Leesh

FERRIMAGNETIC MgFe2O4 NANOPARTICLES
FOR INTRA-ARTERIAL HYPERTHERMIA AGENT

APPLICATIONS
LEE SANGHOON
(M. Eng.), NUS
A THESIS SUBMITTED
FOR THE DEGREE OF MASTER
OF ENINEERING
DEPARTMENT OF ELECTRICAL & COMPUTER

ENGINEERING
NATIONAL UNIVERSITY OF SINGAPORE
2012
Acknowledgment
I appreciate to my advisor, Professor Seongtae Bae. It is him who led me into
the nanomedicine and taught me how to think, talk, write and perform
experiments as an engineer as well as scientist.
I also need to thanks lab member, Minhong Jeun for his support and precious
time. He always supported and encouraged me, which helped me continuously
to focus on research.
I would like to thanks my parents and younger brother for their endless love,
which helped me overcome all the difficulties.
II
Table of Contents
Declaration....I
Acknowledgements..II
Table of Contents.......III
Summary .....V
List of Tables.....VII
List of Figures..... VIII
List of Symbols...........XI
Chapter 1. Introduction
1.1. Background and Motivation........1
1.2. Research Objectives...2
1.3. Organization of Thesis....3
Chapter 2. Literature review

2.1. Background of Magnetism
2.1.1. The Classification of Magnetism ...4
2.1.2. Soft and Hard Magnetic Materials...6
2.1.3. Magnetic Nanoparticle...7
2.1.4. Ferrite......10
2.2. Hyperthermia
2.2.1. History of Hyperthermia......13
2.2.2. Hyperthermia Methods.....14
2.2.3. Side Effects of Hyperthermia.......14
2.2.4. Future of Hyperthermia....15
2.3. Magnetic Hyperthermia
2.3.1. Magnetic Fluidic Hyperthermia........16
2.3.2. Heating Mechanism.....17
2.3.3. Specific Loss Power....20
2.4. Targeting Liver Tumors with Hyperthermia using Ferrimagnetic
Nanoparticle
2.4.1. Liver Cancer.....21
2.4.2. Treatment of Liver Cancer.......22
III
2.4.3. Arterial Embolization Hyperthermia....22

2.5. Synthesis of Magnetic nanoparticles......23
2.6. Synthesis of MFe2O4 as hyperthermia agents...26
Chapter 3. Experiment
3.1. Sol- gel Method...................27
3.2. Preparation Synthesis..27
3.3. Synthesis Procedures using Modified Sol-gel Method...................32
3.4. Characteristics Measurement .....38
Chapter 4. Results & Discussion
4.1 Ferrimagnetic MFe2O4 (M=Ni, Co and Mg) Nanoparticles
4.1.1. Physical Properties of Ferrimagnetic MFe2O4..47
4.1.2. AC Magnetically Induced Heating Characteristics of
MFe2O4 (M=Ni, Co and Mg)...48
4.1.3. The Magnetic Properties of MFe2O4 (M=Ni, Co and Mg).50
4.1.4. Biocompatibility.52
4.2. Ferrimagnetic MgFe2O4 Nanoparticles Modified by Modified Sol-gel
Method
4.2.1. Ferrimagnetic MgFe2O4 Modified by Calcining Process ..53
4.2.2. Ferrimagnetic of MgFe2O4 Modified by Sintering Process..63
4.2.3. Ferrimagnetic of MgFe2O4 Modified by Ball Mill Process...67
4.2.4. AC magnetically Induced Heating Characteristics in Solid and
Liquid States ....71
4.2.5. Emulsion Formation with Lipiodol and AC Heating
Characteristics in Emulsion states....79
Chapter 5. Conclusion & Future work .......83
Bibliogrphy.......86
IV
Summary
Ferrimagnetic Fe3O4 nanoparticles as a hyperthermia agent for liver cancer
have been limited by the large size and low specific loss power (SLP).
Accordingly, a new ferrimagnetic nanoparticle agent with a smaller size, a
narrower size distribution and a higher SLP, is required for intra-arterial
hyperthermia modality.
In this thesis, ferrimagnetic MFe2O4 (Ni, Co, Mg) nanoparticles were
synthesized by conventional sol-gel method to investigate and compare the
feasibility for a hyperthermia agent. AC magnetically induced heating
temperature (TAC,mag) of the synthesized nanoparticles in the size range of
30~40 nm in diameter was measured in solid state at the biologically and
physiologically tolerable range of magnetic field (Happ =140 Oe) and
frequency (fapp=110 kHz). In addition, MTT assay (methylthiazol tetrazolium
bromide test) using normal rat liver epidermal cells, was also investigated for
evaluating cytotoxicity.
In the second part, ferrimagnetic MgFe2O4 nanoparticles that exhibited the
fastest frequency response, the highest AC heat power generation and high
biocompatibility, were chemically and mechanically modified by a modified
sol-gel synthesis process in order to achieve higher SLP for intra-arterial
hyperthermia agent applications while maintaining a small size and a narrow
size distribution. Ferrimagnetic MgFe2O4 nanoparticles were synthesized by
controlling calcining temperatures (400 C, 500 C and 600 C) with the fixed
sintering temperature (700 C). Then, Ferrimagnetic MgFe2O4 nanoparticles
were synthesized by controlling sintering temperatures (700-900 C) with the
V
fixed calcining temperature (600 C) that exhibited the highest SLP. Finally,
ball milling process with different ball sizes (diameter : 5 mm, 3mm) was
added between the fixed calcining temperature (600 C) and sintering
temperature (850 C) in order to mechanically modify the nanoparticles. The
crystal structure, mean particle size, size distribution and magnetic properties
of the modified ferrimagnetic MgFe2O4 nanoparticles were measured to
investigate the effect of each process on the synthesized nanoparticles. In
addition, TAC,mag in solid state and a ferrofluid as well as emulsion state where
the oleic acid coated nanoparticles were mixed with lipiodol, was also
measured to evaluate the feasibility for the clinical use of liver cancer
treatment. The ferrimagnetic MgFe2O4 nanoparticles modified by calcining
temperature of 600 C, ball milling process (ball diameter: 3 mm) and
sintering temperature of 850 C, had proper size (~40 nm), narrower size
distribution (~20 %) and higher SLP (525 W/g) in a ferrofluid. In addition, the
oleic acid coated ferrimagnetic MgFe2O4 nanoparticles could be well mixed
with lipiodol and it exhibited high AC heating characteristics, enabling them to
be a suitable agent for the clinical use of liver cancer treatment in intra-arterial
hyperthermia modality.
VI
List of Tables
Table 2-1. Type of magnetism ...5
Table 3-1. Name, chemical formula and molecular weight of compounds used
in the sol-gel methods..31
Table 3-2. Name, chemical formula and molecular weight of additional
compounds used in the sol-gel methods.31
Table 3-3. The specification of Al2O3 balls..37
Table 4-1. Calculation results of hysteresis loss energy and the real
contributions of Phystersis loss to the Ptotal of the sample A, B, C and previous one
synthesized by conventional sol-gel method....60
Table 4-2. Mean size measured by FE-SEM and hydrodynamic diameter and
PDI measured by DLS.............................................................................77
VII
List of Figures
Fig. 2-1. MH curves are shown for the ferromagnetic (FM) injected particles,
where the response can be either multi-domain (in FM diagram), singledomain (in FM diagram) orsuperparamagnetic (SPM), depending on the size
of the particle...8
Fig. 2-2. The spinel Structure .....10
Fig. 2-3. Arrangements of metal ions in the two octants A and B, showing
tetrahedrally (A) and octahefrally (B) coordinated sites .......11
Fig. 2-4. Magnetic structures of normal and inverse spinels (a) normal
manganese ferrite, Mn Fe2O4 (b) inverse nickel ferrite, NiFe2O4 (c) normal
zinc ferrite, ZnFe2O4 ..........12
Fig. 2-5. Blood supply to the liver and hepatic tumour. The large, blue vessel
is the portalvein, and the thin red vessel is the hepatic artery which feeds the
tumor.....21
Fig. 3-1. (a) Sol-gel Systems (b) Three neck round bottom flask and magnetic
stirrer bar (c) Corning hot-plate/magnetic stirrer (d)TECPEL digital
thermometer (e) Ohaus digital analytical balance.............................28
Fig. 3-2. (a) Natural Convection Oven (b) Mortar and Pestle (c) Crucible (d)
Program Muffle Furnaces29
Fig. 3-3. Reactants used in sol-gel method (From left: Iron (III) nitrate
nonahydrate, Magnesium acetate tetrahydrate, Cobalt (II) acetate tetrahydrate,
Nickel (II) acetate tetrahydrate............................................................30
Fig.3-4. Chemicals and synthesis time for the modified sol-gel method.....33
Fig. 3-5. Change in calcining temperature of modified sol-gel method......34
Fig. 3-6. Schematic of a ball mill in cataracting motion ...........................35
Fig. 3-7. Change in ball milling process of modified sol-gel method.....36
Fig. 3-8. Change in sintering process of modified sol-gel method.........37
Fig. 3-9. Schematic Diagram of X-Ray Diffractometer .....38
Fig. 3-10. FE-SEM principle...............................................40
Fig. 3-11. Schematic diagram and picture of VSM ....................43
Fig. 3-12. Frequency & Magnetic field tunable AC inductive coil-capacitor
VIII
system .....44
Fig. 3-13. The scattered light falling on the detector and picture of DLS
..46
Fig. 4-1. Fig. 4-1. The sizes and the size distributions of CoFe2O4 (28.7 nm
6.7 nm), NiFe2O4 (34.3 nm 9.8 nm), and MgFe2O4 (30.3 nm 7.2 nm)
determined by an FE-SEM48
Fig. 4-2. AC magnetically induced heating characteristics of MFe2O4 (M=Co,
Ni, Mg)....49
Fig. 4-3. The magnetic major/minor systeresis loops of MFe 2 O 4
(M=Co, Ni, Mg)...50
Fig. 4-4. Iinitial M-H curve of MFe2O4 (M=Co, Ni, Mg)..51
Fig. 4-5. Cell survival rate of all the ferrimagnetic MFe2O4 (M=Co, Ni, Mg)
nanoparticles with normal rat liver epidermal cells....53
Fig. 4-6. XRD patterns of the sample A(400 C), B(500 C) and C (600 C)
fixed sintering temperature at 700 C.................................................55
Fig. 4-7. The sizes and the size distributions of the sample A (36 nm 10
nm), B (37 nm 11 nm), and C (58 nm 13 nm) determined by an FE-SEM.
..56
Fig. 4-8. The AC magnetically induced heating characteristics of the sample A,
B and C in solid state (60 mg) at the biologically tolerable range of frequency
and magnetic field (f appl = 110 kHz, H appl = 140 Oe). ......57
Fig. 4-9. Magnetic major hysteresis loop of the sample A, B, C.58
Fig. 4-10. (a) Magnetic minor hysteresis loops of the sample A, B and C at the
sweeping field of 140 Oe (b) The initial M-H loops of the sample A, B and
C.......59
Fig. 4-11. (a) The comparison of the Ms and Hc depending on the sample A, B
and C (b) Hc depending on the mean particle size of the sample A, B and
C.........61
Fig. 4-12. The AC magnetically induced heating characteristics of the
sample A, B and C in liquid state (5mg/ml in toluene) at the biologically
tolerable range of frequency and magnetic field (fappl = 110 kHz, Happl = 140
Oe). ............................................................................................................62
Fig. 4-13. Spicific loss power (SLP) of the samples in the range of frequency
an d magn et i c fi eld (fappl = 110 k Hz, Happ l = 1 40 Oe).
.....................................................................................................................63
IX
Fig. 4-14 (a) The XRD patterns of the samples (b) The mean size depending
on sintering temperature. ...........................................................................65
Fig. 4-15 (a) Magnetic minor hysteresis loops (b) The AC magnetically
induced heating temperature and the rate of temperature rise depending on the
sintering temperature in solid state (60 mg) at the biologically tolerable range
of frequency and magnetic field (f appl = 110 kHz, H appl = 140 Oe).
....................................................................................................................67
Fig. 4-16. The mean particle sizes and its size distributions of the sample I
(101 33 nm, Sdv.: 32 %), J (67.4 19.6 nm, Sdv.: 29%), and K (40.7 8.7
nm, Sdv.: 21.3 %) determined by an FE-SEM.......69
Fig. 4-17. Magnetic major hysteresis loop of the sample I, J and K........70
Fig. 4-18. Schematic of oleic acid coating ..71
sample A, B and C in (a) solid state (60 mg) and (b) liquid state (5 mg/ml in
ethanol) at the biologically tolerable range of frequency and magnetic field
(fappl = 110 kHz, Happl = 140 Oe). ....73
Fig. 4-20. (a) Magnetic DC minor hysteresis loops of the samples I, J and K in
solid states (b) Magnetic DC minor hysteresis loops of the OA coated sample I,
J and K in ferrofluids...73
Fig. 4-21. Hydrodynamic diameter measured by DLS76
Fig. 4-22. SLP of the sample I, J, K ..78
Fig. 4-23. Emusion formation with lipiodol by pumping method.80
Fig. 4-24. Emusion formation with lipiodol depending on mixing rate81
Fig. 4-25. The AC magnetically induced heating characteristics of the sample
A, B and C in (a) solid state (60 mg) and (b) liquid state (5 mg/ml in ethanol)
at the biologically tolerable range of frequency and magnetic field (fappl = 110
kHz, Happl = 140 Oe)82
List of Symbols
Ms saturation magnetization
Mr remanence magnetization
Magnetic moment per unit volume
Hc Coercivity
'' Imaginary susceptibility

m Magnetic susceptibility
0 is the permeability of free space

Ku Magnetic anisotropy constant
Energy barrier to moment reversal

Boltzmann constant
VH Hydrodynamic volume of particle

Viscosity of colloidal medium
H Applied magnetic field strength
f Applied magnetic field frequency
Nel relaxation time constant
Brownian relaxation time constant

Bragg angle
Full Width Half Maximum of diffracted x-ray beam intensity

Wavelength of x-rays
dhkl is the interplanar spacing

lattice parameter a
d crystallite size
D particle diameter
TAC,mag
AC magnetically induced heating temperature
SLP
Specific Loss Power
FE-SEM
Fied Emission Scanning Electron Microscope
XRD
X-Ray Diffraction
VSM
Vibrating Sample Magnetometer
XI
CHAPTER 1
INTRODUCTION
1.1 Background and Motivation

