Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles

Abstract

In this review, we have presented the latest results and highlights on biomedical applications of the group of noble metal nanoparticles and their compounds, such as gold, silver, platinum, and the group of magnetic nanoparticles, such as cobalt, nickel, iron, and their compounds. Their most important related compounds are also discussed in biomedical applications for treating various diseases, typically as cancers . At present, both physical and chemical methods have been proved very successful to synthesize, shape, control, and produce metal- and oxide-based homogeneous particle systems, e.g. nanoparticles and microparticles. Therefore, we have mainly focused on functional magnetic nanoparticles for nanomedicine because of their high bioadaptability to the organs inside human body. Here, bioconjugation techniques are very crucial to link nanoparticles with conventional drugs, nanodrugs, biomolecules or polymers for biomedical applications. Biofunctionalization of engineered nanoparticles for biomedicine is shown respective to in vitro and in vivo analysis protocols that typically include drug delivery, hyperthermia therapy, magnetic resonance imaging (MRI), and recent outstanding progress in sweep imaging technique with Fourier transformation (SWIFT) MRI. The latter can be especially applied using magnetic nanoparticles, such as Co-, Fe-, Ni-based nanoparticles, α-Fe2O3, and Fe3O4 oxide nanoparticles for analysis and treatment of malignancies. Therefore, this review focuses on recent results of scientists, and related research on diagnosis and treatment methods of common and dangerous diseases by biomedical engineered nanoparticles. Importantly, nanosysems (nanoparticles) or microsystems (microparticles) or hybrid micronano systems are shortly introduced into nanomedicine. Here, Fe oxide nanoparticles ultimately enable potential and applicable technologies for tumor-targeted imaging and therapy. Finally, we have shown the latest aspects of the most important Fe-based particle systems, such as Fe, α-Fe2O3, Fe3O4, Fe–FexOy oxide core–shell nanoparticles, and CoFe2O4–MnFe2O4 core–shell nanoparticles for nanomedicine in the efficient treatment of large tumors at low cost in near future.

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Review
Journal of
Nanoscience and Nanotechnology
Vol. 15, 10091–10107, 2015
www.aspbs.com/jnn
Biomedical Applications of Advanced Multifunctional
Magnetic Nanoparticles
Nguyen Viet Long123∗, Yong Yang1, Toshiharu Teranishi3,
Cao Minh Thi4, Yanqin Cao1, and Masayuki Nogami5
1State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics,
Chinese Academy of Sciences, 1295, Dingxi Road, Shanghai 200050, China
2Posts and Telecommunications Institute of Technology, km 10 Nguyen Trai, Hanoi 100000, Vietnam
3Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan
4Ho Chi Minh City University of Technology, 144/24 Dien Bien Phu, Ward 25, BinhThach, Ho Chi Minh City 700000, Vietnam
5Toyota Physical and Chemical Research Institute, 41-1 Yokomichi Nagakute, 480-1192, Japan
In this review, we have presented the latest results and highlights on biomedical applications of
a class of noble metal nanoparticles, such as gold, silver and platinum, and a class of magnetic
nanoparticles, such as cobalt, nickel and iron. Their most important related compounds are also
discussed for biomedical applications for treating various diseases, typically as cancers. At present,
both physical and chemical methods have been proved very successful to synthesize, shape,
control, and produce metal- and oxide-based homogeneous particle systems, e.g., nanoparticles
and microparticles. Therefore, we have mainly focused on functional magnetic nanoparticles for
nanomedicine because of their high bioadaptability to the organs inside human body. Here, bio-
conjugation techniques are very crucial to link nanoparticles with conventional drugs, nanodrugs,
biomolecules or polymers for biomedical applications. Biofunctionalization of engineered nanopar-
ticles for biomedicine is shown respective to in vitro and in vivo analysis protocols that typically
include drug delivery, hyperthermia therapy, magnetic resonance imaging (MRI), and recent out-
standing progress in sweep imaging technique with Fourier transformation (SWIFT) MRI. The latter
can be especially applied using magnetic nanoparticles, such as Co-, Fe-, Ni-based nanoparticles,
-Fe2O3, and Fe3O4oxide nanoparticles for analysis and treatment of malignancies. Therefore, this
review focuses on recent results of scientists, and related research on diagnosis and treatment
methods of common and dangerous diseases by biomedical engineered nanoparticles. Importantly,
nanosysems (nanoparticles) or microsystems (microparticles) or hybrid micronano systems are
shortly introduced into nanomedicine. Here, Fe oxide nanoparticles ultimately enable potential and
applicable technologies for tumor-targeted imaging and therapy. Finally, we have shown the latest
aspects of the most important Fe-based particle systems, such as Fe, -Fe2O3,Fe
3O4, Fe–FexOy
oxide core–shell nanoparticles, and CoFe2O4–MnFe2O4core–shell nanoparticles for nanomedicine
in the efficient treatment of large tumors at low cost in near future.
Keywords: Fe Nanoparticles, Fe Oxide Nanoparticles, Au Nanoparticles, Ag Nanoparticles,
Pt Nanoparticles, Drug Delivery, Hyperthermia, Magnetic Resonance Imaging, Drug,
Cancers, Tumors, Cancer Therapy.
CONTENTS
1. Introduction . .......................................10092
2. Nanoparticles . ......................................10095
2.1. Metal Nanoparticles . .............................10097
2.2. Magnetic Nanoparticles ...........................10098
2.3. Alloy and Core–Shell Nanoparticles . . . ..............10098
∗Author to whom correspondence should be addressed.
3. Synthesis..........................................10099
4. BiomedicalApplication ...............................10099
5. Drug Delivery ......................................10100
6. Hyperthermia.......................................10101
7. MagneticResonance Imaging ..........................10102
8. Conclusions........................................10103
Acknowledgments . ..................................10104
Referencesand Notes ................................10104
J. Nanosci. Nanotechnol. 2015, Vol. 15, No. 12 1533-4880/2015/15/10091/017 doi:10.1166/jnn.2015.11691 10091

Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
1. INTRODUCTION
At present, biology and medicine, e.g., traditional ther-
apy, are considered as the traditional methods of treat-
ing various diseases through conventional materials.
Nguyen Viet Long He is Young researcher at Shanghai Institute of Ceramics, Chinese
Academy of Sciences, China. His interest focuses on new functional magnetic metal and
oxide nanoparticles with bio-conjugates for biomedical applications in Nanomedicine. He
was a Researcher in Kyushu University, Fukuoka, Japan. He received B.Sc. degree of
Physics in Solid State Physics at Department of Physics, Hanoi National University of
Education, Hanoi, Vietnam. He received M.Eng. degree in Semiconductor, and Ph.D.
degree in Optical and Photonic materials at International Training Institute for Materials
Science, Hanoi University of Science and Technology, Hanoi. He was a Lecturer in Gen-
eral Physics. Then, he worked as a Researcher in Department of Materials Science and
Engineering, Nagoya Institute of Technology, Nagoya, Japan. His main research directions
of Pt and Pd based catalysts are focused on fuel cells, and energy conversion with Pro-
fessor Masayuki Nogami. He worked as researcher or visiting Professor in Kyushu University, Fukuoka, Japan. He
became a member of Laboratory for Nanotechnology, Vietnam National University at Ho Chi Minh City.
Yong Yang He works at the Shanghai Institute of Ceramics, Chinese Academy of Sci-
ences. He received B.Eng. and M.Eng., Department of Materials Science and Engineering,
from Shanxi University of Science and Technology, China. He also received Dr. Eng.,
Shanghai Institute of Ceramics, Chinese Academy of Sciences, China. He worked as JSPS
postdoctoral research fellow and project Associate Professor in Department of Materials
Science and Engineering, Nagoya Institute of Technology, Nagoya, Japan. At present, he
was officially appointed as Professor in Shanghai Institute of Ceramics, Chinese Academy
of Sciences. His main interest in scientific areas of research are focused on the prepa-
ration and self-assembly of metal nanomaterials, catalytic properties and optical proper-
ties such as Surface Plasmon Resonance (SPR) for potential applications SPR sensors,
Surface-enhanced Raman spectroscopy (SERS), and nonlinear optical properties, surface
modification of materials and optical film. He is the author of more than 60 scientific publications in international
peer-reviewed journals.
