantly after
three intravenous injections, showing that the
nano-micelle can accumulatew the elimilation of
doxorubicin in most tissues. It is deduced that the
study was effects of doxorubicin after clinical use
may be reduced significantly. [31]
Pegylated liposomal doxorubicin is effective
and well tolerated in relapsed ovarian cancer. When
compared with topotecan in a phase III randomized
trial, pegylated liposomal doxorubicin showed
several advantages: improved quality of life, fewer
severe adverse events, fewer dose modifications,
less hematologic support, and lower total cost per
Doxorubicin nanoparticles
A novel hyaluronic acid-poly(ethylene
glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA)
copolymer was synthesized and characterized by
infrared and nuclear magnetic resonance
spectroscopy. The nanoparticles of doxorubicin
(DOX)-loaded HA-PEG-PLGA were prepared and
compared with monomethoxy (polyethylene glycol)
(MPEG)-PLGA nanoparticles. Nanoparticles were
prepared using drug-to-polymer ratios of 1:1 to 1:3.
Drug-to-polymer ratio of 1:1 is considered the
optimum formulation on the basis of low particle
size and high entrapment efficiency. The optimized
nanoparticles were characterized for morphology,
particle size measurements, differential scanning
calorimetry, x-ray diffractometer measu- rement,
drug content, hemolytic toxicity, subacute toxicity,
and in vitro DOX release. The in vitro DOX release
study was performed at pH 7.4 using a dialysis
membrane. HA-PEG-PLGA nanoparticles were
able to sustain the release for up to 15 days. The
tissue distribution studies were performed with
DOX-loaded HA-PEG-PLGA and MPEG-PLGA
nanoparticles after intravenous (IV) injection in
Ehrlich ascites tumor–bearing mice. The tissue
distribution studies showed a higher concentration
of DOX in the tumor as compared with
39
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
protein as a typical membrane protein. Landscape
phage peptides specific for specific tumors can be
obtained by affinity selection, and purified fusion
coat proteins can be assimilated into liposomes to
obtain specific drug-loaded nanocarriers. As a
paradigm
for
inceptive
experiments,
a
streptavidin-specific phage peptide selected from a
landscape phage library was incorporated into
100-nm liposomes. Targeting of liposomes was
proved by their specific binding to streptavidincoated beads.[35]
MPEG-PLGA nanoparticles. The in vivo tumor
inhibition study was also performed after IV
injection
of
DOX-loaded
HA-PEG-PLGA
nanoparticles up to 15 days. DOX-loaded
HA-PEG-PLGA nanoparticles were able to deliver
a higher amount of DOX as compared with
MPEG-PLGA nanoparticles. The DOX-loaded
HA-PEG-PLGA nanoparticles reduced tumor
volume
significantly
as
compared
with
MPEG-PLGA nanoparticles.[33] Chitosan, PCEP
(poly{[(cholesteryl oxocarbonylamido ethyl) methyl
bis(ethylene) ammonium iodide] ethyl phosphate}),
and magnetic nanoparticles (MNPs) were evaluated
for the safe delivery of genes in the eye. Prow et al
studied ocular nanoparticle toxicity and transfection
of the retina and retinal pigment epithelium. Rabbits
were injected with nanoparticles either intravitreally
(IV) or subretinally (SR) and sacrificed 7 days later.
Eyes were grossly evaluated for retinal pigment
epithelium abnormalities, retinal degeneration, and
inflammation. All eyes were cryopreserved and
sectioned for analysis of toxicity and expression of
either enhanced green or red fluorescent proteins.