In recent years, although superparamagnetic nanoparticles through
intravenous injection have been primarily considered as a local hyperthermia
agent due to their bio-feasible small particle size and easy control of surface
modification
for
water
dispersible
(mono-dispersible)
nanofluids,
ferrimagnetic nanoparticles and the water dispersible ferrofluids have also

been used and considered as a hyperthermia agent due to their sufficiently
high AC magnetically-induced heating characteristics and other potential bioapplications such as a MRI contrast agent, a multi-functional drug delivery
agent and a cell targeting agent etc. Accordingly, ferrimagnetic Fe3O4
nanoparticles with a mean diameter of 100~200 nm have been clinically used
as a local hyperthermia agent for liver cancers through intra-arterial injection
[1,2]. However, the ferrimagnetic Fe3O4 nanoparticles were found to be
biotechnically limited by both "side effects" caused by severe aggregation of
the nanoparticles during intra-arterial injection due to a large particle size and
caused by the systematic problem required a large amount of nanoparticles
due to a lower specific loss power (SLP) at the biologically and
physiologically tolerable range of AC magnetic field [2-5]. Therefore, the
development of a newly designed ferrimagnetic nanoparticle agent, which has
a smaller particle size, a narrower size distribution as well as exhibits a higher
specific loss power (SLP), is urgently required for inter-arterial hyperthermia
modality.
1
CHAPTER 1. INTRODUCTION
MFe2O4 (Ni, Mg, Co) ferrite magnetic materials have been paid attention
to be a hyperthermia agent because of their wide range of size, diversity, and
chemical stability as compared to metal nanoparticles [3]. CoFe2O4 is a hard
magnetic material with large coecivity and high anisotropy energy leading to
large hysteresis loss [6]. NiFe2O4 and MgFe2O4 are soft magnetic materials
leading to relatively fast frequency response [7, 8]. Particularly, MgFe2O4
nanoparticles have been paid considerable attention to be a potential
hyperthermia agent [3, 4]. The main reason is that magnesium not only makes
magnetic property softer leading to a larger DC hysteresis area that is a crucial
factor but it is also a vital element which plays a major role in many metabolic
processes in the human body as well as in neuron bioelectric activity [6-7].
1.2. Research Objectives

The main objective of this thesis is the development and modification of
ferrimagnetic MgFe2O4 nanoparticles in order to achieve the clinical use of
liver cancer treatment in intra-arterial hyperthermia modality. The specific
objectives of this work were to:
1) investigate and compare AC heating generation ability of ferrimagnetic
MFe2O4 (Ni, Mg, Co) nanoparticles in the size range of 30~40 nm
synthesized by conventional sol-gel method
2) explore in-vitro cytotoxicity study of the ferrimagnetic MFe2O4 (Ni,
Mg, Co) nanoparticles using normal rat liver epidermal cells
3) modify ferrimagnetic MgFe2O4 nanoparticles by controlling calcining
2
temperatures, sintering temperatures and ball milling process,

respectively
4) investigate and compare AC heating generation ability of the modified
ferrimagnetic MgFe2O4 nanoparticles in solid state, a ferrofluid and
emulsion state that mixed with lipiodol
1.3. Organization of Thesis

Chapter 1 presents the background, motivations, and objectives of this
thesis. Chapter 2 reviews the current literature and describes in detail the
background information of the project. Chapter 3 presents synthesis methods
(conventional and modified sol-gel methods). In addition, the various
characterization techniques are introduced. In chapter 4, ferrimagnetic MFe2O4
(Ni, Mg, Co) nanoparticles are investigated and compared by AC heating
generation ability and biocompatibility. Furthermore, ferrimagnetic MgFe2O4
nanoparticles synthesized by the modified sol-gel method are also investigated
and compared. The physical and magnetic properties as well as AC heating
characteristics were also measured. Finally, chapter 5 concludes with a
summary of this thesis.
CHAPTER 2
LITERATURE REVIEW
This chapter reviews the current literature and describes in detail the
background information of the project. Also, the challenges faced in previous
studies are identified here.
2.1. Background of Magnetism

2.1.1. The classification of Magnetism
Magnetism is a property of materials that respond to an applied magnetic

field. If a magnetic material is placed in an applied magnetic field of strength
H, the individual atomic moments will contribute to an overall response
known as magnetic induction,
= 0 ( + ) .(2-1)
where is the permeability of free space and the magnetization M = m/V
is the magnetic moment per unit volume, where m is the magnetic moment on
a volume V of the material. The most commonly seen magnetic materials are
diamagnetism, paramagnetism, ferromagnetism, antiferromagnetism and
ferrimagnetism in terms of magnetic behavior depending on their bulk
magnetic susceptibility (m). It is the degree of magnetization (M) of a material
in response to a magnetic field (H). The magnetic susceptibility or m, where
4
CHAPTER 2. LITERATURE REVIEW
= ......(2-2)
In SI units m is dimensionless and both M and H are expressed in Am1. The
atoms in diamagnetic material have no magnetic moments and no spontaneous
magnetization. Also, the susceptibility of diamagnetic material is quite small
and negative (-10-6 < m < -10-3). In comparison, the atoms of paramagnetic
material have magnetic moments that are randomly oriented and the
susceptibility positive, but still small (10-5 < m < 10-5) [11].
Table 2-1. Type of Magnetism [11].
Ferromagnetic, antiferromagnetic, and ferrimagnetic are classified as magnetic

materials. As can be shown in Table 2-1, for a ferromagnetic material, all the
5
magnetic moments align in one direction, showing very strong interactions

even in the absence of a magnetic field. However, for a ferrimagnetic material,
the magnetic structure is composed of two magnetic sublattices; A and B,
separated by oxygen. Indirect or superexchange interactions mediated by the
oxygen anions result in an antiparallel alignment of spins between the A and B
sublattice where the magnetic moments are not equal and lead to a net
magnetic moment. It shows all the hallmarks of ferromagnetic characteristics,
spontaneous magnetization, hysteresis, remanence and Curie temperatures, but
it has very different magnetic ordering. Magnetite is a well known
ferrimagnetic material. [10].
2.1.2. Soft and Hard Magnetic Materials
Magnetic materials can be also widely classified into two different types:
soft magnetic materials and hard magnetic materials. Soft magnetic materials
have a small coecivity (Hc), low magnetic anisotropy (Ku), high magnetic
permeability and susceptibility so that they are easily magnetized or
demagnetized exhibiting a small hysteresis cycle. Soft ferrites such as
manganese ferrite, nickel ferrite and magnesium ferrite can be an example of
soft magnetic materials. On the other hand, hard magnetic materials show high
Hc, Ku, low magnetic permeability and susceptibility showing a large
hysteresis cycle caused by the difficulty of demagnetization. Hard ferrites,
aluminium-nickel-cobalt alloy and still can be examples of hard magnetic
materials.
2.1.3. Magnetic Nanoparticles
Magnetic nanoparticles are a class of nanoparticles which can be

manipulated using magnetic field. The particles commonly consist of magnetic
elements such as iron, nickel and cobalt and their chemical compounds.
Nanoparticle usually refers to particles with a diameter smaller than 1
micrometer (typically 5-500 nanometers) and those with diameters larger than
micrometer (0.5-500 micrometer) refers to microbeads. Nowadays, magnetic
nanoparticles have been received attention for bio-application owing to their
attractive properties. First, their controllable size ranges from a few
nanometers up to tens of nanometers, which means that they are smaller than
or comparable to those of a cell (10100m), a virus (20450 nm), a protein
(550 nm) or a gene (2 nm wide and 10100 nm long) enabling them not only
to approach a biological entity of interest, but also to be coated with biological
molecules for interacting with or binding to a biological entity [14]. Secondly,
magnetic nanoparticles can be manipulated by external magnetic field
gradients with the intrinsic penetrability into human tissue, opening up in
guided transport/delivery of drugs and genes, as well as immobilization and
separation of magnetically tagged biological entities [14, 15]. Thirdly, the
magnetic nanoparticles resonantly respond to a time-varying magnetic field
providing advantageous results. For instance, it transfers energy from exciting
field to the nanoparticles. It enables magnetic nanoparticles injected into
tumors to damage or necrotize the tumors by magnetically induced heating,
called hyperthermia treatment [16].
2.1.3-1. Unique Properties of Magnetic Nanoparticles
For ferromagnetic and ferrimagnetic materials, it exhibits irreversibility in

the magnetization process with sweeping field, H called hysteresis. It leads to
M-H curves called hysteresis loops. For magnetic nanoparticles, the shapes of
hysteresis loops are related to particle size. For large particles (of the order >1
micron), there is a multi-domain ground state which leads to a narrow
hysteresis loop since it takes relatively little magnetic energy to move domain
walls caused by low anisotropy due to the minimization of magnetic static
energy in the multi domains. For small particles (in the 100s of nanometer
range), there is a single domain ground state which leads to a broad hysteresis
loop. Even smaller sizes (of the order of tens of nanometer or less) than a
critical size of single domain, the particles undergo a magnetic transition from
ferro- or ferrimagnetic particles to superparamagnetic in nature referring to
superparamagnetism.
Fig. 2-1. MH curves are shown for the ferromagnetic (FM) injected particles,
where the response can be either multi-domain (in FM diagram), singledomain (in FM diagram) or superparamagnetic (SPM), depending on the size
of the particle[17].
Since the magnetization of a superparamagnetic nanoparticle can be easily

8
reversed by thermal fluctuations, it exhibits zero Mr or Hc without an external

magnetic field. However, it shows high magnetic moments under a net
external field. This leads to the hysteretic, but still sigmoidal, MH curve
shown in Fig. 2-4 [17].
The physics of superparamagnetism represented by an activation law for
the relaxation time, of the net magnetization of the particle [18, 19]
= .. (2-3)
where E is the energy barrier to moment reversal, and kBT is the thermal
energy. is the relaxation factor. For non-interacting particles the pre-
exponential factor is of the order 1010~1012s and only weakly dependent
on temperature [19]. The energy barrier has several origins, including both
intrinsic and extrinsic effects such as the magnetocrystalline and shape
anisotropies, respectively; but in the simplest of cases it has a uniaxial form
and is given by,
= . (2-4)
where K is the anisotropy energy density and V is the particle volume. is
the energy barrier to moment reversal or the amount of energy separating two
energetically equivalent easy directions of magnetization. When > ,
i.e. thermal energy ( ) exceeds the energy barrier (E), the magnetization is
flipped, and the particle exhibits superparamagnetism.

9
2.1.4. Ferrite
Ferrites are usually non-conductive ferrimagnetic ceramic compounds

derived from iron oxides such as hematite (Fe2O4) or magnetite (Fe3O4) as
well as oxides of other metals. Ferrites are used in electronic inductors,
transformers, and electromagnets due to the high electrical resistance leading
to very low eddy current losses.
2.1.4-1. Spinel Ferrite
Fig. 2-2. The spinel Structure (Closed-packed spheres)[12]
The general chemical formula of ferrites that have the spinel structure (i.e.
the same structure as the mineral spinel MgAl2O4) is MFe2O4, where M is a
divalent metal ion. M is usually a transition metal such as Mn, Fe, Co, Ni or
Cu, or Zn Mg or Cd, which is widely used for various applications. It is also
possible to make ferrimagnetic spinels that are solid solutions of two or more
ferrites, e.g. Mn-Zn and Ni-Zn ferrite. Furthermore, it is sometimes possible
10
for M to be a mixture of ions that have an average valence of 2.

The spinel structure is shown in Fig. 2-1. The relatively large oxygen ions
(Anion X) form an fcc lattice where there are 32 octahedral sites (i.e. sites
surrounded by 6 oxygen ions) and 64 tetrahedral sites (surrounded by 4
oxygen ions). However, in the spinel structure only 8 of the tetrahedral sites
and 16 of the octahedral sites are occupied by metal ions. These tetrahedral
and octahedral sites are referred to as A and B sites respectively (Fig. 2-2) [13].
Fig. 2-3. Arrangements of metal ions in the two octants A and B, showing
tetrahedrally (A) and octahefrally (B) coordinated sites[13].
2.1.4-2. Types of Spinel
Three different types of spinels are determined by the preference of cation

occupancy for A and B-sites. A normal spinel has its A-sites occupied by metal
M2+ cations and its B-sites occupied by Fe3+ ions. For inverse spinel, the Asites are occupied by Fe3+ ions and B-sites are randomly occupied by M2+ and
Fe3+ cations. If A and B-sites both contain a fraction of M2+ and Fe3+ cations,
the spinel is called a mixed spinel.
11
Fig. 2-4. Magnetic structures of normal and inverse spinels (a) normal
manganese ferrite, Mn Fe2O4 (b) inverse nickel ferrite, NiFe2O4 (c) normal
zinc ferrite, ZnFe2O4 [12].
The ferrites MnFe2O4, ZnFe2O4 and CdFe2O4 are known as normal spinels
because the divalent ions Mn2+, Zn2+ and Cd2+ ions occupy tetrahedral A sites.
This distinction between normal and inverse spinels is not rigid, since there
are many examples where ions of a particular species can be found on both A
and B sites in the same material, where the relative occupation depends on
12
composition, preparation conditions and heat treatment [12].
2.2. Hyperthermia
2.2.1. History of Hyperthermia
Hyperthermia as a treatment of cancer has been recorded since ancient