Toshiharu Teranishi He is a professor at Institute for Chemical Research, Kyoto Univer-
sity. He received his Ph.D. from the University of Tokyo under the direction of Professor
N. Toshima in 1994. He spent seven and a half years at Japan Advanced Institute of Sci-
ence and Technology as an Assistant Professor and an Associate Professor. In 2004, he
moved to University of Tsukuba as a Full Professor, and moved to Kyoto University in
2011. His current research interests include precise structural control of inorganic nano-
materials and structure-specific functions for high-performance devices and photo-energy
conversion.
Cao Minh Thi He studied in Mathematics and Physics, and Solid State Physics, in Ho
Chi Minh University of Technology, 144/24 Dien Bien Phu, Ward 25, Binh Thanh, Ho Chi
Minh City. He received B.sc. in Physics, Hanoi National University of Education (HNUE)
in 1960. Then, he studied in Mathematics and Physics at Lomonosov Moscow State Uni-
versity (1966), and received Ph.D. in Mathematics and Physics at Lomonosov Moscow
State University (1970). He was also the Lecturer in Physics at HNUE, Vietnam (1960),
Lecturer of Faculty of Physics, HNUE in the years of 1972–1975. He was appointed by
Vietnamese Leaders of the Vietnam country as vice President of Ho Chi Minh City Univer-
sity of Education or Saigon National Pedagogical University (1975), President of Ho Chi
Minh City University of Education (Saigon College) (1981), Associate professor (1984),
Deputy Director or Leader of Sector of Education and Training in the entire Ho Chi Minh
City (1989). Now He is Vice-president of Vietnam Physical Society, President of Ho Chi Minh City Physical Society.
Recently, nanomedicine science has appeared through the
application of nanomaterials and nanotechnology com-
bined with above traditional methods.1–5 To obtain bio-
logical applications, particle systems must be combined
10092 J. Nanosci. Nanotechnol. 15, 10091–10107,2015

Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
Yanqin Cao She studies at the Shanghai Institute of Ceramics (SIC), Chinese Academy of
Sciences (CAS). She received B.Eng., Department of Materials Science and Engineering,
Wuhan University of Science and Technology, China. Her research focuses on the con-
trollable synthesis of noble metal (Pt, Pd, Au, and Ag) nanostructures and their Catalytic
characterization and Surface enhanced Raman spectroscopy (SERS).
Masayuki Nogami He is Senior researcher at Toyota Physical and Chemical Research
Institute. He worked at Nagoya Institute of Technology (NIT), Nagoya, Japan. He received
B.S. in Ceramics, then M.S. in Ceramics at NIT, and Dr. Eng. at Osaka University. He is
Professor Emeritus at NIT, President of The Japanese Sol–Gel Society, Senior Researcher
at Nagoya Industrial Science Research Institute, Senior Researcher at National Industrial
Research Institute, Osaka, Visiting Research Associate at Rensselaer Polytechnic Institute,
USA, and Associate Professor at Aichi Institute of Technology. He has over 400 pub-
lications, 20 books, and 20 patents. He was co-editor to Journal Sol–Gel Science and
Technology (Springer-USA), Director Chairman of Glass Division in The Ceramics Soci-
ety, Japan, Visiting Professor at National Engineering College for Industrial Ceramics,
France. He was Senior Researcher at Laboratory of Science of Ceramic Processes and of
Surface Treatments, National Research Council (CNRs), French. In 2012–2013, he was an International Scientist at
Shanghai Institute of Ceramics, Chinese Academy of Science, China.
with numerous bioconjugates.2For example, researchers
need to prepare conjugates and labeled molecules for use
in nanomedicine. Fundamentally, the special antibodies
for cancers can be used.2Today, particle systems can be
prepared in the various sized ranges, as small as macro-
molecules (10 nm), and larger up to approximately the
diameter of cells, such as red blood cells (10 m).2So far,
various engineered nanoparticles have been very poten-
tially used for clinical and biomedical applications, such as
polymeric nanoparticles, carbon nanotubes (CNTs), silica
(SiO2, silver (Ag) nanoparticles, gold (Au) nanoparticles,
quantum dots (QDs), magnetic nanoparticles, superpara-
magnetic iron (Fe) oxide nanoparticles (SIONs), carbon
nanoparticles, and various nanoparticles and nanomaterials
(Figs. 1–3).1–6 They are very important particle structures,
such as micro-, nano-, and micronano-systems as the core
platforms for drug delivery systems (DDSs). These specific
formulations can be bioconjugated, typically with targeting
biomolecules, nanodrugs or traditional drugs, for therapeu-
tic and diagnostic approaches. Thus, DDSs are used to
enhance biocompatibility, bioavailability and pharmacoki-
netics of therapeutics or nanotherapeutics.1–5 According to
the improved research directions in Japan, nanomedicine
has been focused on diagnostic devices, ultrafine imaging
systems, invasive and noninvasive medical devices, espe-
cially on early point-of-care diagnosis for the detection and
treatment of several diseases, such as malignant/benign
tumors at any beginning stages of brain, muscle, lung,
kidney, liver etc. Therefore, nanobiotechnology provides
an integration of detection, diagnosis and therapy as well
as modern molecular imaging and living-cell detection.11
In the past, through an interesting research, therapeutic
DDSs using gas-filled microspheres and a therapeutic were
created, and various methods for employing such micro-
spheres in therapeutic drug delivery applications were also
provided.7In one typical case, the DDSs comprising gas-
filled liposomes having encapsulated a drug were preferred
in drug delivery applications. To provide therapeutic deliv-
ery to organs such as the liver and to allow differentia-
tion of tumor from normal tissue, smaller microspheres of
around 30–100 nm were preferred. These systems (from
several nm to tens m in size) greatly offer drug delivery
applications in common diseases in humans.7Alterna-
tively, they were designed to replace invasive adminis-
trations. Therefore, those DDSs were suitably used to
improve bioavailability, biocompatibility, and pharmacoki-
netics of therapeutics.78For example, albumin described
as a plasma protein was used for DDS approach. Thus,
a nanoDDS is created involving various nanocarriers. In
addition, the nanoDDSs offer most advantages of con-
venience, flexibility, and efficacy in delivering drugs in
diseased tissue, increase the solubility of drugs in aque-
ous media, overcome various kinds of biological bar-
riers, such as blood brain barrier (BBB), and increase
chemical stability of the drug to the diseased areas.910
Most solid tumors possess unique pathophysiological
characteristics that are not observed in normal tissues or
organs, such as extensive angiogenesis and hence hyper-
vasculature, defective vascular architecture, impaired lym-
phatic drainage/recovery system, and greatly increased
J. Nanosci. Nanotechnol. 15, 10091–10107, 2015 10093

Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
Biomedical functionalization
(a) Polymeric micelles (b) Dendrimer
Multifunctional
dendritic carrier
(c) Liposome carrier
(d) Functional
core-shell quantum dot
(f) Drug is bioconjugated with
polymer-protected Au nanoparticle
(e) SiO2nanoparticle
with anticancer (CPT)
–600 –400 –200 0 200 400 600
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
0.2
0.4
0.6
0.8
1.0
HC
MR Sample 3
Sample 2
Sample 1
M(emu/g)
H(Oe)
–15000 –10000 –5000 0 5000 10000 15000
–3
–2
–1
0
1
2
3Sample 3
Sample 2
Sample 1
M(emu/g)
H(Oe)
(I) Types of Nanoparticles and Microparticles
Pt nanoparticles
(size range: 10 nm)
(size range: 10
μ
m)
α-Fe2O3
microparticles
(VI) α-Fe2O3 particles (Micronano system)
(IV) Alloy/Coreshell system
Pt-Pd
Pd (shell)
Pt (core)
(V)
(II) Nanosystem (III) Microsystem
Biomedical Functional Particles
Functional nanoparticles
Functional microparticles
Functional micronano particles
Hydrophilic
Shell
Hydrophobic
Core
Large pores of SiO2
(size range: 25 nm)
Figure 1. (I)–(IV), and (VI) Typical functional engineered nanoparticles for nanosystems in potential biomedical applications. Reprinted with permis-
sion from [6], (a) N. V. Long, et al., Curr. Phys. Chem. 4, 1 (2014), © 2014. All Rights Reserved. (II) Pt nanoparticles. Reprinted with permission
from [63], N. V. Long, et al., New J. Chem. 36 (2012), © 2012. All Rights Reserved. (III) -Fe2O3microparticles, Reprinted with permission from [79, 80],
N. V. Long, et al., RSC Adv. 4(2014), © 2014. All Rights Reserved, N. V. Long, et al., RSC Adv. 4, 6383 (2014), © 2014. (IV) HRTEM images of Pt–Pd
core–shell nanoparticles. Reprinted with permission from [34], N. V. Long, et al., Acta Mater. 59, 2901 (2011). © 2011. All Rights Reserved. (V) M–H
curve of new -Fe2O3microparticles with grain and grain boundary structure showing supermagnetic nature for hyperthermia therapy. (VI) SEM images
of new -Fe2O3microparticles. Reprinted with permission from [78], N. V. Long, et al., Colloids Surf., A 456 (2014). © 2014. All Rights Reserved.
