7/23/2019 Cancer therapy using EM feild http://slidepdf.com/reader/full/cancer-therapy-using-em-feild 1/24 DEPT.OF ECE CANCER THERAPY BY HEATING OF GNPs USING EM FIELD JOHN COX MEMORIAL CSI INSTITUTE OF TECHNOLOGY Page 1 CHAPTER 1 INTRODUCTIONAlthough RF and microwave electromagnetic (EM) fields have been used for tissue heating for many years renewed attention has been given to the EM-field approach, a method combining a noncontact, capacitive coupled E-field arrangement with electrically conductive particles to heat tissue. It is well known that systemic chemotherapy has serious, debilitating side effects, frequently without producing a substantial increase in survival. In this method, RF current passes through a medium without physical contact between the medium and the transmitter – receiver pair, thus avoiding the need for contact electrodes. The noncontact approach is appealing for treating small animals and for whole-body treatment of various systemic cancers, which would preclude the use of contact electrodes. Additionally, RF-EM fields can penetrate deeply within tissue, thus making the method promising for treating a wide range of cancers, potentially anywhere within the human body. The concept goes a step further from traditional RF-hyperthermia by incorporating metal ions or metal particles to enhance heating in localized regions as compared to surrounding regions, where enhancers are not present. Low concentrations of conductive nanoparticles consisting of gold nanospheres or carbon nanotubes cause dramatically increased absorption of RF-EM energy, which is then dissipated in the form of heat. It has also been demonstrated that metal ion solutions produce a similar effect. Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via External Beam Radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many
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DEPT.OF ECE CANCER THERAPY BY HEATING OF GNPs USING EM FIELD
JOHN COX MEMORIAL CSI INSTITUTE OF TECHNOLOGY Page 1
CHAPTER 1
INTRODUCTION
Although RF and microwave electromagnetic (EM) fields have been used for
tissue heating for many years renewed attention has been given to the EM-field
approach, a method combining a noncontact, capacitive coupled E-field arrangement
with electrically conductive particles to heat tissue. It is well known that systemic
chemotherapy has serious, debilitating side effects, frequently without producing a
substantial increase in survival.
In this method, RF current passes through a medium without physical contact
between the medium and the transmitter – receiver pair, thus avoiding the need for
contact electrodes. The noncontact approach is appealing for treating small animals
and for whole-body treatment of various systemic cancers, which would preclude the
use of contact electrodes. Additionally, RF-EM fields can penetrate deeply within
tissue, thus making the method promising for treating a wide range of cancers,
potentially anywhere within the human body.
The concept goes a step further from traditional RF-hyperthermia by
incorporating metal ions or metal particles to enhance heating in localized regions as
compared to surrounding regions, where enhancers are not present. Low
concentrations of conductive nanoparticles consisting of gold nanospheres or carbon
nanotubes cause dramatically increased absorption of RF-EM energy, which is then
dissipated in the form of heat. It has also been demonstrated that metal ion solutions
produce a similar effect.
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) isthe use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy
can be administered externally via External Beam Radiotherapy (EBRT) or internally
via brachytherapy. The effects of radiation therapy are localised and confined to the
region being treated. Radiation therapy injures or destroys cells in the area being
treated (the "target tissue") by damaging their genetic material, making it impossible
for these cells to continue to grow and divide. Although radiation damages both
cancer cells and normal cells, most normal cells can recover from the effects of
radiation and function properly. The goal of radiation therapy is to damage as many
DEPT.OF ECE CANCER THERAPY BY HEATING OF GNPs USING EM FIELD
JOHN COX MEMORIAL CSI INSTITUTE OF TECHNOLOGY Page 3
reported thermal power dissipation by iron oxide is a relatively low ~500 W/g of
nanomaterial (at magnetic field amplitude of ~11 kA/m). Therefore, the
concentrations of iron oxide required for effective therapy are much higher than can
be reasonably achieved in vivo. Recently, it is shown that gold nanoparticles heat
under capacitively coupled radio frequency fields. RF heating of gold nanoparticles
within cancer cells overcomes the major limitations associated with other noninvasive
nanoparticle heating methods, since RF energy penetrates well into the body to
efficiently heat gold nanoparticles within deep tissue tumors. Previous studies
evaluated the therapeutic benefits of capacitive RF heating of gold nanoparticles, but
the mechanism of thermalization of RF energy by gold nanoparticles has remained
unaddressed and poorly understood.