times. A fire stick was used to burn away a breast tumor by an Egyptian and
Induced fevers were shown to aid in the treatment of cancers in the late 19th
century. The hot metals and burning lenses were also used in cancer treatment
until the 19th century. After the early 20th century, high frequency currents
could generate in-depth heating of tissues. For instance, thermotherapy using
RF power, hot water coils and microwave became popular throughout the
1930s - 1950s. Even though some techniques such as chemotherapy and
radiotherapy have improved in the 1950s, there had been less interest in
hyperthermia therapy until 1970s which saw a resurgence in research into
hyperthermia [20].
Nowadays, hyperthermia techniques such as whole body, regional and
local hyperthermia are used in conjunction with other cancer treatment
modalities because they have been found to enhance the effectiveness of
radiation and some chemotherapeutic drugs [21]. However, there is still the
difficulty of heating a local tumor region to the desired temperature without
significant damage to normal tissue. Thus, the development of novel
hyperthermia systems that are able to heat tumor cells above 43C without
damaging normal tissues is required. Magnetic nanoparticle mediated
intracellular hyperthermia is a largely experimental modality for hyperthermia
13
application, which has the potential to overcome these drawbacks.
2.2.2. Hyperthermia Methods
There are 2 main ways in which hyperthermia can be used: Firstly, very
high temperatures are used to kill the cancer cells, coagulate the proteins, and
destroy the blood vessels. In effect, the area is exposed to the heat by radio
waves, microwaves, ultrasound waves, and other forms of energy. This is often
called local hyperthermia or thermal ablation.
Secondly, the temperature of a part of the body (or even the whole body)
can be raised to a higher than normal level. It is not hot enough to kill the cells
directly, but this can allow other types of cancer treatments such as radiation
therapy, immunotherapy, or chemotherapy to work better. This is known as
regional hyperthermia or whole-body hyperthermia [22].
2.2.3. Side Effects of Hyperthermia
Regional or local hyperthermia can lead to pain at the site, swelling,

infection, bleeding, blistering, blood clots, burns, and damage to the skin,
nerves, and muscles near the treated area. For whole-body hyperthermia, it can
give rise to nausea, vomiting, and diarrhea. More serious side effects can
include problems with the heart, blood vessels, and other major organs, though
rare. Experience, improved technology, and better skills in using hyperthermia
treatment have led to fewer side effects. In most cases, the problems that
people do have are not serious [22].
14
2.2.4. Future of Hyperthermia
Even though hyperthermia is considered as a promising way to improve

cancer treatment, it is largely an experimental technique at this time and is not
commonly used. Many clinical trials of hyperthermia are being done to better
understand and improve this technique. For instance, the induction heating of
magnetic materials, the use of nanoparticles that are implanted into tumors are
some new types of hyperthermia that are under study. And researchers
continue to look at how hyperthermia is best used along with other cancer
treatments to improve outcomes [22].
2.3. Magnetic Hyperthermia
Magnetic heat induction of magnetic nanoparticles provides various

advantages over conventional hyperthermia treatment. Firstly, magnetic
nanoparticles have the sizes ranging from a few tens of nanometers, and hence
are easily absorbed by tumor cells, which enhances the effectiveness of
delivering heat specifically to targeted tissue regions [23]. Second, the
magnetic fields in the harmless range to human body are used [24]. Thirdly,
magnetic nanoparticles can effectively cross the blood-brain-barrier, opening
up a new modality of treatment for brain tumors [25]. Fourthly, magnetic
nanoparticles can be easily manipulated in a colloidal form with numerous
drug delivery methods [26]. Finally, it can be functionalized for controlled
drug delivery of drugs, promising possible therapeutic approaches for treating
15
a number of diseases [27].

Based on this context, local hyperthermia using magnetic nanoparticles has
been considered to be a promising therapeutic modality of cancer treatment in
nanomedicine [5, 28].
2.3.1. Magnetic Fluidic Hyperthermia
The application of magnetic fluidic hyperthermia treatment was

investigated in the work of Chan et al. [29] and Jordan et al. [30] in 1993. The
high efficiency of a superparamagnetic suspension could absorb the energy
from alternating magnetic field and convert into heat generation, which was
experimentally demonstrated in these studies. Since tumor cells are sensitive
to high temperature than normal cells, increasing the temperature of tumor
tissue in vivo enables to destroy the pathological cells [28, 31]. Developing
nanotechnology has contributed to the improvement of magnetic fluid
hyperthermia for a few decades. This is a promising method for cancer
treatment owing to ease in targeting the cancerous tissue with fewer side
effects than radiotherapy and chemotherapy. The results of current/ongoing
clinical trials show significant reduction in side effects [30]. They injected 100
mg dextran magnetite into the tail vein of SpragueDawley rats, treated with
AC magnetic field (12 min, 450 kHz, unknown field and SAR), and saw tumor
shrinkage and tissue necrosis [31].
Rand et al. introduced additional radiofrequency heating up to more than
55 C on the renal surface of rabbits. In this way, total coagulation necrosis of
a renal cancer model could be achieved, possibly more as a result of the
16
hyperthermia treatment than caused by the occlusion [34, 35].

The first clinical patient trials [33] used a hyperthermia-generating
prototype instrument which is able to generate variable magnetic fields in the
range of 015 kA/m at a frequency of 100 kHz. The machine also enables to
measure the temperature of patient in real time so an examiner ensures
whether therapeutic temperature threshold is exceeded or not [36-49].
Currently, only local hyperthermia is considered for magnetic fluid
hyperthermia. For this purpose, magnetic nanoparticles in a carrier fluid are
placed inside the tumor through direct injection or tumor specific antibody
targeting, after which the tumor is exposed to an alternating magnetic field.
This field makes the particles generate heat by magnetic relaxation
mechanisms.
For hyperthermia treatments knowing the temperature profile obtained in
the tissues is of utmost importance. The ideal temperature profile is one where
the body temperature in healthy tissue is maintained, while the therapeutic
temperature of 45 C inside the tumor is reached immediately and maintained
constant. In reality these temperature profiles are not flat, neither in the tumor
nor in normal tissue, because of thermal diffusion.
2.3.2. Heating Mechanisms

2.3.2-1. Hysteresis Loss
Ferromagnetic
nanoparticles
generate
heating
by
hysteresis
loss
mechanism. Especially, DC minor hysteresis loss (or loss power, Physteresis loss)
17
dominantly contributes to the Ptotal (total heating power). Physteresis loss can be
expressed by
= , = ..(2-5)
where, 0 is the permeability of free space (4 x 10-7 H/m), f is the frequency
of the applied magnetic field, HDC,appl is the intensity of DC magnetic field, M
is the magnetization and A is the area of hysteresis loop. Total heating is
proportional to the frequency of the applied field and the area of the magnetic
hysteresis loop.
2.3.2-2. Relaxation Loss
Superparamagnetic nanoparticles show two different kinds of heat

generating mechanism, Nel relaxation and Brown relaxation mechanism. The
Nel relaxation mechanism is characterized by the rotation of the magnetic
spin moment. In this case, the magnetic anisotropy energy barrier of the
superparamagnetic nanoparticles needs to be overcome before the reversal of
the magnetization of the superparamagnetic nanoparticles can occur. Thus, the
intrinsic anisotropy (material, surface, shape etc.) and the volume of the
superparamagnetic nanoparticles affect the Nel relaxation time and hence the
heating efficiency of the superparamagnetic nanoparticles. The formula for the
Nel relaxation time constant is
18
= (
) . (2-6)
where 0 is the relaxation factor, K is the magnetic anisotropy energy density,
is the mean particle volume, kB is the Boltzmann constant, and T is the

absolute temperature.
The Brownian relaxation mechanism is characterized by the rotational

Brownian motion of nanoparticle itself. In this case, the energy barrier is
determined by the rotational friction within the medium. The viscosity of the
physiological medium it is immersed in and the hydrodynamic diameter
(nanoparticle core diameter plus any capping) will then influence the
Brownian relaxation time and hence heating efficiency. Thus, the formula for
the Brownian relaxation time constant is
.... (2-7)
where is the viscosity of the medium, is the hydrodynamic volume of the
particle, kB is the Boltzmann constant and T is the absolute temperature.
In the general case, the faster of the relaxation mechanisms is dominant

(i.e. shorter time constant) and the effective relaxation time when both
relaxation mechanisms take place in parallel is
.. (2-8)
19
For small field amplitudes, and assuming minimal interactions between the
constituent superparamagnetic nanoparticles, the imaginary part m of
magnetic susceptibility m is related to magnetic losses. The volumetric power
dissipation P is related to m according to the following equation:
= . (2-9)
where
is the out-of-phase magnetic susceptibility, is the amplitude of
the magnetic field and is the frequency of the field applied. This equation
can be interpreted physically as, if the magnetization M lags H, there is a
positive conversion of magnetic energy into internal energy. In the framework

of a linear response function, M = mH and where m is expressed as a complex
number, =

, where
becomes the loss component of
magnetic susceptibility.
2.3.3. Specific Loss Power (SLP)
Specific Loss Power (SLP) is useful for comparison with the heat
generating performance of magnetic nanoparticles. The heating capacity of
magnetic nanoparticles is given by the SLP:
(2-10)
where = ( ): specific volumetric heat capacity of the nanoparticle

20
and dispersion medium,
: change in temperature with respect to time (or
slope of the time-dependent temperature curve), : mass of the ferrite.

2.4. Targeting Liver Tumors with Hyperthermia using Ferrimagnetic
Nanoparticle
2.4.1. Liver Cancer
Hepatocellular carcinoma (HCC), or primary liver cancer, accounts for 80%

- 90% of all liver cancers. The cause of liver cancer is unknown, but
contributing factors include chronic liver disease, viral hepatitis, carcinogens,
and food toxins. Fig. 2.5 shows the blood supply to the liver and hepatic tumor
[51]. The tumor receives 95% of its blood supply from the hepatic artery,
while the normal liver tissue receives 75% of its blood supply from the portal
vein and the rest from the hepatic artery.
Fig. 2-5. Blood supply to the liver and hepatic tumor. The large, blue vessel is
the portalvein, and the thin red vessel is the hepatic artery which feeds the
tumor [51].
21
2.4.2. Treatment of Liver Cancer
Surgical resection or liver transplants are the optimal treatment options,

but for the 85%-90% of patients who are not eligible for this treatment
prognosis is poor and there is a need for alternative curative and palliative
treatments. New forms of local treatment are available, but large tumors are
still difficult to treat [51]. The differential in blood supply between hepatic
tumors and normal hepatic parenchyma (NHP) has been successfully exploited
in treatment modalities such as Hepatic Arterial Chemotherapy (HAC),
Selective
Internal
Radiotherapy
(SIRT)
and
Transcatheter
Arterial
Chemoembolization (TACE), which target liver tumors with chemotherapeutic

agents and radiation (Burton et al. 1989; Ho et al. 1998; Kemeny et al. 1999;
Campbell et al. 2000). However, chemotherapy and radiotherapy were limited
by side effects such as poor survival rates of patients. Therefore, the
development of targeted hyperthermia as a treatment is appealing because it
allows for a greater number of repeated localized treatments without limitation
by the accumulation of toxic side effects.
2.4.3. Arterial Embolization Hyperthermia (AEH)
Due to the advantage of the treatment using ferrimagnetic nanoparticles

such as the availability of selective treatment and combined with other
treatment, it has been studied for the past two decades as a local hyperthermia
agent for liver cancer [1, 2, 52].
Arterial Embolization Hyperthermia (AEH) is an experimental modality of
22
hyperthermia. It consists of the selective arterial embolization of liver tumors

with ferrimagnetic particles, followed by applied AC magnetic field to
generate hysteretic heating of the embolized particles.
Mitsumori et al. and Jones et al reported significant tumor response using
this technique. Paul Moroz et al. studied for hyperthermia targeted liver
tumors (hepatic VX2 carcinomas) with ferromagnetic embolization in a rabbit
liver tumor model. Magnetic iron oxide particles (Fe2O3, 100-200 nm) were
suspended in lipiodol, which was catheterized the cystic artery of a rabbit [1].
This study has demonstrated that hepatic arterial infusion of ferromagnetic
particles suspended in lipiodol results in excellent tumor targeting. However,
due to a large particle size (>150 nm) and a lower heating characteristic,
higher applied magnetic field (Happ = 376 Oe) at the frequency (fapp=53 kHz)
and a large amount of nanoparticles (100 mg) were required, causing the
aggregation of the nanoparticle agents during intra-arterial injection. Therefore,
the development of a newly designed ferrimagnetic nanoparticle agent, which
has a smaller particle size, a size distribution as well as exhibits a high specific
loss power (SLP), is urgently required for inter-arterial hyperthermia modality.
2.5. Synthesis of Magnetic Nanoparticles
Magnetic nanoparticles are a promising material for biomedical

applications as mentioned above. Naturally, the synthesis of magnetic
nanoparticles with controlled-size and a high degree of monodispersity has
been an interest of the scientific and engineering fields [53]. Over a few
decades, various synthetic methods have been established for the syntheses of
23
magnetic nanoparticles from physical methods to chemical methods. Due to

the advantages in controlling particle size distribution, crystallinity and
dispersity, the chemical methods such as co-precipitation, microemulsions,
high temperature thermal decomposition (HTTD), and sol gel techniques are
more suitable than physical methods for biomedical applications such as
magnetic resonance imaging (MRI) and hyperthermia.
Co-precipitation
Co-precipitation is a simple and convenient approach to synthesis iron
oxides from simultaneous precipitation of Fe2+/Fe3+ ions in basic aqueous
media [54,55]. Generally, the co-precipitation technique involves the complex
hydrolysis equilibria of ferric and ferrous ions. The size, shape, and quality of
the synthesized magnetic nanoparticles depends largely on a large number of
synthetic parameters such as the type of salts used (e.g. chlorides, sulfates,
nitrates), the Fe2+/Fe3+ ratio, the reaction temperature, the pH value and ionic
strength of the media. They are difficult to control and require careful
adjustments during the experiment [53, 56, 57]. As particles prepared by coprecipitation are unfortunately difficult to control, this method tends to yield
particles with a broad size distribution of greater than 50% [58]. Despite the
intrinsic problems such as large polydispersity, broad size distribution and low
degrees of crystallinity, this approach is well-documented and allows mass
production of magnetic iron oxide particles with good reproducibility [56, 59,
60].
Microemulsions
24
Water-in-oil (W/O) microemulsions (i.e. reverse micelle solutions) are

transparent, isotropic, thermodynamically stable liquid media. In these
systems, fine microdroplets of the aqueous phase are trapped within
assemblies of surfactant molecules dispersed in a continuous oil phase. The
surfactant-stabilized microcavities (typically in the range of 10 nm) provide a
confinement effect that limits particle nucleation, growth, and agglomeration
[61]. This microemulsion method offers the advantage over the co-precipation
method for producing nanoparticles with better size control, but results in
complicated purifying procedures to remove surfactants, low yield and is
difficult to scale up.
High Temperature Thermal Decomposition (HTTD)