production of a number of permeability mediators. The
phenomenon of enhanced permeability and retention
(EPR) effect for lipid and macromolecular agents was
observed to be universal in solid tumors in the find-
ings of Maeda and co-workers.910 The enhanced vascular
permeability will sustain an adequate supply of nutrients
and oxygen for rapid tumor growth. On the other hand, the
EPR provides a great opportunity for more selective tar-
geting of lipid- or polymer-conjugated anti-cancer drugs,
such as SMANCS and PK-1 to the tumor. The important
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Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
(A)
(C)
Fe3O4
Fe-Pt
(B)
Fe3O4-SiO2
Nanorods
Fe-Pt Fe-Pt
Fe-Pt
Fe-Pt Fe-Pt
Figure 2. (A) TEM images of magnetite nanoparticles (12 nm).
Reprinted with permisson from [117], (a) J. Park, et al., Nat. Mater.
3, 891 (2004). © 2004. All Rights Reserved. (B) Silica shell-magnetic
core nanoparticles. Reprinted with permission from [117], (b) C. Vogt,
et al., J. Nanopart. Res. 12, 1137 (2010). © 2010. (C) Types of magnetic
Fe–Pt nanoparticles by the chemical methods. Reprinted with permission
from [55], D. Ung, et al., Cryst. Eng. Comm. 11, 1309 (2009). © 2009.
American Scientific Publishers.
characteristics of EPR and its modulation for improv-
ing delivery of macromolecular drugs to the tumor are
described. The EPR effect showed evidences of vascula-
ture in tumors and healthy organs or tissues. Nonethe-
less, blood vessels in tumors are leakier according to
their very fast growth. Interestingly, tumor cells are less
densely packed than cells in healthy tissue. The vascu-
lar permeability effect in tumor tissues, macromolecu-
lar drug delivery, and pathophysiology of tumor vessels
were carefully investigated in EPR.7–10 It is certain that
DDSs are categorized into various approaches of drug tar-
geting, which include passive targeting, active targeting,
and physical targeting.7–10 It is known that the potential
applications of nanotechnology and nanomaterials (in the
range of 100 nm) for the treatment, diagnosis, monitoring,
and control of animal and human biological systems are
referred to as nanomedicine.11–18 The common trials in
animals and humans are aimed at assessing a hoped low
toxicity along with a high efficacy. Briefly, the important
roles of size, composition, morphology, and structure of
nanomaterials and drugs are very meaningful in DDSs to
treat the diseases.4For instance in Japan, nanomedicine is
developed with many projects by the Ministry of Health,
Labour and Welfare (MHLW).11 So far, a nanodrug using
curcumin has been commercialized with high quality prod-
ucts used in treatment of cancerous diseases for skin and
face of humans.17
In our critical review, we have mainly presented the
latest results and highly exciting research aspects of
inorganic/organic particle systems prepared by chemi-
cal and physical methods with potential applications in
biology and medicine (traditional biomedicine) as well
as nanomedicine (nanotechnology). The inorganic/organic
particle systems are well combined with bioconjugates
with potential biomedical applications for drug delivery,
therapeutic hyperthermia, and magnetic resonance imaging
(MRI) in the important assays of the treatment of cancers
with the utilization of functional magnetic nanoparticles
from the latest research of scientists in the world. To this
end, nanomedicine technology must be further studied in
health and safety of humans through the clinic assays for
issues of toxicity and risks to our society, and its appli-
cations for humans should be done with low cost before
complete comerciallization.
2. NANOPARTICLES
To begin these interestingly practical topics of biomed-
ical applications,1–3 we have known that the term can-
cer includes a group of diseases that spring from by
abnormal changes in reproduction, growth and function
of cells in humans. The normal cells become abnormal
after a number of DNA mutations and they uncontrol-
lably proliferate. They can invade near tissues by local
invasion or by long-distance invasion (metastasis) via lym-
phatic system or blood vessels. Metastasis is one main
cause of death. The treatment methods of cancers are
to detect, prevent, and block their processes of devel-
opment at various stages, especially at the early and
beginning periods. In biomedical applications of inor-
ganic and organic particles, DDSs play extremely impor-
tant roles to carry and protect anti-cancer or anti-disease
drugs, biomolecules, and other targeted pharmaceuticals
according to treatment time.1–36They are reliably formed
by the stable bioconjugated particles for treating can-
cers. Both the functional bio-conjugated microsystems
and nanosystems can be potentially used for treatment of
tumors and other serious diseases, including cardiovas-
cular disease, rheumatic disease, gastrointestinal/hepatic
disease, infections such as bacterial, viral, parasitic, and
implant infections, tuberculosis, inflammation, diseases
of skin, face, eye, ear, brain, muscle, lung, kidney, and
liver etc. In DDSs approaches, abovementioned particles
are the main cores for biomedical multifunctional sys-
tems, such as microsystems, nanosystems, and micronano
systems with main features of targeting, drug delivery,
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Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
(A)
(B)
Uniform magnetic nanosystem
CoFe2O4-MnFe2O4
Tumor growth
and its volum
e
are controlled.
Figure 3. (A) TEM and high-resolution TEM images of 15 nm CoFe2O4–MnFe2O4nanoparticles. (B) In vivo hyperthermia treatment in the case of
diseased mouse with tumors. Reprinted permission from [151], (a) J. Lee, et al., Nat. Nanotechnol. 6, 418 (2011). © 2011. All Rights Reserved.
and treatment of diseases etc. exhibiting high selectiv-
ity for treating malignances that are found in animals
and humans that originate from themselves and from
living and surrounding environments.12–19 Such surface
functionalization of nanoparticles with bioconjugates can
lead to design various useful platforms for biomedical
applications. Multifunctional nanosystems lead to reduce
the dose of drugs, to avoid side effects, to target useful
anti-cancer drugs towards the diseased locations and to
avoid side effects in healthy cells and tissues. The main
features of particles (nanoparticles and microparticles) are
the sizes, the shapes, and the morphologies. They should
be homogeneous in terms of structure, composition, size,
and shape for important biomedical applications. Typically,
metal nanoparticles with bioconjugates in the nanosized
range of 10 nm are adopted in a platform to carry various
anticancer drugs to the local diseased regions.1–3
In many cases of biomedical applications, it is well
known that Au nanoparticles are demonstrated for molec-
ular imaging, drug delivery, in vivo cancer diagnosis
and therapy. The functional group of amino (–NH2and
thiol (–SH) groups can be used for bioconjugation to
Au nanoparticles (Fig. 2). At the nanosized range, Au
nanoparticles have high atomic density, and high surface
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Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
area. Therefore, these Au nanoparticles can absorb radi-
ation much more than tissue cells, thus resulting in a
better local radiation-driven treatment of tumors. There-
fore, Au nanoparticles are used in medical applications
with various large advantages and benefits. At present,
common and rare diseases are typically classified as car-
diovascular diseases, malignant/benign tumors, infectious
diseases, proliferative and inflammatory disorders, syn-
drome diseases etc.612–15 To treat some cases of cancers,
Au nanoparticles can be directly injected intravenously.