A primary objective of this paper is to present and explore the RF-EM therapy
method, from the circuit design and characterization, to the experimental application
of the method for heating GNP suspensions, characterization of GNP heating, and
exploration of the potential for cancer therapy in vitro.
Colloidal gold is a suspension (or colloid) of sub-micrometre-sized particles
of gold in a fluid — usually water. The liquid is usually either an intense red colour
(for particles less than 100 nm), or a dirty yellowish colour (for larger particles) Dueto the unique optical, electronic, and molecular-recognition properties of gold
nanoparticles, they are the subject of substantial research, with applications in a wide
variety of areas, including electron microscopy, electronics,nanotechnology, and
materials science.Properties and applications of colloidal gold nanoparticles strongly
depend upon their size and shape. For example, rodlike particles have both transverse
and longitudinal absorption peak and anisotropy of the shape affects their self-
assembly Chrysotherapy (or aurotherapy), often self-administered allegedly by
alchemists and snake oil vendors before modern medicine isolated effective
compounds, relates to the intake of gold salts and or colloidal gold. Although
colloidal gold has been successfully used as a therapy for rheumatoid arthritis in
rats one noticeable side-effect in humans to whom are administered gold
based DMARDs is the coloring of the skin in shades of mauve to a purplish dark grey
when exposed to sunlight, if the salts are taken on a regular basis over a long period of
time. Excessive intake of gold salts and colloidal gold while undergoing
chrysotherapy result -through complex redox processes- in the saturation by relatively
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CHAPTER 2
BACKGROUND
2.1 RF-EM CIRCUIT DESIGN CONSIDERATIONS
Several modeling approaches were utilized in the analysis of the circuit design.
A circuit mesh equation analysis using MathCad was first performed, followed by a
two-port model with a two variable solver routine to find the best values of C 1 and C 2
to use for tuning. Analysis was also performed with a SPICE circuit modeling
package to make additional verifications against laboratory and mesh model data. The
circuit-tuning technique involves the measurement of the reflected power at the input
node, which can be accomplished with a vector network analyzer. Correct circuitoperation occurs when the reflected power is low and can be assessed with the voltage
reflection coefficient at the input node.
The design utilizes a cascaded LC matching network to transmit 13.56 Hz electrical
energy from a standard 50 Ω source across an air gap to a receiving circuit that steps
down the impedance to a 50 Ω load. Since an air gap presents large reactive load
impedance, several LC sections are necessary to match to the load (three sections for
transmission matching and three for reception matching), while maintaining
reasonable component values and immersions; hence, this mode is referred to as a
transmission-mode design. Tissue-like samples placed within the gap modify the load
impedance, and consequently, tuning of both the transmission and receiving circuits is
necessary to minimize power reflected back into the generator and maximize power
transmitted across the air gap. A modest amount of energy is absorbed from the
applied E-field by samples placed within the gap.
Radiation dose to each site depends on a number of factors, including theradiosensitivity of each cancer type and whether there are tissues and organs nearby
that may be damaged by radiation. Thus, as with every form of treatment, radiation
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RESONANT MODE DESIGN
Fig 2.1
Resonant mode‖ RF-EM circuit with the major circuit components labeled and in the
loss resistances associated with the inductors and the C 2 capacitor are omitted for brevity. Rt andCt are the resistance and capacitance, respectively, of the sample placed
in the gap.
A practical resonant-mode schematic shown in Fig. (a) includes three LC stages to
produce an easily adjusted circuit, which provides a real 50 Ω input through the use of
multiple, nonidentical s-plane poles. The voltage is increased at the output of each
stage, which culminates in a very large voltage available as the E-field source for
noncontact heating.