This procedure involves the high temperature thermal decomposition of
organometallic precursors in high boiling organic solvents in the presence of
stabilizing surfactant molecules that regulate the nucleation and growth
kinetics of the particles. In principle, the ratios of the starting reagents (such as
organometallic compounds, surfactant and solvent), the reaction temperature,
reaction time, and aging period are critical parameters for the control of the
size and morphology of magnetic nanoparticles [60]. High quality samples, in
terms of crystallinity and size dispersion, can be produced in reasonable
amounts, and the approach can be scaled up [59]. As a result, HTTD is a
popular and efficient method that is used for nanoparticle synthesis. It
provides good particle size control, monodisperse particles, high degree of
crystallinity of synthesized particles and easy and economic synthesis
procedures.
25
2.6. Synthesis of MFe2O4
Sun et al. found the synthesis monodispersed MFe2O4 (M=Fe,Co,Mn)

nanoparticles by simply changing the metal acetylacetonate precursor that is
to be added to the mixture of Fe(acac)3 and 1,2-hexadecanediol [53]. They
also found that higher reaction temperatures cause larger particle size as well
as they introduce a surface manipulation step (by mixing with a bipolar
surfactant, tetramethylammonium 11-aminoundecanoate) to make them
water-soluble.
MgFe2O4 nanoparticles have been synthesized by many groups with
various ways. However, a few groups have dealt with MgFe2O4 nanoparticles
as hyperthermia agents. Maehara et al. studied the heating of MgFe2O4 powder
by an AC magnetic field (fapp=370 khz, Happ=400 A/m 5 Oe) for thermal
coagulation therapy. The size of the MgFe2O4 purchased from Kojundo
Chemical Laboratory Co. Ltd were 2~10 um (99.9%) and the heating ability in
the AC magnetic field was 1.4 W/g [4].
Asahi Tomitaka et al. studied evaluation of magnetic and thermal
properties of ferrite nanoparticles including MgFe2O4 by an AC magnetic field
(fapp=10 khz, Happ= 50 ~ 500 Oe). The size of the MgFe2O4 were 27.4 9.2 nm,
34.4 16.1 nm, 130.2 40.7 nm synthesized by sol-gel method demonstrating
that the optimum field strength of the MgFe2O4 is 100 150 Oe and MgFe2O4
nanoparticles are not suitable for biomedical application due to their low
magnetization. However, it showed high viability of human cervical
carnimoma cells (HeLa cells) [3].
26
CHAPTER 3
EXPERIMENT
3.1. Sol-gel Method
The sol-gel method is a wet-chemical technique and widely used in the

fields of material science and ceramic engineering. In this process, the sol
evolves gradually towards the formation of a gel- like network containing both
a liquid phase and a solid phase. The basic structure or morphology of the
solid phase can range anywhere from discrete colloidal particles to continuous
chain-like polymer networks. It also is an efficient method for preparing
nanomaterials, and it enables high yield and more promising results of the
synthesis of ultra fine particles with good chemical homogeneity, high purity
at a fairly low temperature [62, 63].
In this work, the conventional sol-gel method that included only sintering
process was used for the synthesis of ferrimagnetic MFe2O4 (M=Co, Ni, Mg)
nanoparticles. However, a modified sol-gel method, consisted of calcining
process, ball milling process and sintering process, was used for the synthesis
of modified ferrimagnetic MgFe2O4 nanoparticles.
3.2. Preparation of Synthesis

3.2.1. Equipment
Fig. 3-1(a) shows sol-gel systems that consist of three neck round bottom
flask (Fig. 3-1(b)), coil condenser and hot-plate/magnetic stirrer (Fig. 3-1(c)).
27
CHAPTER 3. EXPERIMENT
It was used for sol-gel formation. The liquid temperature inside three neck
round bottom flask was measured by TECPEL digital thermometer (Fig. 31(d)). Digital analytical balance was used for the weight of powders.
Fig. 3-1. (a) Sol-gel Systems (b) Three neck round bottom flask and magnetic
stirrer bar (c) Corning hot-plate/magnetic stirrer (d)TECPEL digital
thermometer (e) Ohaus digital analytical balance
28
Fig. 3-2. (a) Natural Convection Oven (b) Mortar and Pestle (c) Crucible (d)
Program Muffle Furnaces
A natural convection oven for removing unnecessary chemicals, mortar
and pestle for grinding, crucible and program muffle furnaces for baking, were
used for calcining process. It is shown in Fig. 3-2.
29
3.2.2. Chemical and Reagents
The chemicals and reagents were required for the synthesis of

ferrimagnetic MFe2O4 (M=Co, Ni, Mg) nanoparticles using the sol-gel
methods.
First, Iron (III) nitrate nonahydrate (98+%) was used as a metal precursor,
providing Fe3+ ions, which is highly soluble in organic solvents. Magnesium
(II) acetate tetrahydrate, in the form of powder, contributed to the required
Mg2+ ions for magnesium ferrite formation. For nickel ferrite formation,
Nickel (II) acetate tetrahydrate, in the form of powder, was used for the
required Ni2+ ions. Cobalt (II) acetate tetrahydrate, in the form of powder,
contributed to the required Co2+ ions for cobalt ferrite formation. Fig. 3-3
shows the picture of powders from Sigma-Aldrich and Table 3-1 shows the
name, chemical formula and molecular weight of compounds used in the solgel methods.
Fig. 3-3. Reactants used in the sol-gel methods (From left: Iron (III) nitrate
nonahydrate, Magnesium acetate tetrahydrate, Cobalt (II) acetate
tetrahydrate, Nickel (II) acetate tetrahydrate
30
Chemical
Name of Reagents
Linear Formula
Molecular
Weight
Fe(NO3)39H2O
404
(CH3COO)2
Mg 4H2O
214.4
Ni (OCOCH3)2
4H2O
248.84
(CH3COO)2 Co
4H2O
249.08
Formula
Iron (III) nitrate
nonahydrate
(98+%)
Magnesium acetate
tetrahydrate
(99.999%)
Nickel (II) acetate
tetrahydrate
(99.998%)
Cobalt (II) acetate
tetrahydrate
(98%)
Table 3-1. Name, chemical formula and molecular weight of compounds used
in the sol-gel methods
Name of
Linear
Compound
Formula
Molecular
Weight
Acetic Acid
CH3CO2H
60.05
2Methoxyethanol
CH3O CH2 C
H2 OH
76.09
Ethylene Glycol
HOCH2 CH2OH
62.07
Chemical Formula
Table 3-2. Name, Chemical Formula and Molecular Weight of additional

chemicals used in the sol-gel methods
31
Secondly, three other chemicals; Acetic acid, 2 Methoxyethanol and

Ethylene Glycol were also necessary for the sol-gel methods. Acetic acid
serves as a catalyst increasing the rate of hydrolysis. 2-Methoxyethanol serves
as solvent. Finally, ethylene glycol serves as a precursor to polymers. The
chemical formula and molecular weight of chemicals are shown in Table 3-2.
3.3. Synthesis Procedure using Modified Sol-gel Method
The experimental procedure of modified sol-gel method consists of three

stages. The first stage is the preparatory stage, which is the preparation of the
reagents/chemicals to be added and mixed together in the three neck round
bottomed flask. The second stage is heating and stirring of the mixture for sol
and gel formation using magnetic stirrer/hot plate. The final stage is to control
temperature of furnace for the formation of nucleation and growth of magnetic
nanoparticles using the program muffle furnaces.
3.3.1. Preparatory Stage
A stoichiometric molar proportion (8 mmol/ 4 mmol) of iron(III) nitrate

nonahydrate [Fe(NO3 )3 9H2O] (3.308 g) and magnesium acetate tetrahydrate
[Mg(CH3CO2)2 4H2O] (0.874 g), were used as a metallic powder precursor
for MgFe2O4. For NiFe2O4 and CoFe2O4, [Ni(CH3CO2)2 4H2O] (1.014 g) and
[Co(CH3CO2)2 4H2O] (1.015 g) were used, respectively. These starting
materials put in the three neck flask and 10 ml of ethanol was added during the
32
stirring on the hot plate/magnetic stirrer.
3.3.2. Sol-gel Formation Stage
The starting materials and ethyl alcohol were well mixed in the three neck
flask. After 10 minutes, 1 ml of acetic acid was slowly added as a catalyst,
which increases the rate of hydrolysis. After 20 minutes, 2-methoxyethanol (2MOE) was slowly added as a solvent. As can be seen in Fig. 3-4, the rest of
chemicals including H2O, ethylene glycol, ethyl alcohol were added together
during heating and stirring process until the solutions became a gel states. The
chemically synthesized gelatin state stock solutions by the metallic powder
precursor and the solvent were dried at 100 C in oven to remove the chemical
binders.
Fig. 3-4. Chemicals and synthesis time for the sol-gel methods
33
3.3.3. Baking Stage

3.3.3-1. Controlling Calcining Temperature
The modified sol-gel method includes this calcining process. However, the
conventional sol-gel method does not include this calcining process. After 1
day, the dried sample was well ground using mortar and pestle (Fig. 3-2 (b))
then, it put into the crucible (Fig. 3-2 (c)) and it was calcined at temperatures
(400 C, 500 C and, 600 C), respectively for 1 hour using programmable
muffle furnaces (Fig. 3-2 (d)). After finishing completing the calcining process,
the sample was well ground by using mortar and pestle.
Fig. 3-5.Change in calcining temperature of modified sol-gel method
3.3.3-2. Ball Milling Process
The well-ground samples from the calcining process were put into a mill
and rotated for the ball milling process. The speed of the mill is an important
34
factor because it influences the trajectory of the balls and mechanical energy
supplied to the powder. Defining the critical speed of rotation as the speed
required to take the balls to the apex of revolution, the critical speed can be
defined as,
= ( ) ...(3-1)
, where r is the radius of the mill and g is the acceleration due to gravity. In
practic, ball mills are operated at ~75% of the critical speed so that the balls do
not reach the top of the mill (Fig. 3-6).
Fig. 3-6. Schematic of a ball mill in cataracting motion
In addition, the ball milling process does not lend itself easily to rigorous
theoretical analysis so empirical relationship of rate of milling can be defined
as,
....(3-2)
35
, where A is numerical constant that is specific to the mill being used and the
powder being, a is the radius of the mill, is the density of the balls, d is the
particle size of the powder, and r is the radius of the balls. Based on this
equation, the change in the size of balls (diameter : 3 mm and 5 mm) keeping
the rate of milling with other experimental conditions, resulted in the change
in the size of nanoparticles. The milling time was limited within 6 hours to
avoid undesired side effect such as induced heating. For 6 hours, the induced
heating was less than 3 C.
Fig. 3-7.Change in ball milling process of modified sol-gel method
The information of Al2O3 balls that was used is shown in table 3-3. Based
on the information which was calculated by theoretical equation, the weight
ratio between the balls and the powders was set approximately 8:1 [64].
36
Table 3-3. The specification of Al2O3 balls
3.3.3-3. Controlling Sintering Temperature
After ball milling process, the samples put into programmable muffle
furnaces and they were sintered at the temperatures (700 C, 750 C, 800 C,
850 C and, 900 C). Then, the nanoparticles (in powder form) were ground by
using mortar and pestle. This concludes the synthesis of magnetic
nanoparticles.
Fig. 3-8.Change in sintering temperature of modified sol-gel method
37
3.4. Characteristics Measurement
3.4.1. X-ray Diffractometer (XRD)
Fig. 3-9. Schematic Diagram of X-Ray Diffractometer [66].
The crystal structure of the magnetic nanoparticles was measured by

Siemens Powder X-ray Diffractometer with CuK radiation. X-ray diffraction
is quite a common technique for the study of atomic spacing and crystal
structures.The monochromatic X-ray generated by a cathode ray tube and
filtered, are collimated to concentration, and directed toward the substance.
When
Bragg`s
Law
(n=2d sin )
that
relates
the
wavelength
of
electromagnetic radiation to the diffraction angle and the lattice spacing in a

crystalline sample, is satisfied, the interaction of the incident rays with the
sample produces constructive interference. Then, the diffracted X-rays are
detected, processed and counted (Fig. 3-9).
In order to obtain all possible diffraction pattern, the detector (or a sample)
38
rotates to various 2 angles to measure diffraction from the sample [66].