It is generally accepted that they are accumulated in the
diseased areas, where there are the blood vessels that
can carry them, and functional Au nanoparticles reach
tumor areas efficiently. In this field, Pt nanoparticles were
not much considered in in vivo cancer diagnosis and
therapy. On the other hand, Ag nanoparticles were pri-
marily used for preventing bacteria, against infectious
diseases. Moreover, Fe-based nanoparticles, e.g., Fe3O4
(Fig. 2(A)), -Fe2O3,FeS
2,Fe
3S4,Fe
3O4–SiO2, and oth-
ers have excellent biomedical applications in magnetic
hyperthermia and magnetic resonance imaging (MRI).20–23
Figure 1 shows the various types of important functional
particles, such as noble metal nanoparticles, dendrimers,
e.g., poly(amido)amine (PAMANs), ligands, liposomes,
polymeric micelles for studying normal and tumor cells,6b
mesoporous SiO2nanoparticles for treating breast can-
cer in vitro and in vivo,6c polymeric nanoparticles, and
quantum dots (QDs).6To enhance delivery therapy to the
local diseased areas, QDs are commonly used for can-
cer imaging and treatment with high contrast. To treat
diseases efficiently, artificial virus-based nanoparticles are
also designed in testing and treatment of effects of various
viruses, such as HIV-1.6d In addition, various other parti-
cles are also used as magnetic nanoparticles (Co, Ni, and
Fe-based nanoparticles as well as their alloy and core–shell
nanostructures), carbon nanomaterials, and virus-based
nanoparticles. Their typical applications will be very cru-
cial in a near future for clinical trials in humans. Recently,
innovative drug delivery, diagnosis, treatment, and ther-
apy of diseases with biomedical applications through DDS
micro, nano, and/or micronano systems have been com-
prehensively investigated and developed.19–23
To date, cancer is one of the most common diseases of
human society, which derives from an uncontrolled growth
of a single cell. In particular, cancer is caused by mutations
in DNA that lead to the unlimited growth of cells, which
often causes mortality in patients.
To treat some aggressive cancers, scientists try to
open up a new therapeutic approach that turns traditional
medicines based on natural herbs (curcumin, pomegranate,
green tea etc.) combined with clinical approach methods,
and based on the key foundation of modern nanomedicine
through nanotechnology,2425170b In particular, curcumin
is considered as one of the most powerful natural drugs
against many kinds of various cancers without side effects.
At the same time, curcumin seems to enhance specific
receptors of tumor cells towards some targeting-anticancer
drugs, and reduces the high toxicity of chemotherapy,
and radiation therapy for treating invasive cancers. Most
interestingly, curcumin has the high ability to fight breast
cancer, lung cancer, brain tumor, leukemia, liver, intes-
tine, esophagus, colon cancer, melanoma, and gynecologi-
cal cancers etc. Based on preclinical testing and scientific
research associated with clinical trials, the curcumin com-
bined with nanosystems (typically chitosan nanoparticles,
Au nanoparticles for detecting biological molecules, sil-
ica nanoparticles and various biofunctional engineered
nanosystems26) is very successfully and widely used as
DDSs. However, for biomedical applications, it has to
be emphasized that efficiently synergistic collaborations
between researchers and scientists in many various areas
are indispensable to develop useful biomedical and diag-
nostic solutions by nanotechnology and traditional phar-
maceutics. In principle, biomedical applications through
nanomaterials and nanotechnology need to adopt particle
systems in the size range of 1–100 nm being the most
useful advantage at clinical level.
2.1. Metal Nanoparticles
So far, noble metal nanoparticles, typically such as Au,
Ag, Cu, and Pt nanoparticles (in fact Pt complexes to
be preferred) etc. have been widely investigated in the
biomedical trials in the treatments of the known dis-
eases of animal and human. Metal nanoparticles with
the same sizes and morphologies generally lead uni-
form nanosystem as a platform for biomedical applica-
tions. At present, noble nanoparticles, e.g., Au, Ag, Pt
and their specific compounds show excellent applications
in nano-biomedicine, especially for intrinsic therapeutic
applications of noble metal nanoparticles.2627 Importantly,
Au nanoparticle has become one of the most practical
nanoparticles for nanomedicine. It can be used as thera-
peutic element, and drug delivery in a process of treating
cancer disease. Additionally, Au nanoparticles are chemi-
cally facilely synthesized with uniform characterization of
the size and the shape. In many reports, Au nanoparti-
cles have been investigated in anti-cancer nanotechnology.6
In recent years, the scientists have proved that the injec-
tion of Au nanoparticles for treating cancers selectively
influences tumor cells. Most importantly, the other cells in
the healthy normal tissues are not affected or they have
very small side effects by Au nanoparticles. In the assays,
Au nanoparticles exhibited exciting phenomena in Surface
Plasmon Resonance (SPR), and Surface-Enhanced Raman
(SER) bands for biomedical applications for detection of
biomolecules or biomarkers.6e
For biomedical application, silver (Ag) nanoparticle is
also of great importance. Most typically, the efficiently
practical ability and role of Ag nanoparticles are proved
for preventing, protecting, and killing various danger-
ous and harmful bacteria appearing in animal, human,
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Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
and agriculture. In this aspect, the unique capabilities of
Ag nanoparticles can be considered as “nano bullets” to
kill bacteria in clinical medicine and biology.28 Like Au
nanoparticles, at a nanosized range, antivirus activity of
Ag nanoparticles increases much higher than that of ion
Ag in solution. Notably, Ag nanoparticles significantly kill
most of fungal infections, harmful bacteria and viruses.
In particular, bacteria’s immunity cannot be developed in
respective to Ag nanoparticles’s effect. It is known that
Ag nanoparticles are considered to be non-toxic, non-
allergic, non-accumulation inside the body of human, and
they are also known to be friendly, and not harmfully to
the surrounding environments. Similar to Ag nanoparticles,
copper (Cu) nanoparticles with their efficiently powerful
antimicrobial characteristics are discussed,29 but Cu and
CuO possibly show a very high toxicity to health of human
at the high degree of doses and contents. Based on our crit-
ical review, the development of nanomedicine with the use
of nanomaterials and nanoparticles are very fast to ther-
apeutic applications.29–31 Recently, soluble Pt(II) species
have been efficiently used for treating cancers,3233 exploit-
ing their cellular uptake and DNA platination at nontoxic
dosages. In addition to biomedical applications, Pt and
Pt–Pd bimetal nanoparticles have potential applications of
catalyst materials for fuel cells. The main reasons are that
their synthesis processes have been facile and efficient by
chemical and physical methods,243435a and discussed in
detail.35b Thus, bimetal nanoparticles belong to a group
of bimetallic nanosystem with potential applications for
nanomedicine.