All of the nanoparticles were able to transfect cells
in vitro and in vivo. IV chitosan showed
inflammation in 12/13 eyes, whereas IV PCEP and
IV MNPs were not inflammatory and did not induce
retinal pathology. SR PCEP was nontoxic in the
majority of cases but yielded poor transfection,
whereas SR MNPs were nontoxic and yielded good
transfection. Therefore, researchers concluded that
the best nanoparticle evaluated in vivo was the least
toxic nanoparticle tested, the MNP.[34]
Drug
Loading
and
Release
From
Biodegradable Microcapsules
Microcapsules made of biopolymers are of
both scientific and technological interest and have
many potential applications in medicine, including
their use as controlled drug delivery devices. The
present study makes use of the electrostatic
interaction between polycations and polyanions to
form a multilayered microcapsule shell and also to
control the loading and release of charged drug
molecules inside the microcapsule. Micron-sized
calcium carbonate (CaCO3) particles were
synthesized and integrated with chondroitin sulfate
(CS) through a reaction between sodium carbonate
and calcium nitrate tetrahydrate solutions suspended
with CS macromolecules. Oppositely charged
biopolymers were alternately deposited onto the
synthesized
particles
using
electrostatic
layer-by-layer self-assembly, and glutaraldehyde
was introduced to cross-link the multilayered shell
structure. Microcapsules integrated with CS inside
the multilayered shells were obtained after
decomposition of the CaCO3 templates. The
integration of a matrix (i.e., CS) permitted the
subsequent selective control of drug loading and
release. The CS-integrated microcapsules were
loaded with a model drug, bovine serum albumin
labeled with fluorescein isothiocyanate (FITC-BSA),
and it was shown that pH was an effective means of
controlling the loading and release of FITC-BSA.
Such CS-integrated microcapsules may be used for
controlled localized drug delivery as biodegradable
devices, which have advantages in reducing
systemic side effects and increasing drug efficacy.
Liposomes targeted by fusion phage
proteins
Targeting of nanocarriers has long been sought
after to improve the therapeutic indices of
anticancer drugs. Jayanna et al provide the proof
of principle for a novel approach of nanocarrier
targeting through their fusion with target-specific
phage coat proteins. The source of the targeted
phage coat proteins are landscape phage
libraries—collections of recombinant filamentous
phages with foreign random peptides fused to all
4000 copies of the major coat protein. Prashanth et
al exploit in our approach the intrinsic
physicochemical properties of the phage major coat
[36]
40
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
long as 24 hours after application, thus apparently a
suitable inert carrier for ophthalmic drug delivery.
Amphotericin B–intercalated liposomes
Nanotechnology in drug delivery is a rapidly
expanding field. Nanosized liposomal preparations
are already in use for efficient drug delivery with
better therapeutic indices. Existing methods of
liposome preparation are limited by problems of
scale-up, difficulty in controlling size, and
intercalation efficiency. Here researchers prepare
amphotericin B–intercalated liposomes by a novel
process where amphotericin B and purified
phosphatidyl choline are solubilized in suitable
solvent and precipitated in supercritical fluid carbon
dioxide (known as a gas antisolvent technique), to
obtain microsized particles that are subsequently
introduced into a buffer solution. The morphology
of liposomes was characterized through a
phase-contrast microscope, and the particle size
distribution studied by laser technique showed
nanosize with a narrow range of size distribution
(between 0.5 and 15 µm) and a higher intercalation
efficiency. In vitro studies conducted using
Aspergillus fumigatus (MTCC 870) strain proved to
be efficient in the retardation of the growth of the
organism.[37]
[38]
Paclitaxel nanoparticles
Karmali et al have used tumor-homing
peptides to target abraxane, a clinically approved
paclitaxel-albumin nanoparticle, to tumors in mice.
The targeting was accomplished with two peptides,
CREKA and LyP-1 (CGNKRTRGC). Fluorescein
(FAM)-labeled CREKA-abraxane, when injected
intravenously into mice bearing MDA-MB-435
human cancer xenografts, accumulated in tumor
blood vessels, forming aggregates that contained
red blood cells and fibrin. FAM-LyP-1-abraxane
co-localized with extravascular islands expressing
its receptor, p32. Self-assembled mixed micelles
carrying the homing peptide and the label on
different subunits accumulated in the same areas of
tumors as LyP-1-abraxane, showing that Lyp-1 can
deliver intact nanoparticles into extravascular sites.
Untargeted, FAM-abraxane was detected in the
form of a faint meshwork in tumor interstitium.
LyP-1-abraxane produced a statistically highly
significant inhibition of tumor growth compared
with untargeted abraxane. These results show that
nanoparticles can be effectively targeted into
extravascular tumor tissue and that targeting can
enhance the activity of a therapeutic nanoparticle.