Conversion of the diffraction peaks to d-spacing enables identification of the
substance because each substance has a set of unique d-spacing. Normally, it is
achieved by comparison of d-spacing with standard reference patterns [65].
Also, the lattice parameter a, can be determined from the following equation:
+ +
................................................(3-3)
where dhkl is the interplanar spacing and hkl are the Miller indices.
3.4.2. Field Emission Scanning Electron Microscopy (FE-SEM)
The mean size and size distribution of the magnetic nanoparticles were
measured by FE-SEM (JSM series). A FE-SEM is a microscope that works
with electrons that are liberated by a field emission source. The object is
scanned by electrons according to a zig-zag pattern. The field emission
cathode in the electron gun provides narrower probing beams at low as well as
high electron energy, resulting in both improved spatial resolution and
minimized sample charging and damage. The electrons generated by a field
emission source are accelerated in a field gradient,
= .. (3-5)
where V is the applied voltage on the tip, and r is the radius of the tip. A
39
smaller tip enables a larger field and more electrons. The electrons can be
focused by magnetic lenses (Fig. 3-10). Furthermore, an accelerated electron
excites a secondary electron from another atom and the secondary electrons
that are released from a depth of 1-5 nm can be detected by FE-SEM. Raised
areas of a sample will produce more secondary electrons and appear as bright
spots in the image compared to trenches and valleys, which will appear as dark
spots [67].
.
Fig. 3-10. FE-SEM Principle [67]
3.4.3. Vibrating Sampled Magnetometer (VSM)
The magnetic characteristics of the synthesized nanoparticles including

magnetic major hysteresis loop (15 kOe), minor hysteresis loop (140 Oe)
40
and initial M-H loop were measured by VSM of Lake Shore 7400 series (Lake
Shore Cryotronics, Inc) in order to investigate their dependence on the
synthesis condition.
The principle of VSM is to measure the electromotive force induced by the
rotating magnetic sample with a constant frequency under the presence of a
static and uniform magnetic field. According to Faradays Law, the
electromotive force induced in the sensing coil is:
(3-6)
Where is the magnetic flux and t is time. The magnetic induction B inside
of a solenoid coil of cross-sectional area A consisting of N turns is,
(3-7)
From equation 3.6 and 3.7, we can get the equation,
... (3-8)
The magnetic moment of the sample may be written as
() = () .. (3-9)
41
where f is the frequency at which it is vibrating and m0 is the amplitude of the

magnetic moment. Since = + , where the volume magnetization
= , H is constant,
()
.(3-10)
Substituting equation 3.10 into 3.8, we obtained,
= (
)() . (3-11)
= ..(3-12)
where, is voltage induced in the coils, m0 is magnetic moment, A is
amplitude of vibration (1.4mm), f is frequency of vibration (82 Hz) and S is

sensitivity function of the coils [70].
The schematic diagram of detection-coil arrangement and picture of VSM
are shown in Fig. 3-11.
42
Fig. 3-11. Schematic diagram [70] and picture of VSM
43
3.4.4. Frequency & Magnetic field tunable AC inductive coil-capacitor

system
A specially designed frequency and magnetic field tunable AC inductive

coil-capacitor system (Fig. 3-12) is composed of a wave generator, a high
frequency amplifier, and magnetic induction coils. AC magnetic-field-induced
heating temperature (Tac,mag) of magnetic nanoparticle both in a solid and
liquid were measured using this system in the range of magnetic field (Happl =
140 Oe) and frequency (fappl = 110 kHz) that were fixed for the measurement
in the biologically tolerable ranges of magnetic field.
Fig. 3-12.
Frequency & Magnetic field tunable AC inductive coil-capacitor

system
3.4.5. Dynamic Light Scattering (DLS)
A Zetasizer Nano ZS Dynamic Light Scattering by Malvern Instrument

Ltd. was used to measure hydrodynamic diameter, its distribution and PDI of
44
the nanoparticles. For the consistent preparation, the same amount of

nanoparticles (Powder) was prepared for coating process and it was conducted
by same coating condition. After that, the concentration of coated
nanoparticles was measured by VSM. All samples were diluted as 0.1 mg/ml
(The minimum concentration for the samples in the range of diameter from 0.3
nm to 10 um). It filled into a specific unique cell for the Zetasizer Nano ZS.
The machine shows the mean values after measuring more than ten times.
Dynamic Light Scattering (Photon Correlation Spectroscopy) measures
Brownian motion that relates to the size of the particles by illuminating the
particles with a laser and analyzing the intensity fluctuations in the scattered
light. If a small particle is illuminated by a light source, light is scattered by
the particle in all directions. Then, the screen that is held close to the particle
will be illuminated by the scattered light. The screen would show a speckle
pattern that will consist of areas of bright light and dark areas where no light is
detected [71].
The diagram below shows the propagated waves from the light scattered
by the particles in Fig. 3-13(a). The bright areas are the light that are scattered
by the particles arrived at the screen with the same phase and interferes. On
the other hand, the dark areas are where the phase additions are mutually
destructive and cancel each other out.
The particles are continuously moving due to Brownian motion due to the
random collision with the molecules of the liquid. The relationship between
the size of a particle and its speed due to Brownian motion is defined in the
Stokes-Einstein equation (Eq. 3.13). The diffusion of spherical particles
through liquid is,
45
..(3.13)
,where kB is the Boltzmann constant, and T is the absolute temperature, r is the

radius of the spherical particle and is viscosity.
As the particles are constantly in motion the speckle pattern will also
appear to move. As the particles move around, the constructive and destructive
phase addition of the scattered light will cause the bright and dark areas to
grow and diminish in intensity - or to put it another way, the intensity appears
to fluctuate. The Zetasizer Nano system measures the rate of the intensity
fluctuation and then uses this to calculate the size of the particles [71].
Fig. 3-13. (a) The scattered light falling on the detector (b)The picture of DLS
[71]
46
CHAPTER 4
RESULTS & DISCUSSION
4.1. Ferrimagnetic MFe2O4 (M=Co, Ni, Mg) Nanoparticles
Ferrimagnetic MFe2O4 (Ni, Mg, Co) nanoparticles were synthesized by

conventional sol gel method to investigate and compare the feasibility for an
intra arterial hyperthermia agent. In order to evaluate and compare AC heat
generation ability of the synthesized ferrimagnetic nanoparticles that had the
size range of 30~40 nm, TAC,mag (AC magnetically induced heating
temperature) in solid state was measured. The cytotoxicity using the normal
rat liver epidermal cells was also investigated to estimate the bio-feasibility to
hyperthermia agent applications.
4.1.1. Physical Properties of Ferrimagnetic MFe2O4 (M=Ni, Co and Mg)

Nanoparticles
The mean particle size and the size distribution of ferrimagnetic MFe2O4
(M=Ni, Co and Mg) nanoparticles determined by an FE-SEM are shown in
Fig. 4-1. The mean particle size (diameter) and the size distribution were
measured by the FE-SEM image. The size of all nanoparticles on the image
were measured based on the scale bar on the image. Then, mean value was
calculated. The error was calculated based on standard deviation () showing
how much variation or dispersion exist from the mean.
CoFe2O4 (28.7 nm 6.7 nm), NiFe2O4 (34.3 nm 9.8 nm), and MgFe2O4
47
CHAPTER 4. RESULTS & DISCUSSION
(30.3 nm 7.2 nm) had a round shape and were well segregated. These
indicates that ferrimagnetic MFe2O4 (M=Ni, Co and Mg) nanoparticles that
have well controlled size (30 ~ 40 nm) with the narrow size distribution (<
29%) were successfully synthesized by conventional sol-gel process.
Fig. 4-1. The sizes and the size distributions of CoFe2O4 (28.7 nm 6.7 nm),
NiFe2O4 (34.3 nm 9.8 nm), and MgFe2O4 (30.3 nm 7.2 nm) determined by
an FE-SEM.
4.1.2. AC Magnetically Induced Heating Characteristics of Ferrimagnetic

MFe2O4 (M=Ni, Co and Mg) Nanoparticles
The TAC,mag of ferrimagnetic MFe2O4 (M=Ni, Co and Mg) nanoparticles

(solid state, 60 mg) were measured at the magnetic field (140 Oe) and
48
frequency (110 kHz). Ferrimagnetic nanoparticles that had around 30~40 nm

size and size distribution of 23~28% were chosen since the ideal size for
ferrimagnetic nanoparticle is less than 50 nm [76]. This is because that the
particles in the size range of 50-150 nm are typically cleared by the Kupffer
cells of a liver [77].
Fig. 4-2. AC magnetically induced heating characteristics of MFe2O4 (M=Co,

Ni, Mg)
As can be seen in Fig. 4-2, MgFe2O4 showed the highest TAC,mag (T = 33
C) after applying the AC magnetic field at 300 seconds. On the other hand,
NiFe2O4 (T = 28 C) showed relatively lower TAC,mag, in particular, CoFe2O4
showed the lowest TAC,mag (T = 6.7 C).
49
4.1.3. The Magnetic Properties of Ferrimagnetic MFe2O4 (M=Co, Ni and

Mg)
Fig. 4-3. The magnetic major/minor systeresis loops of MFe2O4 (M=Co, Ni,
Mg)
In order to investigate the relationship between the magnetic properties

and TAC,mag, magnetic major/minor hysteresis loops and initial M-H curve of
MFe2O4 (M=Co, Ni, Mg) were measured by VSM. DC minor hysteresis
behavior of the nanoparticles was investigated by sweeping the magnetic field,
Happl, of 140 Oe at room temperature (RT). As can be seen in Fig. 4-3 (b),
the MgFe2O4 and the NiFe2O4 nanoparticles showed relatively large DC minor
hysteresis area indicating that TAC,mag was caused by DC minor hysteresis loss.
This is because that the relationship between TAC,mag and DC minor hysteresis
loss can be explained by considering physical models relevant to the
magnetic hysteresis loss, especially DC minor hysteresis loss (or loss power,
Physteresis loss) which dominantly contributes to the Ptotal (total heating power) for
ferrimagnetic nanoparticles [78]. Physteresis
loss
can be expressed by the
following equation (4-4),
= , = ..(4-4)
50
where, 0 is the permeability of free space (4 x 10-7 H/m) and A is the area of
hysteresis loop. However, although the CoFe2O4 nanoparticles showed a large
hysteresis loss at the sweeping field, Happl, of 15 kOe, they had almost zero
DC minor hysteresis loss with very small magnetization value at the Happl of
140 Oe. This is mainly though to be due to their high magnetic anisotropy [78].
Fig. 4-4. Iinitial M-H curve of MFe2O4 (M=Co, Ni, Mg)
Initial M-H curve of MFe2O4 (M=Co, Ni, Mg) are shown in Fig. 4-4. As
illustrated in Fig. 4-4, MgFe2O4 and NiFe2O4 nanoparticles showed fast
response to the applied magnetic fields less than 1000 Oe indicating that softer
magnetic properties gave rise to large DC minor hysteresis loss. In contrast,
CoFe2O4 that showed hard magnetic properties resulted in no hysteresis loss.
Initial susceptibility can be explained by below equations,
51
= + " .....(4-5)
= ....(4-6)
In-phase susceptibility () is directly related to DC minor hysteresis loss,
which causes larger magnetization. This magnetic softness (or magnetic
exchange coupling) can be one of important factors for higher heating power
for ferrimagnetic nanoparticles.
4.1.4. Biocompatibility
In-vitro cytotoxicity of the ferrimagnetic MFe2O4 (M=Co, Ni, Mg)

nanoparticles were investigated by employing MTT assay (methylthiazol
tetrazolium bromide test) using normal rat liver epidermal cells to evaluate the
feasibility to a local hyperthermia agent. Fig. 4-5 shows the cell survival rate
of the ferrimagnetic MFe2O4 (M=Co, Ni, Mg) nanoparticles under different
nanoparticle concentrations. As can be seen in Fig. 4-5, the MgFe2O4 and
CoFe2O4 nanoparticles showed high cell survival rates of 90% ~ 80 % (noncytotoxicity) but the NiFe2O4 showed slightly lower cell survival rates of 87 %
~ 65 % (mid-cytotoxicity) with standard deviations of 8 % ~ 10 % depending
on the nanoparticle concentrations. The relatively high biocompatibility of the
MgFe2O4 and CoFe2O4 nanoparticles demonstrated that they can be potentially
considered to be an in-vivo hyperthermia agent in nanomedicine.
52
Fig. 4-5. Cell survival rate of all the ferrimagnetic MFe2O4 (M=Co, Ni, Mg)
nanoparticles with normal rat liver epidermal cells
4.2. Ferrimagnetic MgFe2O4 Nanoparticles Modified by Modified Sol-gel

Method
In this section, ferrimagnetic MgFe2O4 nanoparticles which exhibited

faster frequency response, higher biocompatibility and higher TAC,mag were
thermally, chemically and mechanically modified by modified sol-gel
synthesis process in order to achieve higher SLP while maintaining a small
size and a narrow size distribution for intra-arterial hyperthermia agent
applications.
4.2.1. Ferrimagnetic MgFe2O4 Nanoparticles Modified by Calcining

process
53
Calcining process allows the constituents to interact by inter-diffusion of

their ions and so reduces the extent of the diffusion that must occur during
sintering in order to obtain a homogeneous body [79]. The calcining
temperature is also an important factor in controlling shrinkage during
sintering. By controlling calcining temperature, the size and size distribution
of nanoparticles can be controlled [80-83].
In this part, we controlled calcining temperatures (400 C, 500 C and 600
C) during the modified sol-gel method. For the sake of investigating the
effect of calcining temperatures on the synthesized nanoparticles, the mean
size and the size distribution as well as magnetic major/minor hysteresis loops,
initial M-H loop and AC heating characteristics were measured. The samples
were calcined at 400 C, 500 C and, 600 C, respectively for 1 hour. Then,
after a grinding process they were sintered at 700 C for 6 hours, respectively
(Sample A, Sample B and Sample C).
4.2.1-1. Physical Properties
In order to investigate the effects of calcining temperature on the crystal

structure, the mean particle size and the size distribution of the samples A, B
and C were measured by XRD and FE-SEM. The XRD patterns of samples A,
B, and C, are shown in Fig. 4-6. As can be seen in Fig. 4-6, the diffraction
peaks showed a well defined single-phase cubic spinel structure and the
synthesized nanoparticles did not exhibit any undesirable crystalline phase.
Also, lattice parameters of the sample A, B and C were calculated based on
XRD data, which were 8.39, 8.38 and 8.37 , respectively. It indicated that the
54
sample C that showed 8.37 had less defect than the sample A and B because
it is close to that of bulk MgFe2O4 (8.36 ).
Fig. 4-6.
XRD patterns of the sample A(400 C), B(500 C) and C (600 C)

fixed sintering temperature at 700 C
The mean particle size and the size distribution determined by an FE-SEM are
shown in Fig. 4-7. Sample A (36 10 nm, Sdv.: 27 %), B (37 11 nm, Sdv.:
29 %), and C (58 13 nm, Sdv.: 22 %) had a round shape and were well
segregated. These indicated that the MgFe2O4 nanoparticles that have well
controlled size (approaching to 50 nm) with the narrow size distribution (<
29%) were successfully synthesized by controlling the calcining process.
55
Fig. 4-7. The sizes and the size distributions of the sample A (36 nm 10 nm),
B (37 nm 11 nm), and C (58 nm 13 nm) determined by an FE-SEM.
56
4.2.1-2. AC Magnetically Induced Heating Characteristics
Fig. 4-8. The AC magnetically induced heating characteristics of the sample A,