In Fig. a high capacity voltage source (Vs) operating at 13.56 MHz (f0)with output
impedance (Rs) of 50 Ω drives the passive circuit. All thr ee inductors L1 , L2 , and L3
are custom made from soft copper refrigerator tubing. L1 and L3 are wound using
6.35-mm diameter copper tubing and L2 is wound using 4.76-mm diameter copper
tubing. The capacitors C1 and C2 are adjustable. C1 consists of a 500 ± 20% pF fixed
door-knob capacitor in parallel with a 20 – 450 pF air-variable capacitor , C2 is a 10 –
110 pF vacuum variable capacitor. The C3 component is a lumped equivalent
capacitance created from a ground shield around the L3 inductor; the C4 capacitor is a
parasitic component, and the two Ccp capacitances are the air coupling capacitances
to the sample shown as a simple RC element. Very important loss components for the
three inductors as well as for the variable capacitor C2 are considered, but omitted in
the figures for brevity. The loss resistances are all in series with their respective L or
C component. The real part of the input power delivered to the RF-EM circuit will be
divided unequally among these loss components and the Rt in the intended load.
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2.1.1. PHYSICAL CIRCUIT OF RESONANT MODE
In the circuit individual components are labeled.C3 is the parasitic capacitance
formed between a sheet of copper clad and the grounded shield labeled to the left (and
the ground plane). L3 is hidden from view inside the grounded shield, and C4 is the
distributed parasitic capacitance between L3 and the shield (including the ground
plane). The sample placed in the gap consists of a 2-mL Eppendorf tube containing a
green neon lamp, which is illuminated in the RF-EM field. The circuit is tuned by
adjusting C1 and C2 via the control knobs shown in order to minimize reflected
power.
2.1.2. CAPACITIVE RF HEATING SYSTEM
Fig 2.2 Capacitive Heating System
A 13.56 MHz signal is applied across two metal electrodes that are coated with an
insulating Teflon layer which produces a high-voltage RF field (|E| = 15 kV/m at 600
W of RF generator power) over a variable air gap. Gold nanoparticle suspensions
contained within a cylindrical cuvette are placed on a Teflon platform (not shown) between the two electrodes. The metal chassis contains high voltage matching circuits
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CHAPTER 3
METHODS
3.1.RF-EM CIRCUIT MODELLING
Several modeling approaches were utilized in the analysis of the circuit
design. A circuit mesh equation analysis using Math Cad was first performed,
followed by a two-port model with a two variable solver routine to find the best
values of C 1 and C 2 to use for tuning. Analysis was also performed with a SPICE
circuit modeling package to make additional verifications against laboratory and mesh
model data. The circuit-tuning technique involves the measurement of the reflected
power at the input node, which can be accomplished with a vector network analyzer.
Correct circuit operation occurs when the reflected power is low and can be assessed
with the voltage reflection coefficient at the input node.
The three custom inductors and the two adjustable capacitors were directly
measured for use in the circuit modeling. The modeling of the effective series loss
resistance for each of the three custom-built inductors was found to be critically
important to a reasonable estimation of circuit operation. The loss resistances have theundesirable effect of power consumption (especially L2 ), but otherwise provide
easier circuit tuning, since absolutely zero resistive loss would create very high Q
elements resulting in difficult tuning adjustments as component values change with
temperature and thermal expansion.
Since capacitances C 4 and C cp are very small, the direct measurement of
these components is extremely challenging. To arrive at reasonable estimates of these
values, a Finite-Element Analysis (FEA) model was assembled for their estimationusing a charge integration (ΣQ) technique on the metal surface of the electrodes at
unity voltage with the application of ΣQ = CV . Both C 4 and C cp were estimated by
dividing theelectrode surface into regions contributing to one or the other capacitance.