Diclofenac-loaded biopolymeric nanosuspensions
Polymeric nanoparticle suspensions (NS) were
prepared from poly(lactide-co- glycolide) and
poly(lactide-co-glycolide-leucine) {poly[Lac (GlcLeu)]} biodegradable polymers and loaded with
diclofenac sodium (DS), with the aim of improving
the ocular availability of the drug. NS were
prepared by emulsion and solvent evaporation
technique and characterized on the basis of
physicochemical properties, stability, and drug
release features. The nanoparticle system showed an
interesting size distribution suitable for ophthalmic
application. Stability tests (as long as 6 months'
storage at 5°C or at 25°C/60% relative humidity) or
freeze-drying were carried out to optimize a suitable
pharmaceutical preparation. In vitro release tests
showed a extended-release profile of DS from the
nanoparticles. To verify the absence of irritation
toward the ocular structures, blank NS were applied
to rabbit eye and a modified Draize test performed.
Polymer nano- particles seemed to be devoid of any
irritant effect on cornea, iris, and conjunctiva for as
[39]
Nano–atropine sulfate dry powder inhaler
The work of Raisuddin Ali et al was to develop,
characterize, and carry out a clinical trial with
nano–atropine sulfate (nano-AS) dry powder inhaler
(DPI), because this route may offer several
advantages over the conventional intramuscular
route as an emergency treatment, including ease of
administration and more rapid bioavailability.
Different batches of nanoparticles of AS were
produced using variants of nanoprecipitation
method. The influence of the process parameters,
such as the types and quantity of solvent and
nonsolvent, the stirring speed, the solventto-nonsolvent volume ratio, and the drug
concentration, was investigated. The methodology
resulted in optimally sized particles. Bulk properties
of the particles made by the chosen methodology
41
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
adeno- carcinomas and in 5/34 (15%) lymph node
metastases. In contrast, normal squamous and
cardiac mucosa, as well as noninvasive Barrett
lesions, failed to label with mesothelin. Mesothelin
was expressed in the esophageal adenocarcinoma
cell line JH-EsoAd1 but not in primary human
esophageal epithelial cells. Anti-mesothelin
antibody–conjugated CdSe/CDS/ ZnS quantum rods
were synthesized, and confocal bioimaging
confirmed robust binding to JH-EsoAd1 cells.
Anti-mesothelin antibody– conjugated nanoparticles can be useful for the diagnosis and therapy
of mesothelin-overexpressing esophageal adenocarcinomas. [42]
were evaluated. A clinical trial was conducted in six
healthy individuals using a single DPI capsule
containing 6 mg nano-AS DPI in lactose. Early
blood bioavailability and atropinization pattern
confirmed its value as a potential replacement to
parenteral atropine in field conditions. The
formulation seems to have the advantage of early
therapeutic drug concentration in blood due to
absorption through the lungs as well as sustained
action due to absorption from the gut of the
remaining portion of the drug. [40]
Drug delivery of siRNA therapeutics
A
review
by
Daniela Reischl
and
Andreas Zimmer focuses on different pathways for
siRNA delivery and summarizes recent progress
made in the use of vector-based siRNA technology.
Gene therapy is a promising tool for the treatment
of human diseases that cannot be cured by rational
therapies. The major limitation for the use of small
interfering RNA (siRNA), both in vitro and in vivo,
is the inability of naked siRNA to passively diffuse
through cellular membranes due to the strong
anionic charge of the phosphate backbone and
consequent electrostatic repulsion from the anionic
cell membrane surface. Therefore, the primary
success of siRNA applications depends on suitable
vectors to deliver therapeutic genes. Cellular
entrance is further limited by the size of the applied
siRNA molecule. Multiple delivery pathways, both
viral and nonviral, have been developed to bypass
these problems and have been successfully used to
gain access to the intracellular environment in vitro
and in vivo, and to induce RNA interference
(RNAi). [41]
Research and development of nanomedicines
in the future
Nanotechnology will alter our relationship with
molecules and matter profoundly. Research on
productive nanosystems will eventually develop
programmable, molecular-scale systems that make
other useful nano-structured materials and devices.