B and C in solid state (60 mg) at the biologically tolerable range of frequency
and magnetic field (fappl = 110 kHz, Happl = 140 Oe).
The TAC,mag of samples A, B and C (solid state, 60 mg) were measured to
investigate the effect of calcining temperatures on TAC,mag, which is shown in
Fig. 4-8. As can be seen in Fig. 4-8, sample C showed the highest TAC,mag (T
= 93 C) after applying the AC magnetic field at 1000 seconds. Even though
sample A (T = 56 C) and sample B (T = 63 C) showed relatively low
TAC,mag in comparison with sample C, the TAC,mag of all samples was increased
in comparison with previous one synthesized by conventional sol-gel method.
4.2.1-3. Magnetic Properties
57
Fig. 4-9. Magnetic major hysteresis loop of the sample A, B, C.
In order to explore the effect of calcining temperatures on the magnetic

properties, the magnetic major hysteresis loop was measured. As can be seen
in Fig. 4-9, sample C showed slightly higher Ms (saturation magnetization,
24.5 emu/g) than sample A (19.7 emu/g) and B (20.4 emu/g), which
approaches that of bulk MgFe2O4 as (27 emu/g). This was because the
calcining temperature at 600 C enabled the nanoparticles to have few defects
and enhanced crystalline structure leading to higher magnetization. Some
defects on the surface of nanoparticles might have surface disorder spins,
which is unable to completely align all spins of nanoparticles in the direction
of applied magnetic field leading to relatively less saturation magnetization. In
addition, the coherent magnetization reversal of the sample C caused by the
relatively larger particle size and wider size distribution (58 nm 13 nm)
might result in slightly higher saturation magnetization by means of additional
m1m2 [78].
58
Fig. 4-10. (a) Magnetic minor hysteresis loops of the sample A, B, C and the
previous sample by conventional sol gel method at the sweeping field of 140
Oe (b) The initial M-H loops of the sample A, B, C.
For the sake of investigating the physical reasons of the highest TAC,mag of
sample C, magnetic minor hysteresis loop at the sweeping field of 140 Oe
and initial M-H loop of the samples were measured (Fig. 4-10 (a) and (b)). As
can be seen in Fig. 4-10 (a), sample C showed the largest hysteresis loss in
59
response to the magnetic field. To quantitatively compare AC heat generation

ability, the hysteresis loss energy, Physteresis loss and Ptotal of the samples were
calculated based on the experimentally measured results, which is shown in
table 1. The Ptotal was determined from equation (4-7),
= .....................................(4-7)
where, Cvol is volumetric heat capacity, m is mass of nanoparticles and T is

AC heating temperature rise. The sample C showed the largest hysteresis loss
energy and the largest Physteresis
loss
which was directly relevant to Ptotal. It
indicates that the highest TAC,mag of the sample C was caused by the largest
DC minor hysteresis loss power. For all samples, more than 96% of Physteresis
loss
contributed to the Ptotal, which strongly demonstrates that the DC minor
hysteresis loss power is a critical factor for determining the TAC,mag of

ferrimagnetic nanoparticles.
Table 4-1. Calculation results of hysteresis loss energy and the real
contributions of Phystersis loss to the Ptotal of the sample A, B, C and previous one
synthesized by conventional sol-gel method.
Furthermore, the DC minor hysteresis loss is directly related to DC magnetic

softness (or magnetic exchange coupling). The higher DC magnetic softness
60
enables a faster response of magnetic spins to the applied magnetic field

caused by a larger magnetic exchange energy (or lower magnetic anisotropy),
which result in a higher initial m and m. Based on the equation (4-4), (4-5)
and (4-6), it causes a larger DC magnetization value as well as a larger
Physteresis loss. As can be seen in Fig. 4-10 (b), sample C showed the softest
magnetic properties in response to the magnetic field, which closely
contributed to higher magnetization leading to the largest DC minor hysteresis
loss. On the other hand, the previous sample showed the smallest hysteresis
loss, which resulted in the lowest AC heating power.
Fig. 4-11. (a) The comparison of the Ms and Hc depending on the sample
A, B and C (b) Hc depending on the mean particle size of the sample A,
B and C.
In order to verify the reason of the higher magnetic softness of the sample
C, the Ms and Hc (coecivity) of the synthesized nanoparticles were compared
based on the calcining temperature and the size, which is shown in Fig. 4.11 (a)
and (b), respectively. As can be seen in Fig. 4.11 (a), Ms were increased but Hc
were decreased at calcining temperature 600 C. It looked like to approach
further to multi-domain region resulting in a smaller coecivity and a higher
saturation magnetization (Fig. 11 (b). It indicates that the sample C shows
61
softer magnetic property due to low anisotropy energy caused by the

minimized magnetic static energy of multi-domains. While, the sample A and
B were in the single domain region with relatively lower Ms and higher Hc,
which resulted in relatively hard magnetic property than that of the sample C.

A, B and C in liquid state (5mg/ml in toluene) at the biologically tolerable
range of frequency and magnetic field (fappl = 110 kHz, Happl = 140 Oe).
To evaluate AC magnetically induced heating characteristics in liquid state
for the feasibility to a in vivo hyperthermia agent, the samples (A, B and C)
were well dispersed in toluene and the TAC,mag were measured in liquid state (5
mg/ml). As shown in Fig. 4-12, the sample C showed the highest TAC,mag (T
= 4.32 C) in liquid state. The sample B (T = 3.46 C) and A (T = 3.38 C)
generated less TAC,mag, which was illustrated the same trends as the result of
the solid state nanoparticles. Since the nanoparticles were dispersed in toluene,
the effect of magnetic dipole interaction of nanoparticles could be negligible,
62
which demonstrated that AC heat generation of the sample C from magnetic

dipole interaction was quite small.
Fig. 4-13. Spicific loss power (SLP) of the samples in the range of frequency
and magnetic field (fappl = 110 kHz, Happl = 140 Oe).
Fig. 4-13 shows SLP of the samples in the range of the magnetic field
(Happl = 140 Oe) and frequency (fappl = 110 kHz). The sample C showed the
highest SLP (600 W/g) among the samples.
4.2.2. Ferrimagnetic MgFe2O4 Nanoparticles Modified by Sintering

Process
In the previous part, we demonstrated that calcining temperature at 600 C

enhanced the SLP of ferrimagnetic MgFe2O4 nanoparticles. However, the
sample C from calcining effect showed slightly the larger size and the wider
63
size distribution (58 nm 13 nm). In order to inject the nanoparticles through

intra-arterial way without clotting problems and capturing by Kupffer cell of
liver, the mean size and the size distribution of nanoparticles should be smaller
and narrower as possible. Therefore, in order to optimize the synthesis
conditions for a smaller particle size, a narrower distribution and a higher SLP,
the ferrimagnetic MgFe2O4 was modified by sintering process with different
temperatures (700 C, 750 C, 800 C, 850 C and 900 C) during the modified
sol-gel method. All samples were calcined at 600 C, respectively for 1 hour.
Then, after a grinding process they were sintered at 700 C, 750 C, 800 C,
850 C and 900 C for 6 hours, respectively (Sample D, Sample E, Sample F,
Sample G, and Sample H). Then, crystal structure, particle size, minor
hysteresis loop and TAC,mag were measured depending on the sintering
temperatures.
4.2.2-1. Physical and Magnetic Properties & AC Magnetically Induced

Heating Temperature (TAC,mag)
In order to investigate the effects of sintering temperature on the crystal

structure, mean particle size and size distribution of the all samples, XRD and
FE-SEM were measured. The XRD patterns are shown in Fig. 4-14 (a), which
did not show any undesirable crystalline phase and also showed a single-phase
cubic spinel structure. The mean particle size and the size distribution
determined by an FE-SEM were plotted versus the sintering temperature,
which is shown in Fig. 4-14 (b). The samples were D (58 11 nm), E (60
15.5 nm), F (78 28 nm), G (101 33 nm) and H (190 50 nm). However,
64
the size of the nanoparticles was continuously increased depending on the

sintering temperatures and was significantly increased after 850 C (> 100 nm).
Overall size was too big to be used for an intra arterial hyperthermia agent.
Fig. 4-14. (a) The XRD patterns of the samples (b) The mean size depending
on sintering temperature.
65
In order to explore the effect of sintering temperatures on the magnetic

properties and TAC,mag, the magnetic DC minor hysteresis loop and TAC,mag
were measured and compared, which is shown in Fig. 4-15. As can be seen in
Fig. 4-15 (a), DC minor hysteresis loss was increased with increase in
sintering temperature, which well corresponded with the TAC,mag in Fig. 4-15
(b). The increased particle size was likely to cause higher magnetization with
larger DC minor hysteresis loss allowing higher the TAC,mag. Even though the
highest TAC,mag was shown at sample H, sample G showed the highest rate of
temperature rise (Fig. 4-15 (b)) indicating that the sintering temperature of 850
C was likely to be considered as the synthesis condition for highly efficient
AC heat generation ability.
66
Fig. 4-15 (a) Magnetic minor hysteresis loop (b) The AC magnetically induced
heating temperature and the rate of temperature rise depending on the
sintering temperature in solid state (60 mg) at the biologically tolerable range
of frequency and magnetic field (fappl = 110 kHz, Happl = 140 Oe).
4.2.3. Ferrimagnetic of MgFe2O4 Nanoparticles Modified by Ball Milling

Process
The process in which small particles are produced by reducing the size of
larger ones by mechanical forces is usually referred to as communication. It
involves operations such as crushing, grinding and milling. Ball mills are
categorized into various types depending on the method used to impart motion
to the balls (e.g., tumbling, vibration, and agitation) [84]. Tumbling ball mill,
usually referred to simply as ball mills, consist of a slowly rotating horizontal
cylinder that is partly filled with grinding balls and the particles to be ground.
In the previous parts, we demonstrated that sintering temperature at 850 C
enhanced the rate of temperature rise. However, the mean size of sample G
67
was too high to use it as hyperthermia agent (~ 100 nm). Therefore, in order to
reduce the size while maintaining the rate of temperature rise, the
ferrimagnetic MgFe2O4 modified by ball milling process with the different
size of balls (No ball milling, 5 mm, 3 mm); sample I, sample J and sample K,
respectively during the modified sol-gel method, was investigated.
4.2.3-1. Physical and Magnetic Properties
In order to investigate the effects of ball milling process on the mean

particle size and the size distribution of the samples, the sample I, J and K
were measured by FE-SEM, which is shown in Fig. 4-16. The sample I (101
33 nm, Sdv.: 32 %), J (67.4 19.6 nm, Sdv.: 29%), and K (40.7
8.7 nm,
Sdv.: 21.3 %) were well segregated. The particle mean size and size
distribution of the samples decreased with decrease in the size of the ball. This
indicated that ferrimagnetic MgFe2O4 nanoparticles modified by ball milling
process were successfully synthesized and corresponded well with the
theoretical expectation.
68
Fig. 4-16. The mean particle sizes and its size distributions of the sample I
(101 33 nm, Sdv.: 32 %), J (67.4 19.6 nm, Sdv.: 29%), and K (40.7 8.7
nm, Sdv.: 21.3 %) determined by an FE-SEM.
69
Fig. 4-17.
Magnetic major hysteresis loop of the sample I, J and K.
In order to explore the effect of ball milling process on the magnetic

properties, the magnetic major hysteresis loop of the samples was measured by
VSM. As can be seen in Fig. 4-17, the sample I showed high Ms with coherent
magnetization reversal owing to low anisotropy energy of multi domains
caused by a large particle size as well as due to higher particle dipole
interaction (E
int)
and higher exchange coupling energy (Jex) caused by the
widest size distribution (32%) [78]. The sample J showed slightly less Ms than
that of the sample I, but it still showed coherent magnetization reversal, which
means it was in multi domain regions but smaller size and narrower size
distribution than that of the sample A. However, for sample K, the hysteresis
loop seemed like superparamagnetic characteristics due to relatively high
anisotropy energy of single domain caused by small particle size as well as
weak particle dipole interaction resulting in a small E int and correspondingly a
70
small Jex , which means there were few magnetic dipole interactions among
the nanoparticles.
4.2.4. AC Magnetically Induced Heating Characteristics in Solid State

and Liquid States
4.2.4-1. Oleic Acid Coating Process
Fig. 4-18. Schematic of oleic acid coating
In order to measure SLP (Specific Loss Power) and mix with lipiodol, the
nanoparticles were coated with oleic acid. As can be seen in Fig. 4-18, oleic
acid enables the nanoparticles to be hydrophilic.
71
4.2.4-2. AC Magnetically Induced Heating Characteristics
For the sake of investigating the AC heating abilities of the synthesized

nanoparticles in solid states and ferrofluids, the TAC,mag of the sample with and
without OA coating were measured, respectively (Fig. 4-19 (a) and (b)). For
the TAC,mag in solid states as illustrated in Fig. 4-19 (a), the sample I showed
the highest heating temperature (T = 126 C). The sample J was 98 C (=T)
and the sample K was 65 C (=T). However, for the TAC,mag of the OA coated
nanoparticles, measured in ethanol (Concentration: 5 mg/ml) as can be seen in
Fig. 4-19 (b), the results were completely reserved. The sample C, displayed
the lowest TAC,mag (T = 65 C) in solid state, showed the highest TAC,mag (T
= 5.1 C) in ferrofluids but the sample I showed the lowest TAC,mag (T=4.26
C) in ferrofluids despite of exhibiting the highest TAC,mag in solid states.
72

sample I, J and K in (a) solid state (60 mg) and (b) liquid state (5 mg/ml in
ethanol) at the biologically tolerable range of frequency and magnetic field
(fappl = 110 kHz, Happl = 140 Oe).
4.2.4-3. Magnetic Properties and Coating Conditions
Fig. 4-20. (a) Magnetic DC minor hysteresis loops of the samples I, J and K in
solid states (b) Magnetic DC minor hysteresis loops of the OA coated sample I,
J and K in ferrofluids.
In order to verify the physical reasons of these phenomena, magnetic DC

73
minor hysteresis loops in solid states and ferrofluids (the OA coated samples)
were measured and compared. As illustrated in Fig. 4-20 (a), the sample I
showed the largest DC minor hysteresis area due to coherent rotation of
dipoles or domains caused by low anisotropy of multi domains and magnetic
dipole interactions caused by wide size distribution in the response to the
magnetic field. This can be well explained by the heating mechanism of
ferromagnetic nanoparticles (FMNPs) owing to hysteresis loss power (Physteresis
loss)
that is mainly contributed to total AC heating power (Ptotal) in solid states
[85]. Then, the hysteresis area of the sample J is larger than that of the sample
K due to relatively higher MS and faster coherent rotation of multi domains.
The sample K seemed to like hard magnetic properties in the range of 140 Oe
leading to the lowest DC minor hysteresis loss. This was because that the
sample K was closer to single domain region with relatively higher anisotropy
and lower magnetization due to the smaller mean size and few magnetic dipole
interaction, precluding from easily rotating magnetic dipoles in response to the
small range of the magnetic field. However, in the ferrofluids, the magnetic
DC minor hysteresis loss of the sample K was significantly increased in
comparison with that in solid states while that of the sample I was
significantly decreased in comparison with that in solid states. Due to
ferrofluid status, meaning that the nanoparticles were coated with OA and well
dispersed in ethanol, magnetic dipolar interactions among the coated
nanoparticles were completely changed in comparison with that in solid states.
Therefore, the AC heating mechanism in ferrofluids should be considered
based on magnetic dipolar interaction and coating status. First of all, the
contribution of Physteresis
loss
to Ptotal might be reduced by the reduction of