The size and morphology of all nanoparticles were confirmed using Transmission
Electron Microscopy(TEM). TEM was performed using a JEM 1010 transmission
electron microscope with an accelerating voltage of 80 kV and digital images were
acquired usingan AMT Imaging System (Advanced Microscopy ). Drops ofnanoparticle suspensions were placed onto a poly- L-lysine treated form var coated
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copper grid for 1 h. Grids were blotted dry with filter paper and air dried before TEM
observation all gold concentrations are reported in ppm by mass and were determined
In order to independently examine nanoparticle diameter and gold contenteffects under RF fields, we tested gold nanoshells. Since nanoshells are composed of
an inner dielectric core (SiO2) and a thin outer shell of gold, the total volume fraction
of gold in solution can be varied while holding the overall diameter of the
nanoparticle constant. Surprisingly, at equivalent gold volume fractions, 150 nm
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3.3. RF-EM POWER DELIVERY TO GNP SOLUTIONS
Colloidal suspensions of citrate-coated GNPs in nominal diameters of 5, 10, 20,
and 50 nm in nominal concentrations of 0.01% Au are taken. A series of 0.5 mL
samples of GNP suspension with varying concentration was placed in 2 mLEppendorf tubes. The region of the tube containing the fluid sample was centered
between two 17 -mm diameter copper electrodes spaced apart by 17 mm, allowing
approximately a 4-mm air gap on either side of the tube . With a sample in place, the
circuit was tuned using the VNA to minimize reflected power (S 11) to better than – 30
dB at 13.56 MHz. After tuning, the circuit was connected to a 1000 W capacity 13.56
MHz RF generator, Prior to RF-EM exposure, the initial temperature of each sample
was measured using the fluoroptic temperature probe. The fluoroptic probe was
removed, and each sample was exposed to 125 W of input power to the RF-EM
system for 30 s. Following exposure, the peak temperature in the center of the sample
was measured.
Heating efficiency was quantified as power per unit mass of Au, i.e., kW/g Au,
which allows for the comparison of heating efficacy of various sizes and
concentrations for a given RF delivery system. Throughout this work this quantity is
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CHAPTER 4
RESULTS
4.1. CHARACTERISTICS OF THE CIRCUIT
The circuit with its estimated component values has been extensively modeled.
For good power transfer at each node, the output and input impedances should be
matched as complex conjugates; this circuit functions well in that regard. The circuit
node terminus produces an output impedance magnitude that is over 3100 Ω and an
output voltage peak above 8800 V (for 125 W input). This high impedance andvoltage make a direct sampling method challenging even with a very high impedance
probe (we used a 40 MΩ sampling probe).
A special E-field probe has been constructed and tested to calibrate the high
E-field generation, but even this carefully designed miniature probe has shown field
loading effects. Alternative measurement methods are in development to enable easy
and accurate monitoring of the field generated.
In figure 4.1 Normalized transfer response magnitude in decibels versus frequency in
megahertz for VNA measured (solid), Mathcad model (dotted), and SPICE model
(dashed). All results are normalized to the peak response at 13.56 MHz for the same
input magnitude. The Mathcad and Spice models are equivalent as indicated by the
near exact agreement between their respective curves. Agreement between the model
and experiment is reasonable considering many parasitic capacitances distributed
throughout the circuit that were not modeled. The influence of parasitic capacitance
due to the measurement is apparent near 13.56 MHz, where the measured response is
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4.2 GNP HEATING
The concentrations of the stock GNP solutions for 5, 10, 20, and 50 nm were
found to be 59, 54, 59, and 75 μg/mL, respectively. Temperature increases measured
in 0.5 mL samples of 5, 10, 20, and 50 nm GNP solutions following 30 s exposures inthe RFEM field using 125 W of transmitted power are summarized in Fig. 5. Heating
is inversely dependent on particle size and directly dependent on concentration up to
approximately 25, 40, 45, and 55 μg/mL for 5, 10, 20, and 50 nm GNPs, respectively.
Beyond these concentrations, heating does not increase with further increases in
concentration. At the highest concentrations, the heating rate ranged from 1.5 to 1.7
.C/s across all particle sizes.
The specific heating rate is inversely dependent on particle size. Exposure of
particles with a diameter of 5 nm resultedin the greatest efficiency with a specific
heating rate of 356 ±78 kW/g Au at a concentration of approximately 16 ìg/mL.