These systems will enable a new manufacturing base
that can produce both small and large objects
precisely and inexpensively. Nano-risk research is
conducted by agencies that oversee health and
environmental regulations. Nanotechnology, dealing
with functional structures and materials smaller than
100nm, is emerging as a truly interdisciplinary research
area spanning several traditional scientific disciplines. In
keeping with the growing trend, there is a strong need for a
platform to share original research related to applications of
nanotechnology in biomedical fields. At the hearing,
leaders of the Nanotechnology Environmental and
Health Implications working group, an interagency
panel that coordinates federal funding on health and
environmental risks of nanotechnology, released a
long-overdue report outlining research needed to
buttress regulation of products in the field. There is
far less agreement on how that money should be
spent and coordinated. Research on Nanotech
environmental health and safety in government
agencies, academic institutions, and industry is being
performed in an ad hoc fashion according to
individual priorities. Yet the vast majority of
nanotoxicology studies focus on those materials,
while ignoring broad classes of other materials
Translational implications for diagnosis and
therapy: Esophageal adenocarcinoma arises in the
backdrop of Barrett metaplasia-dysplasia sequence,
with the vast majority of patients presenting with
late-stage malignancy. Mesothelin, a glycophosphatidylinositol-anchored protein, is aberrantly
overexpressed on the surface of many solid cancers.
Mesothelin expression was assessed in esophageal
tissue microarrays encompassing the entire
histological
spectrum
of
Barrett-associated
dysplasia
and
adenocarcinoma.
Mesothelin
expression was observed in 24/84 (29%) of invasive
42
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
already on the market.[43]
The nanomedicine research is a goal and needs a
long-term plan, which is to quantitatively
characterize the molecular-scale components, or
nanomachinery, of living cells and to precisely
control and manipulate these molecular and
supramolecular assemblies in living cells to improve
human health. Nanomedicine will exploit and build
upon other research findings in nanotechnology and
apply it to the study of molecular systems in living
cells that contain a multitude of nanoscale structures,
such as membrane transporters, processes such as
self-assembly of protein–nucleic acid complexes, and
nanomachines such as molecular motors. The
benefits of nanomedicine include dramatically
expanded knowledge of the human genome, a greater
understanding of the pathophysiology of specific
diseases at the molecular scale, more specific
treatment of diseases, and the ability to understand
the dynamic behavior of dysfunctional cellular
machinery in
the
context of the total cell
machinery.[44] Robert A and Freitas Jr given an
overview of this rapidly expanding and exciting
nanomedicine field. Over the next 5 to 10 years,
nanomedicine will address many important medical
problems by using nanoscale-structured materials and
simple nanodevices that can be manufactured today.
Many approaches to nanomedicine being pursued
today are already close enough to fruition that it is
fair to say that their successful development is almost
inevitable, and their subsequent incorporation into
valuable medical diagnostics or clinical therapeutics
is highly likely and may occur very soon.[45]
The science of nanomedicine exploits and builds
upon novel research findings in 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 by developing novel approaches
and a better understanding of solutions to
health-relatedissues, ultimately improving the quality
of life. The last few years have seen unprecedented
advances in the field of biology. The decoding of the
human genome coupled with improving gene
transfection technologies offer great opportunities for
treating illnesses. In analysis and diagnosis,
lab-on-a-chip methods have surpassed earlier ex-vivo
and in-vivo detection methods while also aiding
toxicology efforts. In medicine, improvements in
targeted drug delivery, imaging, and therapy have led
to such successful interventions in cancer therapies.
[46]
Although there are only a few FDA-approved
nanopharmaceuticals on the market today, these
formulations are already impacting medicine and
promise to alter healthcare. Based on their ability to
reduce time-to-market, extend the economic life of
proprietary drugs and create additional revenue
streams, nanopharmaceuticals should greatly impact
medical practice and healthcare. However, if this is to
happen effectively, there are a few key biological
requirements for nanopharmaceuticals to fulfill: (1)
they must exhibit “ stealth ” qualities to evade
macrophage attack and the immune response; (2) be
nontoxic and traceable; (3) display effective
pharmacokinetic properties; (4) be biodegradable
following systemic administration through any route
(but the polymer must protect the embedded active);
and (5) they must be selective to be effective in
targeting specific tissue sites. Srikumaran Melethil
(Chair and Professor of Pharmaceutical Sciences at
the University of Findlay, Findlay, OH) discussed the
metabolic fate of nanopharmaceuticals upon delivery
to the human body, and presented pharmacokinetic
data relating to numerous nanoparticulate drugs and
highlighted the critical role of the FDA in
nanomedicine. According to him, further knowledge
of how the human body transports, distributes and
clears nanoparticles via the vascular and lymphatic
systems (i.e.,biodistribution of nanoparticles) is also
needed to get a handle on metabolic and toxicity
issues. Nanomedicine will eventually become an
integral part of mainstream medicine and a standard
in the drug industry. For example, the market impact
of nanopharmaceuticals on the pharmaceutical and
biotech industries is already being felt. However, for
nanomedicine to be a viable commercial entity,
desperately needed reforms to overhaul the PTO
along with clearer regulatory guidelines and safety
standards from federal agencies such as the FDA will
be needed.