74
magnetic interaction than that in solid states. Instead, the contribution of

Relaxation loss power (Prelaxation loss) to Ptotal might be increased owing to the
separated nanoparticles in liquid states. It means that smaller particles size can
reduce Neel relaxation time as well as smaller hydrodynamic diameter can
reduce Brownian relaxation time leading to large PNeel relaxation loss based on the
bellow equations,
= +()
.(4-8)
,where 0 is the permeability of free space, 0 is the equilibrium susceptibility,

H0 and f are the amplitude and the frequency of alternating magnetic field and
is the effective relaxation times given by,
.(4-9)
,where N and B are the Neel relaxation and Brownian relaxation time,
respectively. N and B are written as
..(4-10)
.....(4-11)
, where 0 is the average relaxation time in response to a thermal fluctuation, K

75
is magnetic anisotropy energy density, V is its volume, 0 is the Boltzmann

constant and T is the absolute temperature. is the dynamic viscosity of the
suspending medium, Vhyd and Dhyd denote the hydrodynamic particle volume
and diameter, respectively.
Fig. 4-21. Hydrodynamic diameter measured by DLS.
In order to investigate the coating conditions of the samples,

hydrodynamic diameter and PDI (Polydispersity index) were measured by
DLS (Dynamic light scattering), which is shown in Fig. 4-21. The size
measured by FE-SEM as well as hydrodynamic diameter and PDI of the
76
samples are summarized in Table 4-2. As can be seen in table 4-2, the sample
K showed the smallest mean size and narrowest size distribution in solid state
and exhibited the smallest hydrodynamic diameter and PDI in liquid state.
This indicated that the smaller size nanoparticle and narrower size distribution
thought to be well and separately coated with oleic acid, allowing smaller
hydrodynamic diameter and PDI. It enables large Prelaxation
loss
as well as
Physteresis loss that resulted from larger DC minor hysteresis loss caused by the
well coated and dispersed nanoparticles without magnetic dipole interaction in
the response to magnetic field in ferrofluids.
Table 4-2. Mean size measured by FE-SEM and hydrodynamic diameter and
PDI measured by DLS
In contrast, sample I which had the largest size and widest size distribution
thought to be not well coated due to the agglomeration of the nanoparticle,
which resulted in the largest hydrodynamic diameter and PDI. It might show
less Prelaxation
loss
and Physteresis
loss
that resulted from high magnetic dipolar
coupling among the agglomerated nanoparticles, precluding magnetic dipole

from rotating quickly to the applied magnetic field [86]. Therefore, for the
heating mechanism in ferrofluids, the smaller particle size and narrower size
distribution as well as the coating conditions of nanoparticles could be very
important, which means that few dipole interactions resulted from the well
77
coated nanoparticles and mono-dispersion status are desirable for efficient AC

heating generation.
4.2.4-4. Specific Loss Power (SLP)
Fig. 4-22. SLP of the sample I, J, K
For the evaluation of AC heating performance of the samples, SLP of the

samples were calculated. As can be seen in Fig. 4-22, even though the sample
I showed the highest TAC,mag in solid states, it exhibited the lowest TAC,mag in
liquid states. This is because that Brownian relaxation time was long due to
the large size of hydrodynamic diameter as well as large PDI was high owing
to large particle size and wide distribution. On the other hand, the sample K
showed highest SLP in liquid state because it had the smallest particle size
(~40 nm) and the narrowest size distribution (~21%) due to the mechanical
modification by ball milling process (3 mm) as well as smallest hydrodynamic
78
diameter and PDI due to the well coated mono-dispersion condition, leading to
the enhancement of Brownian relaxation loss as well as hysteresis loss. SLP of
the sample K showed the highest SLP (525 W/g), which is higher than that of
Fe3O4 nanoparticles (120 W/g) currently used (Size = 25 nm, Happl = 300 Oe,
fappl= 120 kHz) [86].
4.2.5. Emulsion Formation with Lipiodol and AC Heating Characteristics

in Emulsion States
Lipiodol (Andre Guerbet, Aulnay-sous-Bios, France) also known as

iodized oil is to function as a contrast agent, as a vehicle for chemotherapeutic
agents, and as an embolic agent for Transcatheter arterial chemoembolization
(TACE) [87]. In the early 1980s, it was found for lipiodol to remain selectively
in the neovasculature and extravascular spaces of hepatocellular carcinoma
(HCC) when injected into the hepatic artery [88, 89]. Thereafter, TACE with
lipiodol emulsion and various anticancer drugs has been used as a standard
treatment for unresectable or post peratibely recurrent HCC and as alternative
to surgery, even for resectable tumors [90, 91].
In this part, in order to evaluate the feasibility of ferrimagnetic MgFe2O4
for the clinical use of liver cancer treatment in intra-arterial hyperthermia
modality, the oleic acid coated nanoparticles were mixed with lipiodol for the
emulsion formation. Also, the TAC,mag of the mixed emulsion was measured.
4.2.5-1. Pumping Method

79
Fig. 4-23. Emusion formation with lipiodol by pumping method
For the emulsion state, pumping method using three way cock and
syringes was required. As can be seen in Fig. 4-23, two syringes were
connected by three way cock and the contents were mixed by pumping
syringes several times enough to be completely mixed until water in oil
formation of the emulsion formed. However, it diminished soon due to the
differences of specific gravities between the coated nanoparticles and lipiodol.
For the optimal ratio between the coated nanoparticles and lipiodol for
emulsion state, various ratio of lipiodol and the coated nanoparticles (2:1, 6:1
and 30:1) were mixed and observed for 30 minutes and 1 hour 30 minutes,
which is shown in Fig. 4-24. It indicated that the ratio of 6:1 is proper ratio
between the coated nanoparticle and lipiodol sustaining the emulsion
formation around one hour. However, the concentration and SLP of the coated
80
nanoparticle should be considered together for the use of exact the ratio in the
future.
Fig. 4-24. Emusion formation with lipiodol depending on mixing rate
4.2.5-2. AC Magnetically Induced Heating Characteristic in Emulsion

States
81

A, B and C in (a) solid state (60 mg) and (b) liquid state (5 mg/ml in ethanol)
at the biologically tolerable range of frequency and magnetic field (fappl = 110
kHz, Happl = 140 Oe).
In order to estimate the heating performance in emulsion state, the TAC,mag
of the sample K mixed with lipiodol were measured in emulsion state where
the coated nanoparticles were well dispersed (5 mg/ml). As shown in Fig. 4-25,
AC magnetically heating characteristics of the emulsion state showed slightly
lower heating rate verse time. This was because the viscosity of lipiodol is
quite higher (oil states) than ethanol causing increase in Brownian relaxation
time, which reduce Brownian loss. However, TAC,mag of both at 2000 seconds
were not too different indicating that this emulsion can be suitable for the
clinical use of liver cancer treatment in intra-arterial hyperthermia modality.
82
CHAPTER 5
CONCLUSION
In the first part, ferrimagnetic MFe2O4 (M=Co, Ni, Mg) nanoparticles were
synthesized by the conventional sol-gel method to evaluate the feasibility for
intra-arterial hyperthermia agent applications. The mean particles size, size
distribution and magnetic properties of all samples were investigated. The
TAC,mag of the samples in the size range of 30~40 nm, was measured in solid
state. In addition, biocompatibility test using normal rat liver epidermal cells
was investigated for evaluating the feasibility of hyperthermia agent
applications. The ferrimagnetic MgFe2O4 nanoparticles showed the highest
TAC,mag due to the softer magnetic properties and exhibited the highest
biocompatibility properties among the synthesized ferrimagnetic nanoparticles.
It demonstrated that ferrimagnetic MgFe2O4 nanoparticles can be suitable for
intra-arterial hyperthermia applications.
In the second part, ferrimagnetic MgFe2O4 nanoparticles were synthesized
by the modified sol-gel method in order to enhance the crystal structure, mean
particle size, size distribution, and AC heating generation properties for the
clinical use of liver cancer treatment in intra-arterial hyperthermia modality.
Ferrimagnetic MgFe2O4 nanoparticles were synthesized by controlling
calcining temperatures (400 C, 500 C and 600 C) with the fixed sintering
temperature (700 C). Even though the sample C (calcining temperature at
600 C) showed the highest TAC,mag and SLP in solid state and liquid state
caused by the improvement of magnetic softness and saturation magnetization
leading to the largest hysteresis loss due to few defects and small anisotropy
83
CHAPTER 5. CONCLUSION
energy of multi-domains, it showed slightly the larger mean particles size (58
nm) than the ideal size (< 50 nm) as well as wider size distribution (13 nm).
Accordingly, ferrimagnetic MgFe2O4 nanoparticles were synthesized by
controlling sintering temperatures (700-900 C) with the fixed calcining
temperature (600 C) to improve the properties. Even though the sample G
(sintering temperature at 850 C) was showed the highest rate of temperature
rise, the size of the nanoparticle was too high to be used it as a hyperthermia
agent (~ 100 nm). Therefore, ball milling process with different ball sizes (5
mm, 3 mm) was added in the processes between the fixed calcining
temperature (600 C) and sintering temperature (850 C) in order to
mechanically modify the properties of the nanoparticles. The particle size and
size distribution, magnetic properties as well as TAC,mag in solid state and
liquid state of the modified nanoparticles were measured and compared. Even
though the sample K (ball milling process using 3 mm grinding ball) that had
proper particle size (~40 nm) and narrower size distribution (~21%), it showed
the lowest TAC,mag in solid state, however, it showed the highest TAC,mag and
SLP (525 W/g) in liquid state after oleic acid coating. This was because the
smallest particle size and the narrowest size distribution enabled the
enhancement of Neel relaxation loss and coating conditions leading to the
smallest hydrodynamic diameter and PDI, which enhanced Brownian
relaxation loss and hysteresis loss in ferrofluids. In addition, the TAC,mag in the
emulsion solution where the oleic acid coated nanoparticles were mixed with
lipiodol was measured to evaluate the feasibility for clinical applications. This
sample also showed good TAC,mag in the emulsion solution. All the results, in
this work strongly indicate that the ferrimagnetic MgFe2O4 nanoparticles
84
synthesized by the modified sol-gel method can be suitable for the clinical use
of liver cancer treatment in intra-arterial hyperthermia modality.
85
BIBLIOGRAPHY
[1] P. Moroz, S. K. Jones, J. Winter and B. N. Gray, J. Surg. Oncol. 78, 22 (2001).
[2] P. Moroz, C. Metcalf and B. N. Gray, Biometals, 16, 455 (2003).
[3] A. Tomitaka, M. Jeun, S. Bae and Y. Takemura, Journal of Magnetics, 16, 164
(2011).
[4] T. Maehara, K Konishi, T. Kaminori, H. Aono, H. Hirazawa, T. Naohara, S.
Nomura, H. Kikkawa, Y. Watanabe, and K. Kawachi, J. Mat. Sci. 40, 135
(2005).
[5] R. K. Gilchrist, Richard Medal, William D. Shorey, Russell C. Hanselman,
and John C. Parrott, Ann. Surg. 146, 596 (1957).
[6] D.H. Kim, S.H. Lee, K.N. Kim, K.M. Kim, I.B. Shim and Y.K. Lee, J. Magn.
Magn. Mater. 293, 320 (2005).
[7] S. Bae, S. W. Lee, Y. Takemura, E. Yamashita, J. Kunisake, S. Zurn, and C. S.
Kim, IEEE Trans. Magn., 42, 3566 (2006).
[8] U. Schwertmann, R. M. Cornell, Iron Oxides in the Laboratory
(VCH,Weinheim, 1991).
[9] B.D. Cullity, C.D. Cragam, Introduction to Magnetic Materials, Second
Edition (WILEY, IEEE, 2011).
[10] Zhuhua Cai, Northeastern University, (2010), Chemical Engineering
Dissertations. Paper 6. http://hdl.handle.net/2047/d20000908.
[11] J.P. Jakubovics, Magnetism and Magnetic Materials, 2nd edition, (The
Institute of Materials, London, 1994).
[12] E.J.W. Verwey and E.L. Heilmann, J. Chem. Phys. 15, 174 (1947).
[13] R.A. McCurrie, Ferromagnetic Materials: structure and properties
(Elsevier Science & Technology Books, 1993).
[14] Berry, C. C. and Curtis, A. S. G., J. Phys. D: Appl. Phys. 36, R198 (2003).
[15] Senyei A, Widder K and Czerlinski C. , J. Appl. Phys. 49 3578 (1978).
[16] Kannan M. Krishnan, IEEE Trans. Magn. 46, 2523 (2010).
[17] Q.A. Pankhurst, J. Connolly, S. K. Kones and J. Dobson., J. Phys. D: Appl.
Phys. 36, R167 (2003).
[18] L. Neel, Ann. Geophys. 5, 99 (1949).
[19] W. F. Brown Jr., Phys. Rev. 130, 1677 (1963).
86
[20] Frenkel J and Doefman J, Nature 126, 274 (1930).