2.2. Magnetic Nanoparticles
In general, magnetic nanoparticles with various great
advantages because of unique magnetism show the most
practical and important applications in biomedicine.22ab
In the biomedical applications, magnetic nanoparticles are
mainly used in drug delivery, MRI, and contrast agents
in the efficient treatment of cancers. The most typical
Fe3O4,Fe
2O3,Fe
xOy, and Fe-based oxides are consid-
erably studied in meaning to be “magnetic carriers.”2236
Similarly, their ferrites, MFe2O4nanoparticles (M =Cu,
Ni, Co, Mn, Zn, and Mg) are also investigated for the
most interesting biomedical applications by significant
enhancement of high-contrast agents,36a typically such as
Ni1−xZnxFe2O4nanoparticles,36b and superparamagnetic
Fe oxide nanoparticles.40 Additionally, Co, Ni, Fe-based
nanoparticles can be considered as magnetic nanovec-
tors for drug delivery.36–42 These above results lead that
Co, Ni, and Fe-based bimetal nanoparticles were stud-
ied for the assays of biomedical applications in ani-
mal and human,36–40 especially MFe2O4nanoparticles,41
Fe–Pt nanoparticles with ferromagnetic properties.42 There
is much progress in applications of magnetic nanopar-
ticles in biomedicine in both theoretical and practical
aspects.4344 The onset of ferromagnetism at the nanoscale
was meaningfully discussed in detail in the cases of Pd
and Pt nanoparticles. To increase the stability and dura-
bility, the thin Au or SiO2coatings can be produced on
the surfaces of FePt and Fe3O4nanoparticles to form
novel core–shell nanosystems.44 They can potentially be
useful in biomedical applications with bioconjugates still
under further the investigations. At present, oxide tran-
sition nanoparticles are of interest to researchers. Metal
transition oxide nanoparticles, e.g., Co-based, Ni-based,
and Fe-based nanoparticles lead to be a group of magnetic
oxide nanosystems.45 In addition to the simple synthesis
and preparation methods, they are promising candidates
for MRI and biomedical applications,45–48 especially the
type of superparamagnetic nanoparticles for new drug
delivery systems.47 However, the biocompatibility and tox-
icity of nanoparticles and pharmaceuticals still need to be
further investigated in the long-term and short-term clini-
cal assays in animals and humans in terms of time, con-
tent and dose of pharmaceuticals.4950 Recently, controlled
MnFe2O4nanoparticles and Gd complex-based nanocom-
posites were used as tunable and enhanced T1/T2-
weighted MRI contrast agents.51a For that purpose in MRI,
superparamagnetic CoFe2O4nanoparticles (6 nm) were
facilely synthesized in oleic acid-water-pentanol system at
180 C.51b According to the recent results, superparamag-
netic Fe3O4nanoparticles show a variety of potential appli-
cations of MRI, cell separation, hyperthermia, and drug
delivery in biomedicine and nanomedicine because they do
not exhibit the permanent magnetism in the case of lack
of external magnetic field.
2.3. Alloy and Core–Shell Nanoparticles
Recently, novel Fe-based, Co-based, and Ni-based bimetal-
lic alloys and core/shell nanoparticles have extensively
discovered to be the best candidates, particularly empha-
sizing on the advantages of high stability and dura-
bility in biomedical applications.51–59 According to the
latest research results, currently -Fe2O3oxide, Fe–Pd,
Co–Pt, Fe–Pt (Fig. 2), and Fe–Pt–Pd, and complex
FePt–CdSe core–shell nanoparticles have been used for
medical applications.5455 In this context, there is no
research on Pt–Pd nanoparticles for treating cancers that
has been reported. On the contrary, the nanoparticles
were shown to be one of the most advantageous tools
in catalysis and fuel cells. Among Fe-based nanoparti-
cles, Fe–Pt nanoparticles can be very potentially used
for biomedical applications, such as MRI contrast agent
because of high bioadaptability, durability and stability but
some low toxicity. According to one research, dumbbell-
like PtPd–Fe3O4nanoparticles can be used for catalysis
and associated biomedical applications,56 Fe3O4–SiO2-Au
core–shell nanosystems,57 and other bimetal nanoparticles,
Au–Ag, Ag–Au core–shell bimetallic nanoparticles for
SPRs and SERs applications for detection of biomolecules
or biomedical molecules,58aband Fe3O4–SiO2(Fig. 2(B)),
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Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
oxide-based inorganic/organic and nanoporous spherical
particles,59 respectively.
3. SYNTHESIS
In traditional technology and modern nanotechnology,
chemical and physical synthesis methods or many com-
bined methods have been very successfully proved for
the facile preparation of metal, oxide and complex
nanoparticles.5859 At present, both bottom-up and top-
down technological approaches have been well applied
for producing nanoparticles with controllable size, shape,
morphology, and composition. The main differences
among the above preparation methods are just to be
the homogeneous or inhomogeneous characterization of
size, shape, composition, and structure of the prepared
nanoparticles. Typically, the successful preparation meth-
ods of shaping and controlling nanoparticles included co-
precipitation, thermal decomposition, reduction, micelle
synthesis, hydrothermal synthesis, sonoelectrodeposition,
ultrasonication, etc.5860 Sanchez and co-workers have dis-
cussed common synthetic routes of metal Fe-, Co-, and
Ni-P nanoparticles with the characteristics of their phase
diagrams.61 In this context, Cu-, Fe-, Ni-based nanoparti-
cles necessarily allows new biomedical applications. Gold
(Au) nanoparticles (100 nm) were prepared by modified
polyol methods.62 At present, Rh, Au, Pt, Pd, and Pt–Au
nanoparticles and their compounds are successfully syn-
thesized by polyol methods.63–71 The various sizes and
shapes of Pt nanoparticles were controlled in many size
ranges of 10 nm, 20 nm, and 30 nm in some our works
(Fig. 2). To date, Fe-based metal and bimetal nanoparticle
nanosystems are the most important products that are used
for biomedical applications.72–81 They can be produced by
various methods, such as polyol reduction, precipitation,
thermal decomposition, microemulsion, hydrothermal syn-
thesis under high pressure, sonochemical synthesis etc.
Significantly, Fe oxides possess a variety of specific
crystal structural phases, such as -Fe2O3,-Fe2O3,
-Fe2O3,Fe
3O4,etc.,
72–76 resulting in their various
biomedical applications. At present, scientists have just
very successfully used the pure Fe metal and Fe oxide
particles for biomedical applications. On the other hands,
bimetallic Fe nanoparticles are also promising candidates
towards scientific innovations in biology and medicine.77
In particular, the large -Fe2O3oxide particles were suc-
cessfully produced by polyol methods, drying and heat
treatment in air.78–80 In spite of large size, it is sug-
gested that the as-prepared -Fe2O3oxide microparticles
(microsystems) with the large size of 1–10 m (Fig. 1)
exhibited a superparamagnetic nature as the same as that of
Fe sulfide and Fe oxide nanoparticles (nanosystems) with
very small particle size.78 They can be used as potential
candidates for biomedical applications, such as treatment,
imaging, and therapy of tumors.
4. BIOMEDICAL APPLICATION
According to the recent practical applications, current par-
ticle systems for biomedicine can be classified in the dif-
ferent categories in respective to their particle size, such as
macroparticles (50–200 m), microparticles (1–100 m),
and nanoparticles (1–10 nm, 1–100 nm, even in a wide
range of 1–1000 nm). In addition, the definitions and
concepts of nanosized and microsized ranges can be
overlapped. A lot of special intention of scientists was
paid towards biofunctional nanosysems with the size of
nanoparticles around 10 nm and 30 nm,8283 although
their clearance of small nanoparticles out of human organ
and body is slower than that of large particles. In recent
works, only some reports have been given in accordance
with functional microparticles and their advantages with
biomedical applications about biology and medicine. This
is an open direction in the next studies of scientists. At
present, engineered nanoparticles combined with linkers
and bio-conjugates are being very necessarily tested in
biology and medicine or nanomedicine. They are noble
metal nanoparticles, such as Au, Ag, and Pt nanoparticles.