Ethical question of nanomedicine is an important
issue. Ginger Gruters (The President's Council on
Bioethics, Washington, DC) presented on ethical
considerations that are likely to play a significant role
in nanomedicine, and stated that, as with other
43
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
biomedical advances coming before it, nanomedicine
will face significant ethical challenges as it moves
from proof-of-concept to the clinic. Along the
way,ethical questions regarding social justice,
privacy and confidentiality, long-term risks and
benefits, and human enhancement are certain to
arise.[47]
important
papers
published
in
other
journals,
commentaries, book reviews, correspondence, and articles
about the broader nanotechnology picture — funding,
commercialization, ethical and social issues, and so on. In
this way, the journal aims to be the voice of the
worldwide nanoscience and nanotechnology community.
Nature Nanotechnology offers readers and authors high
visibility, access to a broad readership, high standards of
copy editing and production, rigorous peer review, rapid
Appurtenances:
Introduction to Journals on Nano
publication, and independence from academic societies
and other vested interests.
Nature Nanotechnology
Nature
is
Nanotechnology
a
multidisciplinary
Journal of Nanoscience and Nanotechnology
journal that publishes papers of the highest quality and
Journal of Nanoscience and Nanotechnology (JNN)
and
is an international and multidisciplinary peer-reviewed
nanotechnology. The journal covers research into the
journal with a wide-ranging coverage, consolidating
design, characterization and production of structures,
research activities in all areas of nanoscience and
devices and systems that involve the manipulation and
nanotechnology into a single and unique reference source.
control of materials and phenomena at atomic, molecular
JNN is the first cross-disciplinary journal to publish
and
and
original full research articles, rapid communications of
top-down approaches - and combinations of the two - are
important new scientific and technological findings,
covered. Nature Nanotechnology also encourages the
timely state-of-the-art reviews with author's photo and
exchange of ideas between chemists, physicists, material
short biography, and current research news encompassing
scientists, biomedical researchers, engineers and other
the fundamental and applied research in all disciplines of
researchers who are active at the frontiers of this diverse
science, engineering and medicine. Topics covered in the
and multidisciplinary field. Coverage extends from basic
journal
research in physics, chemistry and biology, including
Nanoscale Materials, Nanofabrication and Processing of
computational work and simulations, through to the
Nanoscale Materials and Device; Atomic and Nanoscale
significance
in
all
macromolecular
areas
of
scales.
nanoscience
Both
bottom-up
include:
Synthesis
Nanostructured
Characterization
applications in a wide range of industrial sectors
Bio-assemblies; Nanoprobes, Properties of Nanoscale
(including
Materials, Nanocatalysis; Nanocomposites, Nanoparticles,
technology,
medicine,
Functional
Nanocrystalline
and environmental technologies). Organic, inorganic and
Superlattices, Quantum Dots, Quantum Wires, Quantum
hybrid materials are all covered. Research areas covered
Wells, Nanoscale Thin Films ; Fullerenes, Nanotubes,
in the journal include: Carbon nanotubes and fullerenes,
Nanorods, Molecular Wires, Molecular Nanotechnology;
Computational nanotechnology, Electronic properties and
Supramolecules,
devices,
Environmental,
health
machines
self-assembly,
Nanobiotechnology,
Nanomagnetism
Nanomedicine,
and
and
Nanometrology
and
Dendrimers,
Nanoclusters;
Self-Assemblies,
safety
Low-dimension Structures; Nanophysics, Nanoelectronics,
Molecular
Nano-Optics, Nanomagnetism and Nanodevices; Atomic
Nanofluidics,
Manipulation, Computational Nanotechnology, Molecular
and
motors,
spintronics,
and
and
manufacturing, high-performance materials, and energy
issues,Molecular
Materials,
Materials
and
development of new devices and technologies for
information
of
of
Nanoscience;
Nanomaterials,
Nanochips,
Nano-integration,
instrumentation,
Nanosensors
Nanofluidics,
and
Nanomachining;
Nanoparticles, Nanosensors and other devices, NEMS,
Structure Analysis at Atomic, Molecular, and Nanometer
Organic–inorganic nanostructures, Photonic structures
range;
and devices, Quantum information, Structural properties,
Applications
Surface patterning and imaging and Synthesis and
Nanobiotechnology, Biochemical Assemblies, BioMEMS,
processing.