[21] OHandley RC, Modern Magnetic Materials: Principles and Applications
(New York, Wiley, 2000).
[22] American
Cancer
Society,
Find
support
&
Treatment
part,
http://www.cancer.org.
[23] I. Brigger, C. Dubernet, and P. Couvreur, Adv. Drug Deliv. Rev. 54, 631
(2002).
[24] R.W. Rand, H.D. Snow, D.G. Elliott, and G.M. Haskins, US Patent
Specification 4, 545, 368, (1985).
[25] Jordan A, R. Scholz, K. Maier-Hauff, F. K. H. van Landeghem, N.
Waldoefner, U. Teichgraeber, J. Pinkernelle, H. Bruhn, F. Neumann, B.
Thiesen, A. von Deimling and R. Felix, J. Neuro-Oncol, 78, 7 (2006).
[26] M. Faraji, Y. Yamini and M. Rezaee, J. Iran. Chem. Soc., 7, 1 (2010).
[27] Kumar, Challa S.S.R. and Mohammad, Faruq. Advanced Drug Delivery
Reviews, 63, 9, 789 (2011)
[28] P. Moroz, S. K. Jones, and B. N. Gray, Int. J. Hyperthermia 18, 267 (2002).
[29] Chan DCF, Kirpotin DB, and Bunn PA. J Magn Magn Mater, 122, 374
(1993).
[30] Jordan A, Wust P, Fahling H, John W, Hinz A, Felix R., Int. J. Hyperthermia,
9, 51 (1993).
[31] Jordan A, Scholz R,Wust P, SchirraH, Schiestel Thomas, Schmidt H,
Schiestel T, Schmidt H, and Felix R, J. Magn. Magn. Mater. 194, 185 (1999).
[32] Maier-Hauff K, Ulrich F, Nestler D, Niehoff H, Wust, Thiesen B, Orawa H,
Budach V, and Jordan A., J. Neuro-Oncol,103, 317 (2011).
[33] Hergt R, Andra W, D'Ambly CG, Hilger I, KaiserWA, Richter U, and
Schmidt HG, IEEE Trans Magn, 34, 3745 (1998).
[34] Rand RW, Snow HD, and Brown WJ., J Surg Res., 33, 177 (1982).
[35] Rand RW, Snow HD, Elliott DG, and Snyder M., Appl. Biochem.
Biotechnol., 6, 265 (1981).
[36] Dudeck O, Bogusiewicz K, Pinkernelle J, Gaffke G, Pech M, Wieners G,
Bruhn H, Jordan A, and Ricke J., Invest. Radiol. 41, 527 (2006).
[37] Johannsen M, Gneveckow U, Eckelt L, Feussner A, Waldfner N, Scholz R,
Deger S, Wust P, Loening SA, and Jordan A, J. Hyperthermia, 21, 637 (2005).
87
[38] Johannsen M, Gneveckow U, Taymoorian K, Cho CH, Thiesen B, Scholz R,

Waldofner N, Loening SA, Wust P, Jordan A., Termoterapia ccer de prstata
mediate el uso de nanopartculas magnticas 31, 660 (2007).
[39] Johannsen M, Gneveckow U, Taymoorian K, Thiesen B, Waldofner N,
Scholz R, Jung K, Jordan A, Wust P, and Loening SA, Int. J. hyperthermia, 23,
315 (2007).
[40] Johannsen M, Gneveckow U, Thiesen B, Taymoorian K, Cho CH, Waldufner
N, Scholz R, Jordan A, Eur Urol 52(6), 1653 (2007).
[41] Johannsen M, Thiesen B, Gneveckow U, Taymoorian K, Waldufner N,
Scholz R, Deger S, Jung K, Loening SA, Jordan A, Prostate, 66(1), 97 (2006).
[42] Johannsen M, Thiesen B, Jordan A, Taymoorian K, Gneveckow U,
Waldufner N, Scholz R, Koch M, Lein M, Jung K, Loening SA, Prostate,
64(3), 283 (2005).
[43] Jordan A. MagForce Nanotherapy: with tumor-specific nanoparticles
against cancer. VDI Berichte, 111 (2005).
[44] Jordan A, and Maier-Hauff K., J. Nanosci. Nanotechnol. 7(12), 4604 (2007).
[45] Jordan A, Maier-Hauff K, Wust P, Rau B, and Johannsen M.,
Thermotherapie mit magnetischen nanopartikeln, 13(10), 894 (2007).
[46] Maier-Hauff K, Rothe R, Scholz R, Gneveckow U, Wust P, Thiesen B,
Feussner A, von Deimling A, Waldoefner N, Felix E, Jordan A, J. Neuro.
Oncol. 81(1), 53 (2007).
[47] Morgul MH, Raschzok N, Schwartlander R, Vondran FW, Michel R, Stelter
L, Pinkernelle J, Jordan A, Teichqraber U, Sauer IM., Int. J. Artif. Organs.,
31(3), 252 (2008).
[48] Thiesen B, and Jordan A., Int. J. Hyperthermia, 24(6), 467 (2008).
[49] Wust P, Gneveckow U, Johannsen M, Buhmer D, Henkel T, Kahmann F,
Sehouli J, Felix R, Ricke J, Jordan A, Int. J. Hyperthermia, 22(8), 673 (2006).
[50] G. D. Dodd, M. C. Soulen, R. A. Kane, T. Livraghi, W. R. Lees, Y.
Yamashita, A. R. Gillams, O. I. Karahan, and H. Rhim., Radiographics, 20, 9
(2000).
[51] M. Danta, E. Barnes, and G. Dusheiko., Eur. J. Gastroenterol. Hepatol,
17(5), 491 (2005).
[52] G.C. Sotiropoulos, M. Malago, E. Molmenti, A. Paul, S. Nadalin, E.
88
Brokalaki, H. Kuhl, O. Dirsch, H. Lang, and C.E. Broelsch., Transplantation,

79(4), 483 (2005).
[53] Sun, S., Zeng, H., Robinson, D. B., Raoux, S., Rice, P. M., Wang, S. X., Li,
G., J. Am. Chem. Soc., 126, 273 (2004).
[54] Qu S.C., Yang H.B., Ren D.W., Kan S.H., Zou G.T., and Li D.M., J Colloid
Interface Sci., 215, 190 (1999).
[55] Kang Y.S., Risbud S., Rabolt J.F., and Stroeve P., Chem Mater 8, 2209
(1996).
[56] Qiao R.R., Yang C.H., Gao M.Y., J. Mater. Chem. 19, 6274 (2009).
[57] Jolivet J. P. Metal Oxide Chemistry and Synthesis: From Solutions to Solid
State (New York, Wiley, 2000).
[58] Massart R., Cr Acad. Sci. C. Chim., 291, 1 (1980).
[59] A. Figuerola, R. Di Corato, L. Manna, and T. Pellegrino., Pharmacological
research the official journal of the Italian Pharmacological Society, 62, 126
(2010).
[60] Lu A.H., Salabas E.L., Schuth F., Angew. Chem. Int. Ed. 46, 1222 (2007).
[61] Frank, J. A., B. R. Miller, A. S. Arbab, H. A. Zywicke, E. K. Jordan, B. K.
Lewis, L. H. Bryant Jr., and J. W. Bulte., Radiology 228, 480 (2003).
[62] Abdel-Mohsen FF, and Emira HS, Pigment. Resin. Technol. 34, 312 (2005).
[63] Cui H, Zayat M, Levy D, J. Sol-gel Sci. Technol. 35, 175 (2005).
[64] S.F. Moustafa, Mater. Lett. 34, 241 (1998)
[65] Barbara L Durow and Christine M. Clark, X-ray Powder diffraction
(XRD), Beochmical Instrumentation and Analysis, Eastern Michigan
University.
[66] Celeste Morris, Bradley Sieve and Heather Bullen, Northern Kentucky
University,
Introduction
to
X-ray
Diffraction
(XRD),
http://www.asdlib.org/onlineArticles/ecourseware/Bullen_XRD/XRDModule_
Theory_Instrument%20Design_3.htm
[67] FESEM principle, Dept of Materials & Metallurgical Engineering, New
Mexico tech. (http://infohost.nmt.edu)
[68] G.W. Van Oosterhout, Apply. Sci. Res. B6 101(1956)
[69] S. Foner, Rev. Sci. Instr. 27, 54 (1956)
[70] Lake Shore Cryotronics, Inc., Vibrating Sample Magnetometry Menual.
89
[71] Techical Note Dynamic Light Scattering: An introduction in 30 minutes,

http://www.malvern.com/common/downloads/campaign/MRK656-01.pdf
[72] Milton Ohring, Materials Scinece of Thin Films 2nd edition (Academic
press, 2001).
[73] F. Yang, M. S. Chen, and D. W. Goodman, J. Phys. Chem. C, 113, 254
(2009).
[74] S. B. Simonsen, I. Chorkendorff, S. Dahl, M. Skoglundh, J. Sehested, and S.
Helveg, J. Am. Chem. Soc., 132, 23, 7968 (2010).
[75] M.A. Asoro, D. Kovar, Y. Shao-Horn, L.F. Allard and P.J.Ferreira,
Nanotechnology, 21, 025701 (2010).
[76] S Purushotham, P. E. J. Chang, H. Rumpel, I. H. C. Kee, R. T. H. Ng, P. K.
H. Chow, C. K. Tan, and R. V. Ramanujan, Nanotechnology, 20, 305101
(2009).
[77] Neuberger T, Schopf B, Hofmann H, Hofmann M and Von Rechenberg B., J.
Magn. Magn. Mater. 293, 483 (2005).
[78] M. Jeun, S. Bae, A. Tomitaka, Y. Takemura, K. H. Park, S. H. Paek, and K.
W. Chung, App. Phys. Lett. 95, 082501, (2009).
[79] A.J. Moulson. And J.M. Herbert, Electroceramics; Materials, Properties,
Applications, (WILEY, 2012).
[80] Cui-Ping, J. Mater. Sci., 42, 6133 (2007).
[81] Santi Maensiri, Nano. Res. Lett, 4, 221 (2009).
[82] Qi Chen, App. Phys. Lett. 73, 21, 3156 (1998).
[83] M. Kubota, J. Ther. Anal. Calor. 92, 2, 461 (2008).
[84] M.N. Rahaman, Ceramic processing and sintering, Marcel Dekker, Inc, p52.
[85] M. Jeun, S. LEE, J. K. Kang, A. Tomitaka, K. W. Kang, Y. I. Kim, Y.
Takemura, K. W. Chung, J. Kwak, and S. Bae, App. Phys. Lett. 100, 092406
(2012).
[86] Anrong Wang, Jian Li, and Rongli Gao, App. Phys. Lett., 94, 212501 (2009).
[87] S. A. Fudoshnikov, B. Ya. Liubimov, A. V. Popova, N.A. Usov, J. Mag. Mag.
Mater, 324, 22, 3690 (2012).
[88] Kim Y.I., Chung J.W., Park J.H., Han J.K., Hong J.W., and Chung J.,
Radiology, 240, 3, (2006).
[89] Komo T, Cancer, 66, 1897 (1990).
90
[90] Nakamura H, Tanaka T, Hori S., Yoshioka H., Kuroda C., Okamura J.,
Sakurai M., Radiology, 147, 401 (1983).
[91] Park J.H., Han J. K., Chung J.W.m Han M. C., Kim S.T., Cardiovasc
Intervent Radiol , 16, 21 (1993).
[92] Lee H. S., Kim K. M., Yoon J. H., Lee T. R., Suh. K. S., Lee K. U., Chung J.
W., Park J. H., and Kim C. Y., J Clin Oncol, 20, 4459 (2002).
91

Leesh

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Leesh

Uploaded by

Copyright:

Available Formats

FERRIMAGNETIC MgFe2O4 NANOPARTICLES

FOR INTRA-ARTERIAL HYPERTHERMIA AGENT

DEPARTMENT OF ELECTRICAL & COMPUTER

Chapter 2. Literature review

2.4.3. Arterial Embolization Hyperthermia....22

'' Imaginary susceptibility

0 is the permeability of free space

Energy barrier to moment reversal

VH Hydrodynamic volume of particle

Brownian relaxation time constant

Full Width Half Maximum of diffracted x-ray beam intensity

dhkl is the interplanar spacing

AC magnetically induced heating temperature

Specific Loss Power

Fied Emission Scanning Electron Microscope

Vibrating Sample Magnetometer

1.1 Background and Motivation

ferrimagnetic nanoparticles and the water dispersible ferrofluids have also

1.2. Research Objectives

temperatures, sintering temperatures and ball milling process,

1.3. Organization of Thesis

2.1. Background of Magnetism

Magnetism is a property of materials that respond to an applied magnetic

CHAPTER 2. LITERATURE REVIEW

Table 2-1. Type of Magnetism [11].

Ferromagnetic, antiferromagnetic, and ferrimagnetic are classified as magnetic

CHAPTER 2. LITERATURE REVIEW

magnetic moments align in one direction, showing very strong interactions

2.1.2. Soft and Hard Magnetic Materials

CHAPTER 2. LITERATURE REVIEW

2.1.3. Magnetic Nanoparticles

Magnetic nanoparticles are a class of nanoparticles which can be

CHAPTER 2. LITERATURE REVIEW

2.1.3-1. Unique Properties of Magnetic Nanoparticles

For ferromagnetic and ferrimagnetic materials, it exhibits irreversibility in

Since the magnetization of a superparamagnetic nanoparticle can be easily

CHAPTER 2. LITERATURE REVIEW

reversed by thermal fluctuations, it exhibits zero Mr or Hc without an external

exponential factor is of the order 1010~1012s and only weakly dependent

flipped, and the particle exhibits superparamagnetism.

CHAPTER 2. LITERATURE REVIEW

Ferrites are usually non-conductive ferrimagnetic ceramic compounds

2.1.4-1. Spinel Ferrite

Fig. 2-2. The spinel Structure (Closed-packed spheres)[12]

CHAPTER 2. LITERATURE REVIEW

for M to be a mixture of ions that have an average valence of 2.

2.1.4-2. Types of Spinel

Three different types of spinels are determined by the preference of cation

CHAPTER 2. LITERATURE REVIEW

CHAPTER 2. LITERATURE REVIEW

composition, preparation conditions and heat treatment [12].

Hyperthermia as a treatment of cancer has been recorded since ancient

CHAPTER 2. LITERATURE REVIEW

application, which has the potential to overcome these drawbacks.

2.2.2. Hyperthermia Methods

2.2.3. Side Effects of Hyperthermia

Regional or local hyperthermia can lead to pain at the site, swelling,

CHAPTER 2. LITERATURE REVIEW

2.2.4. Future of Hyperthermia

Even though hyperthermia is considered as a promising way to improve

2.3. Magnetic Hyperthermia

Magnetic heat induction of magnetic nanoparticles provides various

CHAPTER 2. LITERATURE REVIEW

a number of diseases [27].