In fact, Au nanoparticles have very wide applications for
biosensor, molecular imaging, drug delivery, in vivo can-
cer diagnosis, and therapy. Comparing with Au nanopar-
ticles, Ag nanoparticles can be provided for SERs tests
in biosensing, and biomedical and chemical applications,
especially with the good antimicrobial effects. In addi-
tion to noble metal nanoparticles, dendrimers are also used
for biomedical applications, drug carriers, imaging agents,
gene delivery. Liposomes are widely studied for biomed-
ical applications in drug delivery, and gene encoding.
Another nanosystem, polymeric micelles, is used for drug
delivery (water-insoluble drugs) and nutraceutical deliv-
ery systems. In the biomedical applications, silica (SiO2
nanoparticles with advantage of more stability and dura-
bility than polymeric nanoparticles are widely used for
drug delivery.284 Among engineered nanosystems, poly-
meric nanoparticles are widely used for controlled release
of drug for cancer treatment, and applications for biosen-
sor, drug delivery, immunoassay, cell separation, protein
delivery, gene expression vector. A nanosystem, e.g., quan-
tum dots (QD) can be used as a platform for drug delivery,
diagnostics, medical imaging, and other biomedical appli-
cations. CdSe QDs can be used in drug delivery, diagnos-
tics and nanomedicine to enhance the efficacy of treating
the diseases of animal and human,285 for example QDs
versus organic dyes as fluorescent labels in photodynamic
therapy.8586 In recent years, the scientists have tried to
use carbon nanomaterials for biomedical applications.87
To prevent and kill dangerous diseases resulted from var-
ious viruses, and specific virus-based nanoparticles are
developed for testing and treatment of various viruses.
With the most advantages of drug delivery, MRI, high-
contrast agent, Co-, Ni-, and Fe-based magnetic nanopar-
ticles have been investigated in the biomedical assays.8788
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Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
In nanomedicine, the useful methods of surface function-
alisation of nanoparticles were proposed for biomedical
applications in many significant works.8990 In various sig-
nificant works, scientists proved that Au nanoparticles can
be potentially used for biosensor, in molecular imaging,
especially for drug delivery therapy, and the assays in vivo
cancer diagnosis and therapy, and other applications.91–100
Alternatively, Ag nanoparticles have potential biomedical
applications of preventing and killing infectious diseases,
such as harmful bacteria and viruses.101102 It is shown that
Ag and its compounds typically show a clear strong tox-
icity to many various bacteria, viruses, algae and fungi.
However, Ag and its compounds do not significantly show
toxicity to humans and if they are, that toxicity is very low.
It is certain that Ag nanoparticles proved typical biological
properties of anti-bacteria, and anti-inflammatory in their
growth and development of bacteria.101102 In addition, Ag
nanoparticles show very good drug delivery, and SERS
measurements for detection dyes in diagnosis and imag-
ing. An in vivo human time-exposure study of orally dosed
commercial Ag nanoparticles was presented. The authors
exactly demonstrated that 14-day monitored human oral
dosing of a commercial oral Ag nanoparticle product does
not produce observable clinical toxicity markers.103 There-
fore, fundamental parameters of toxicity thresholds and
levels of biomedical nanoparticles are used in human that
need to be further studied according to time, dose and
content, and the trials need to be studied in additional
organ systems of human. So far, Ag nanoparticles have
proved very high ability to prevent, block, destroy, and
kill bacterial infections in the assays,104 such as influenza
(A/H5N1), diarrhea (Escherichia coli), and cholera (Vibrio
cholera) but Ag nanoparticles have shown their possible
toxicology at high contents in biomedical applications.
Recently, functionally designed nanoparticles have been
discussed in medicine, biology, and nanomedicine (Fig. 1),
as well as fuel cells,6105–107 and typically for biosens-
ing applications with Pt nanowires.108109 In the out-
standing biomedical applications, Pt nanoparticles show
great potential for treating various cancers. In this case,
the scholars revealed that a fast ion radiation with Pt
nanoparticles improves future cancer therapy protocols.32a
Beyond Pt complexes and Pt nanoparticles, Au com-
plexes can probably be most useful as good anticancer
agents.32 Interestingly, a strategy was proposed on a com-
bination of Pt nanoparticles with irradiation by fast ions
used in “hadron therapy” towards lethal damage in DNA,
and other biomedical applications via Pt nanoparticles.110
Beside the above engineered nanoparticles, polymeric
nanoparticles in DDSs also show very good biomedical
applications in controlled release of drug, cancer treatment,
biosensors, drug delivery, immunoassay, cell separation,
protein delivery, and gene expression vector.111–116 Poly-
meric particles with high bio-adaptability can be obtained
from natural polymers or chemically-synthesized polymers
while magnetic nanoparticles with facile chemical synthe-
sis and preparation processes have very special biomedical
applications in vitro and in vivo analysis to animal and
human,117–127 such as Fe3O4nanoparticles and SiO2–Fe3O4
core–shell nanoparticles.117 In the former applications, Fe-
based nanoparticles are typically used for cell separation
and purification. In the latter applications, they can be
potentially used for targeted drug delivery, high-contrast
magnetic resonance imaging (MRI), and hyperthermia to
cancer treatment. Apart from Fe and Fe2O3oxide par-
ticles with micro- and nano-structures, other magnetic
nanoparticles associated with surfactants and polymer and
biofunctionalisation with biomolecules also offer good
biomedicine applications,121 specially emphasizing on Fe–
Pt, Fe3O4,CoFe
2O4,Fe
3O4–Au, Co–SiO2,Fe
3O4–SiO2,
Fe2O3–CdSe, and other Fe-based particles with core–
shell structures. The core–shell structures greatly show
advantages of biomedical applications in nanomedicine.
Ultra-large-scale syntheses of nanoparticles were presented
(Fig. 2(A)).
In comparison of the magnetic, radiolabeling, and
hyperthermic properties as well as biodistribution proper-
ties of hybrid nanoparticles bearing CoFe2O4and Fe3O4
metal or metal oxide cores,128 scholars proved that metal
cores can have a significant influence on the hyperthermic
properties of overall nanoformulation, and radiolabeling.
However, the properties of in vivo biodistribution remain
unaffected. Both the shell structure and the size seem to
have the significant influence on the in vivo fate of hybrid
magnetic nanoparticles. Among designed nanoparticles,
Fe-based superparamagnetic nanoparticles and their ferrite
compounds are abundant, cheap, and easy to be synthe-
sized for making various multifunctional particle systems
with bioconjugates. Recently, Franchini and his colleagues
have presented the assays of magnetic nanoparticles for
biomedical applications.128 The development of stable
aqueous suspensions of PEGylated superparamagnetic iron
oxide nanoparticles (SPIONs) has been intensively stud-
ied for those biomedical applications.129abSPIONs in MRI
technology enable important development in clinical imag-
ing. Beside nanoparticles discussed, recently we have suc-
cessfully synthesized TiO2nanorods.130 In this context,
TiO2is being a promising candidate to nanomedicine. Sci-
entists show that TiO2nanomaterials have good photo-
catalytic properties, good biocompatibility but they can
exhibit low toxicity in photodynamic therapy for cancer
treatment, drug delivery systems, and cell imaging.131
5. DRUG DELIVERY
At present, nanomedicine includes further studies of med-
ical diagnostics, nanotherapeutics, stem cells, and tissue
engineering.4In various biomedical applications, mag-
netic nanoparticles are efficiently surrounded by common
biodegradable polymers as carriers that can be lipo-
somes for drug delivery, erythrocytes for drug delivery
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Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
and cell separation, phospholipids for enzyme immobiliza-
tion, albumin for drug delivery and cell separation, starch
for drug delivery, MRI, and irradiation, poly(lactic acid)
for irradiation.132 With the above biomedical applications,
dextran carriers can be very efficiently used with mag-
netic nanoparticles for cell separation, enzyme immobi-
lization, MRI, drug delivery, and therapeutic hyperthermia.