Biomimetic
Nanorobotics,
of
Nanotribology,
Nanostructured
Materials
Nanoscale
and
Materials
Genomics,
Novel
and
DNA
Sequencing, Nanomedicines, Drug Delivery, Biomedical
Nature Nanotechnology also publishes review
Nanotechnolog.
articles, news and views, research highlights about
44
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
made in nanoscience and nanotechnology and the future
predictions for this extraordinary technology.
Nano
NANO is an international peer-reviewed journal for
nanoscience and nanotechnology that presents forefront
Journal of Nanotechnology Online
fundamental research and new emerging topics. It
The Online Journal of Nanotechnology is based on a
features timely scientific reports of new results and
free access publishing model, coupled with what is
technical breakthroughs and also contains interesting
believed to be a unique development in the field of
review articles about recent hot issues. NANO provides an
scientific publishing – the distribution of journal revenue
ideal forum for presenting original reports of theoretical
between the authors, peer reviewers and site operators
and experimental nanoscience and nanotechnology
(OARS). The revenue received from the journal related
research.
include:
advertising and sponsorship will be distributed according
nanomaterials including nano-related biomaterials, new
Research
areas
of
interest
to the following general criteria: Authors receive a
phenomena and newly developed characterization tools,
revenue share of 50% of the related revenue their
fabrication methods including by self-assembly, device
contributions attract. Peer reviewers receive a revenue
applications, and numerical simulation, modeling, and
share of 20%. The site administrators receive a revenue
theory.
share of 30%. This revenue share will apply throughout
the on-line published life of the individual article or paper.
The Online Journal of Nanotechnology papers will
Nano Letters
Nano Letters reports on fundamental research in all
benefit from being hosted on the AZoNano.com website
branches of the theory and practice of nanoscience and
and database platform as they will take advantage of the
nanotechnology, providing rapid disclosure of the key
existing AZoNano.com search tools. These search tools
elements of a study, publishing preliminary, experimental,
make it very easy for site visitors to locate nanotech
and theoretical results on the physical, chemical, and
information which directly relates to their research areas,
biological
applications and industrial sectors.
phenomena,
along
with
processes
and
applications of structures within the nanoscale range.
Among the areas of interest the journal covers are:
Journal of Nano Education
Synthesis and processing of organic, inorganic, and
The Journal of Nano Education (JNE) is a
hybrid nanosized materials by physical, chemical, and
peer-reviewed international journal that aims to provide
biological methods; Modeling and simulation of synthetic,
the most complete and reliable source of information on
assembly, and interaction processes; Characterization of
current developments in nanoscale science, technology,
size-dependant
and
engineering, and medical education. JNE publishes a
application of novel nanostructures and nanodevices The
comprehensive range of articles including topics in the
Nano Letters manuscript submission process is fully
following
electronic, to ensure the rapid publication of results.
engineering, and medical education at the K-12,
Manuscripts should be submitted via our secure Web site.
undergraduate and graduate levels (formal and informal,
Manuscripts submitted by hardcopy mail or by e-mail will
including public outreach and dissemination activities);
not be processed. Introduction Nano Letters invites
K-12
original reports of fundamental research in all branches of
development; Scientific and technological literacy/public
the
understanding
theory
properties;
and
practice
and
of
Realization
nanoscience
and
areas:
science
Nanoscale
teacher
of
science,
education
nanoscale
and
science,
technology,
professional
technology,
engineering, and medicine; Curriculum development and
nanotechnology.
assessment; Social and ethical issues associated with
nanoscale science, technology, engineering, and medical
Journal of Nano Research
research;
Journal of Nano Research (J Nano R) is a
Workforce
preparation
(professional
and
multidisciplinary peer-reviewed journal, which publishes
vocational); National and state science standards and their
high quality work on ALL aspects of nanoscience and
relationships to the goals of nanoeducation initiatives
nanotechnology. Currently, it stands alone in serving the
worldwide; Current nanoscale science, technology,
global “nano” community in providing up-to-date
engineering, and medical education research; Other
information on all developments and progresses being
pertinent
45
areas
of
interest
to
nanoscale
science,
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
technology, engineering, and medical researchers &
thermodynamics thought experiments, wear, and much
educators. JNE also will serve as a forum for commentary
more.
and debate on related issues.