Besides, chitosan, carboxydextran, polyalkylcyanoacry-
late, and polyethyleneimine carriers can be used with
magnetic nanoparticles for drug delivery. Different from
biodegradable polymers, and other common polymers, typ-
ically such as ethyl-cellulose, specific synthetic polymers,
polystyrene, and polymethylmetacrylate can be used with
magnetic nanoparticles. The category of ethyl-cellulose
is used for penetrating into artery. Specific synthetic
polymers are used for cell separation and for treat-
ing and kill various dangerous viruses. For the biofunc-
tionalization of the surfaces of engineered nanoparticles,
various polymers can be used with magnetic nanoparti-
cles for biomedical applications. In general, it includes
polyethylene glycol, dextran, and polyvinylpyrrolidone
(PVP) for enhancing circulatory system. Fatty acids are
used for stabilizing suspension system, and providing car-
boxyl groups. A typical polymer, e.g., polyvinyl alcohol
(PVA) is used for homogeneous dispersion of nanosys-
tems. Moreover, polyacrylic acids are used for increasing
high bio-compatibility of functional magnetic nanoparti-
cles. In the clinic assays, polypeptides, phosphorylcholine,
poly(lactide-co-glycolide), poly(N-isopropylacryl amide),
chitosan, and gelatin can be used for biomedical appli-
cations with magnetic nanoparticles. They are used with
Au and magnetic nanoparticles, and various nanoparticles
for drug delivery,132–145 especially as CoFe2O4nanoparti-
cles for the treatment of cancers.140141 Recently, against
glioblastoma,142 targeted delivery methods of Ag nanopar-
ticles and alisertib were carried out in vitro and in vivo
synergistic effect. Of course, nanoparticles have the most
advantages over microparticles in drug delivery. The small-
est capillaries in the body are 5 to 6 m in diameter.142b
The size of particles being distributed into the bloodstream
must be significantly smaller than 5 m, and should not
form aggregates, and ensure that the particles do not form
an embolism.
6. HYPERTHERMIA
In very exciting magnetic hyperthermia or therapeutic
hyperthermia, most of scientists utilize Fe-based parti-
cles that are directly injected into the local regions of
malignancies and heated by a magnetic field in their
research. This method is useful to treat various tumors.
When a magnetic field is applied, the particles vibrate and
generate heat under external magnetic field, which in turn
destroys the tumor cells. At a high temperature, tumor
cells can be destroyed by magnetic hyperthermia at a wide
range of heating temperature 41 C–70 C.6The com-
pounds containing Fe metal or Fe oxide particles (nanopar-
ticles and microparticles) are very commonly used in
magnetic hyperthermia. Specifically, scientists suggest that
external magnetic field is safe and not much harmful to
the body and organs of human. Therefore, the magnetic
nanoparticles are crucially used in biomedical applica-
tions of diagnosis and treatment of various diseases. The
large tumors are usually treated by hyperthermia. In recent
exciting advances of tumor therapies, efficacy of hyper-
thermia requires that temperatures within tumors remain
above 43 C for 30 to 60 min, while safety considerations
limit the operating temperatures in normal tissues to below
42 C. In special cases, temperature range of 40–46 C can
be used for treating seriously large tumors. It is clear that
superparamgentic nanoparticles, such as Fe3O4and Fe2O3
are typically used for therapeutic hyperthermia.146–151 The
necessary clinical trials are used for mouse, rat, and rabbit
or other animals. In fact, Au nanoparticles are also used
for the similar purposes of hyperthermia through the com-
parison of Surface plasmon resonance (SPR).133 Recently,
Cheon and co-workers have performed exciting anti-tumor
study in mice test.151a In comparison with CoFe2O4and
MnFe2O4nanoparticles, they found the most typical mag-
netism of CoFe2O4–MnFe2O4nanoparticles at 300 K
with the persuasively hard evidences of superparamagnetic
nature and zero coercivity (Fig. 3). The attractive results
have been shown to demonstrate the very good potential
of magnetic nanoparticles for nanomedicine in the treat-
ment of invasive cancers of liver, brain, breast etc. (Fig. 4).
Thus, the Co1−xZnxFe2O4nanoparticles can be prepared
for biomedical applications because of their specific mag-
netic properties.151 In addition, magnetic core–shell noble
metal/Fe-based oxide nanoparticles, such as Au–Fe2O3,
Au–Fe3O4, Au–CoFe2O4, etc. were used as MRI contrast
agents in cell culture with DNA-templated nanoparticle
chains.151b At the same time, they also discovered the
superior therapeutic efficacy of these nanoparticles to a
common anticancer drug. They have applied CoFe2O4–
MnFe2O4hyperthermia with the size of magnetic Co, Mn
and Fe based nanoparticles in the homogeneous range of
about 20 nm. They have investigated dose dependency
on tumor volume (measured 18 days) after the treat-
ment and tumor growth was well controlled. The tumors
become much smaller comparable to before treatment by
hyperthermia. For magnetic core–shell nanoparticle hyper-
thermia and doxorubicin treatments, doses (75 gand
300 g) were needed to nearly and completely eliminate a
tumor with a volume of 100 mm3. For Feridex hyperther-
mia, even very high 1,200 g nanoparticle dose did not
adequately suppress and treat tumor growth. Thus, the high
and good efficacy of core–shell ferrite nanoparticle hyper-
thermia was clearly proved in biomedical assays in mice.
Accordingly, the large tumors are greatly reduced in both
volume and size. It is suggested that the local hyperthermia
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Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
Figure 4. Potential biomedical applications of magnetic nanoparticles.
will be most usefully combined with chemotherapy. How-
ever, in our opinion, the long-term treatment of some cases
of tumor diseases will be done with nanomedicine. There-
fore, practical nanodrugs and therapies need to be inex-
pensive when they can be widely applied for human use.