Journal of Biomedical Nanotechnology
Journal of
Nanoscience
Computational
and
Journal of Biomedical Nanotechnology (JBN) is
Theoretical
being created as an international peer-reviewed periodical
Theoretical
that covers applications of nanotechnology in all fields of
Nanoscience is an international peer-reviewed journal
life sciences. JBN publishes original full papers and
with a wide-ranging coverage, consolidates research
timely state-of-the-art reviews with author's photo and
activities in all aspects of computational and theoretical
biography, and short communications encompassing the
nanoscience into a single reference source. This journal
fundamental and applied research aspects. To speed up
offers scientists and engineers peer-reviewed research
the reviewing process, we will provide on-line refereeing
papers in all aspects of computational and theoretical
of all articles submitted in electronic form. Authors
nanoscience and nanotechnology in chemistry, physics,
receive these benefits: Electronic submission of articles,
materials science, engineering and biology to publish
Fast reviewing, Rapid times to publication, No page
original full papers and timely state-of-the-art reviews
charges, Free color where justified, Distinguished
and short communications encompassing the fundamental
editorial board
and applied research. Topics include: Assemblers, basic
editions. Topics include: Broadly speaking, Journal of
physics, biological systems, biochemical systems, bionics,
Biomedical Nanotechnology covers applications of
biophysics, CAD, carbon systems, cellular mechanisms,
nanotechnology in biotechnology, medicine, biosciences,
chaotic systems, circuits, clusters, cluster systems,
and all other related fields of life sciences. The coverage
complex aggregates, computer codes, crystal growth, data
includes applications of nanotechnology in all fields of
analysis, defined chain length molecules, devices,
life sciences, all kinds of nanoscale biomaterials,
diffusion processes, DNA, drug design, dynamics,
biomimetics of biological materials and machines,
electronics, electronic properties, enzyme reactivity and
nanoprobes,
biocompatible
reactions, equation of state, friction, computational
bioengineered
materials,
genomics, gene technology, genetics, holistic views,
biopolymers,
information theory, interactions, ion channelling, kinetics,
nanocomposites, biological macromolecules, proteins,
macromolecules, molecular interactions, large scale
enzymes,
simulations,
Journal
of
Computational
liquids,
and
and Available in print and online
surfaces,
polypeptides,
organic-inorganic
kinases,
functional
bioceramics,
hybrid
biomaterials,
phosphatases,
DNA-based
crystals,
luminescence,
nanostructures, molecular assemblies, biomolecules, cells,
manufacturing,
liquid
many-particle
and glycans, biochips, microarrays, biocompatibility
systems, metallurgy, materials, material properties,
aspects of materials, interactions between biomaterials,
mechanical models, metals, mathematical methods,
protein-surface, cells, tissue and organs, cellular matrix
molecule
molecular
interaction,, artificial muscles and organs, biomembranes,
mechanics, Monte Carlo simulations, multi-scale methods,
bioseparation process, drug delivery, biopolymers for
nanomachines,
nanorobotics,
orthopedic and cardiovascular applications, dentistry,
nanotechnology and ethics, noble gases, nonlinear optics,
bone, bioanalysis, biosensors, molecular sensors, clinical
numerical algorithm, numerical procedures, oligomers,
diagnostic techniques, nanoparticles for drug delivery,
optoelectronics, phase transitions, phenomenological
dendrimers
theory, philosophical implications and positions, photonic
biomechanics, bioinstrumentation, nanoscale physiology
crystals, polymers, potential development, protein folding,
and pathology, bioinformatics, nanoscale genetics and
quantum chemistry, quantum computers, quantum dots,
genome
quantum electronics and optics, quantum technology,
proteomics and protein-based nanostructures, sequencing
replicators, RNA, semiconductors, superconductors, solid
of
state physics, statistical physics, structural chemistry,
biocomputing,
structures, structures on surfaces, surfaces, technological
nanobioscience, nanoscale cellular and tissue engineering,