7. MAGNETIC RESONANCE IMAGING
Magnetic nanoparticles offer very practical applications in
magnetic resonance imaging (MRI). In MRI technology,
nuclear magnetic moment of protons is used as a sen-
sitive probe of the chemical neighborhood of protons in
different tissues and organs of the human body.6119149a
In principle, nuclear moments are aligned by means of
an external magnetic bias field 0.2–3 T and precession
of the spins is excited by transverse RF pulses at the
proton resonance frequency of about 43 MHz T−1.149a
After applying the pulse sequence, the induced magne-
tization decays and the longitudinal (T1and transverse
(T2relaxation times of the processing nuclear magnetic
moments show tissue-specific differences that are used to
generate image contrast.149a Recently, Garwood and col-
leagues have proved quantification of Fe-oxide nanopar-
ticles at high concentration for thermal therapies.149b In
the latest outstanding research, the scientists show that
T∗
2mapping is difficult because of the very fast signal
decays in magnetism of magnetic nanoparticles. They dis-
covered that sweep imaging with Fourier transformation
(SWIFT) sequence is combined with the Look-Locker
method to map T1(Longitudinal/spin-lattice relaxation) of
Fe-oxide nanoparticles at high concentrations for thermal
therapies to overcome the current limitations of MRI. In
research efforts of scientists, Fe-oxide nanoparticles were
used with concentrations less than 53.6 mM. This is an
excellent finding, comparable to conventional methods of
T2(Transverse/spin–spin relaxation) or T∗
2mapping.149b
A new technique of the method of SWIFT MRI was also
applied for detection of breast cancer metastasis to the
lung with significant enhancement of MRI imaging.149c In
International workshop (2014) of MRI section, Professor
Garwood and scholars in his research group proved that
SWIFT method with the introduction of magnetic nanopar-
ticles into aqueous environments can be very clearly
visualized with positive contrast, and with a high Fe con-
centration up to at least 3 mg Fe/mL.149d In general,
imaging is well performed by controlling external field
gradients so that the resonance condition is fulfilled only
in a restricted local region, and then scanning the reso-
nant volume over the body part to be imaged. The tissue-
specific differences of the relaxation times T1and/or T2
or T∗
2can be used for construction of the so-called T1-
or T2-weighted images showing optimal contrast of tissue
features.149a However, most of the MRI treatments must
create a local impact mainly only on the tumor (diseased
region), and does not affect the different sections of differ-
ent cells and tissues of the healthy organs in the inside of
human. In ferromagnetic material, when the size of particle
is reduced into the nanometer-sized range, and at a cer-
tain critical value, their ferromagnetic properties are con-
verted into a typical superparamagnetic nature. However,
even Fe2O3oxide particles have the very large particle size
(1–10 m) with grain and grain boundary structures as the
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Long et al. Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles
same size as the cells in human body.78 They are known
as Fe2O3oxide particulates. It is indicated that they also
showed an important superparamagnetic feature. There-
fore, large Fe2O3oxide particles can be very promising
candidates in nanomedicine for the treatment of very large
tumors, such large brain tumors. The characteristics of
superparamagnetic nanoparticles depend strongly on mag-
netic field but this magnetism disappears when external
magnetic field is not supplied. This is the key foundation
in potential biomedical application for clinical MRI tech-
niques because the superparamagnetic nanoparticles with
nanodrugs will be controlled under magnetic field. They
can accumulate mostly only in the area of cancer tis-
sues for curing them more efficiently. There are not much
works and reports relating to Fe-based microsystems for
biomedical applications.155–158 Although Fe oxides show
high bio-adaptability, and the best bio-adaptability with
bioconjugates to the inner organs of animal and human,
their potential toxicity remained that side effects can occur
in the organs.153154 The proposed methods of molecu-
lar dynamics simulations were used for studying interac-
tion between Fe3O4and biocompatible polymer.155 This
clearly proved that they are layers attached with index
planes of Fe3O4. Certainly, MRI contrast enhancement was
achieved by the designed spinel ferrite nanoparticles,156157
such as MnFe2O4,andCoFe
2O4. At present, scientists
are of great interest in the large brain tumors through
functional magnetic microsystems, and nanosytems, espe-
cially critical for nanotherapeutic approaches for brain can-
cer management.158 Potentially, SPIONs are meaningful to
therapy and treatment of various malignancies. In this very
urgent area, we really need to create novel kinds of innova-
tive magnetic nanocarriers for drug delivery, imaging, and
therapy against large brain tumors.5On these cases, SPI-
ONs or Fe-based nanoparticles with the polymeric coating
of poly(lactic-coglycolicacid)-block-poly(ethylene glycol)
(PLGA-b-PEG) can be efficiently used as a multifunc-
tional platform to carry and deliver imaging and thera-
peutic agents to the local diseased areas inside the body
of animal and human in the clinic assays. In this way,
targeted drug delivery with polymeric nanoparticles could
significantly improve the ability of diagnostic and/or ther-
apeutic agents to reach locally their target inside the brain.
To achieve the aims, the diagnostic agents can be used as
iron magnetic (Fe) based nanoparticles with size and shape
control to determine MRI information. Fe-based nanopar-
ticles will be covered by organic molecules to entrap
the Fe-based nanoparticles inside polymeric nanoparticles.
Therefore, -Fe2O3,Fe
3O4or -Fe2O3Au–Fe3O4,Fe–Pt,
Fe–Pt–Pd, Fe–Co, especially as MnFe2O4,andZnFe
2O4
based nanoparticles will be used for the ultimate goals of
MRI in theranostic applications because of the enhanced
high-contrast imaging agents.159–162 In addition, magnetic
MnFe2O4nanoparticles with 100 nm are prepared by
chemical method.163 Here, the MnFe2O4nanoparticle-
based immunoassays are carried out for rapid detection
of influenza infections by using an integrated microflu-
idic system. When compared with the 4.5 m magnetic
beads, the optical signals of the MnFe2O4nanoparticles
were twice as sensitive. So far, health safety-toxicity and
risk assessments of nanomaterials on animal and human
health as well as the surrounding environments have been
clearly identified.164165 Because of possible toxicity of
nanomaterials, several important biomedical applications
have been limited in the trials in human. In this con-
text, scientists are trying to find the solutions to address
these problems. Notably, the cytotoxicity of nanoparti-
cle encapsulated AsPt compositions on the human were
confirmed at around 37 C in the clinic assays (in vivo,
in vitro,orex vivo cells, tissues, and other organs inside
animal and human).166 In such circumstances, the inten-
sive investigations of nanomaterials-related risks and ben-
efits are being carried out in various kinds of nanoparticles
for use, safety recommendations, specifications and stan-
dards, regulation and policy in products etc.,167–173 espe-
cially critical for toxicity and safety in environment, life,
and health of animal and human. The toxicity and its dif-
ferent effects of magnetic nanoparticles on animal and
human depending on time must be confirmed in the short
or long periods or permanent existence. Tomitaka and
co-researchers presented an in vitro cytotoxicity test of
Fe3O4and NiFe2O4, which was performed using human
cervical carcinoma cells (HeLa).168 Fe3O4nanoparticles
have the size of 20–30 nm, and NiFe2O4nanoparticles
have the size of 20–30 nm. The in vitro cytotoxicity test
showed that exposure of the NiFe2O4nanoparticles to
HeLa cells causes a significant dose-dependent reduction
in the cell number as compared to Fe3O4nanoparticles.
Thanh and colleagues discussed the low and high toxicity
of nanosystems in detail with various doses and content
of nanoparticles and nanodrugs used for most of tumor
cases.5b4354558990124170a For detection and quantifica-
tion of anticancer drugs tagged to Fe3O4nanoparticles,
Huong and coauthors have very successfully presented the
use of Fe3O4nanoparticles (10 nm) with alginate and
curcumin.170b The ultra-high detection sensitivity of the
biosensor shows a value of 30% that was used for checking
magnetic biomarkers in biological systems. In our main
viewpoints, the safely suitable levels of a specific dose
and content of targeting drug and nanoparticles must be
controlled at the lowest toxicity. In fact, only the limit of
very low toxicity can be reliably accepted for the treatment
methods and deliver therapy of oncological patients.
8. CONCLUSIONS
In this review, we have primarily focused on biofunctional
engineered particle systems in relation to potential and
practical biomedical applications of diagnosis and therapy
of life-threatening and common diseases in animals and
humans, especially for tumor diseases. The bioconjuga-
tion methods and techniques are also shortly introduced to
J. Nanosci. Nanotechnol. 15, 10091–10107, 2015 10103

Biomedical Applications of Advanced Multifunctional Magnetic Nanoparticles Long et al.
design multifunctional inorganic/organic particle systems.
Here, the particle systems can be micro-, nano- and hybrid
micronano-systems with bioconjugates for nanomedicine.
The concrete characterizations of size and shape, dose and
content of functional nanoparticles should be classified in
relation to efficacy of treating many diseases. Although
they are very promising candidates for medicine and biol-
ogy, they show a certain degree of toxicity for animals
and humans. The future challenges of next research in tra-
ditional biology and medicine, and nanomedicine will be
focused on clarifying the toxicological aspects of nanopar-
ticles and nanomaterials in in vitro and in vivo trials before
they can be widely introduced for their clinical use.
Acknowledgments: We greatly thank and appreci-
ate the financial supports and projects sponsored by
Chinese Academy of Sciences (Visiting Fellowship for
Researchers from Developing Countries, Grant No.
2013FFGB0007) and China Postdoctoral Science Foun-
dation (No. 2014M551462) from Shanghai Institute of
Ceramics, Chinese Academy of Sciences, and other Uni-
versities for our research on Novel Magnetic Nanoparticles
for Catalysis, Biology and Medicine (Nanomedicine). This
study was supported by a fund from the National Natural
Science Foundation of China (No. 51471182).
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