applications, theoretical biosciences, theoretical physics,
nanodevices, biomedical nanoelectronics, biomedical
magnetic
structures,
design,
molecular
dynamics,
nano-optics,
for
medicine,
research,
nucleic
acid,
gene
DNA
biomedical
expression,
and
instrumentation
implantation,
immunoassays,
RNA,
biomarkers,
techniques
for
microsystems, biochemistry and biophysics aspects,
46
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49
BioMEMS, nanofabrication, nanotubes, lab-on-a-chip,
and nanotechnology research at the interfaces of
biological motors, biomembranes, nanofilters, biosensors,
chemistry, biology, materials science, physics, and
nanotechnologies for cell and tissues, nanofluidics,
engineering. Moreover, the journal helps facilitate
pharmaceutical nanotechnology, drug and gene delivery,
communication among scientists from these research
therapeutic proteins, disease control, cancer therapeutics,
communities in developing new research opportunities,
diagnostic techniques, nanoscale imaging, nanoanalysis,
advancing the field through new discoveries, and reaching
spectroscopic studies using X-ray, STM, AFM, SNOM,
out to scientists at all levels. ACS Nano publishes
systems biology, computational biology, etc., and much
comprehensive
more.
characterization, theory, and simulation of nanostructures
(nanomaterials
self-assembled
International Journal of Nanoscience (IJN)
International Journal of Nanoscience (IJN) This
inter-disciplinary,
internationally-reviewed
articles
and
on
synthesis,
assemblies,
assembly,
nanodevices,
structures),
and
nanobiotechnology,
nanofabrication, methods and tools for nanoscience and
research
nanotechnology, and self- and directed-assembly. In
journal covers all aspects of nanometer scale science and
addition to comprehensive, original research articles, ACS
technology. Articles in any contemporary topical areas
Nano
are sought, from basic science of nanoscale physics and
cutting-edge research, conversations with nanoscience
chemistry to applications in nanodevices, quantum
and nanotechnology thought leaders, and discussions of
engineering and quantum computing. IJN will include
topics that provide distinctive views about the future of
articles in the following research areas (and other related
nanoscience and nanotechnology.
offers
thorough
reviews,
perspectives
on
areas): Properties Effected by Nanoscale Dimensions,
Atomic Manipulation, Coupling of Properties at the
Nanoscale;
Controlled
Synthesis,
Fabrication
Nanomedicine
and
Nanomedicine:
Nanotechnology,
Biology,
and
Processing at the Nanoscale; Nanoscale Precursors and
Medicine (Nanomedicine: NBM) is an international,
Assembly, Nanostructure Arrays, Fullerenes, Carbon
peer-reviewed
Nanotubes and Organic Nanostructures, Quantum Dots,
Nanomedicine: NBM presents basic, clinical, and
Quantum
Superlattices;
engineering research in the field of nanomedicine. Article
Nanoelectronics, Single Electron Electronics and Devices,
categories include basic, diagnostic, experimental, clinical,
Molecular
engineering,
Wires,
Quantum
Electronics,
Wells,
Quantum
Computing;
journal.
Each
pharmacologic,
quarterly
and
issue
of
toxicologic
Nanomechanics, Nanobiological Function and Life
nanomedicine. In addition, regular features will address
Sciences; Nanoscale Instrumentation and Characterization
the commercialization of nanomedicine advances, ethics
and Nano-optics, Photonic Crystals with Nanoscale
in nanomedicine, funding opportunities, and other topics
Structural Fidelity.
of interest to researchers and clinicians. We invite authors
to submit original manuscripts and review articles. The
Journal is indexed or abstracted in PubMed/MEDLINE,
Nano Research
With the development of modern nanotecnology
BIOSIS Previews, EMBASE, SCOPUS, Biological
and the inburst of various new ideas, new concepts and
Abstracts, Science Citation Index Expanded (SciSearch),
new thinking manners, more and more researchers have
Biotechnology Citation Index®, and Journal Citation
realized that nanotechnology must roots in the essences of
Reports/Science Edition.
international culture, with deep apperception to the
traditional
Chinese
characteristics,
absorbing
and
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Raj Bawa, Ryan Tian,
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