Beyond50 mg/mL, the specific heating rates for all particle sizes appear to follow a
common decreasing trend line. For concentrations below approximately 4 mg/mL, the
heating of water begins to dominate, thus explaining the asymptotically increasing
specific heating rate as zero Au concentration is approached (divide by zero condition
Fig. 4.2.Temperature rise of GNP suspensions in ddH2O
Following 30 s exposure to transmitted power of 125 W. Square, circle, diamond, and
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cancer cell lines for three RF treatment protocolsconsisting of 60 s of RF at 100 W, 30
s of RF at 100 W, and no RF. Each treatment group consisted of cells not incubated
with 10 nm GNPs and cells that were incubated with 10 nm GNPs so as to test if the
presence of GNPs influences cell death. For the cells that were incubated with GNPs,
the results shown include all of the cells regardless of GNP uptake. Upon testing the
influence of GNPs for the three treatment groups, a statistically significant increase in
cell death with the addition of 10 nm GNPs occurred for Met-1 cells treated with RF
for 60 s and for PC-3 cells incubated with 10 nm GNPs and treated with RF for both .
Met-1 cells treated for 30 s and incubated with GNPs did not show a significant
increase in cell death . The no-RF controls did not show a significant difference in
death for either Met-1 cells or PC-3 cells . For both cell lines, treatment with RF alone
did produce a significant increase in cell death relative to the no Au, no RF controls .
The maximum temperatures were recorded for the RF-treated cells, and no statistical
difference was found between the temperature rise with and without cells incubated
with GNPs. Average maximum temperatures for the 30 and 60 s treatments ranged
from 53.5 to 55.7◦C and 64.8 to 67.2◦C, respectively. The starting temperatures
averaged across all replicates was 22.6 ± 0.6◦C
The in vitro results presented demonstrate that the combination of cells
incubated with GNPs and exposed to RF causes statistically significant increases in
cell death for both Met-1 and PC-3 cancer cell lines. Significant differences in cell
deathis not observed as a function of GNP presence unless the samples were heated to
above 50◦C.
High temperatures are a prerequisite for the GNP-induced cell death.
Concentrating the cells into a smaller fluid volume may have also played a role inminimizing the shunting of the RF current around the cells and more closely models
tissue. TEM images of PC-3 cells indicate that the combination of GNPs and RF
creates vacuoles within cells, possibly explaining the significantly higher cell death
for RF-treated groups with GNPs. Vacuolization was not observed in RF-treated cells
without GNPs present observed by additionally, degraded GNP aggregates were
consistently observed in RF-treated cells. It may be that as these cells die, lysosomes
break down and release their digestive enzymes and acidic contents into the
cytoplasm, which may lead to degradation of the GNPs.
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The characterization of GNP heating in was performed in ddH2O, which is an ideal
medium for maintaining a colloidal suspension of citrate-coated GNPs with minimal
aggregation. Consequently, it may be possible to improve the method by preventing
aggregation of GNPs in carrier solutions and intra cellularly. More work is needed to
understand the mechanism of GNP heating in RF fields. Selective killing of cancer
cells in vivo requires targeting of GNPs directly to cancer cells by means of passive
and/or active targeting. Fortunately, GNPs are readily functionalized and have been
shown to target a wide range of cancers in vitro . Additionally, GNPs have been
shown to target specific organelles within cells, such as the nucleus .studies evaluated
in vivo tumor uptake of Tumor Necrosis Factor (TNF) bound to GNPs with and
without a protective layer of PEGTHIOL. Following intravenous injection in mice,
they found significant accumulation of the PEGTHIOL protected TNFGNPs in MC-
38 colon carcinoma tumors with little observable accumulation in the liver and spleen.
The increased RF induced heating rates of gold nanoparticles <50 nm in
diameter and gold nanoshells 10 -15 nm thick can be explained by the higher
resistivity of small metal nanostructures compared to bulk metals . Recent studies
have shown that the resistivity of silver nanowires 15 nm in diameter is approximately
twice that of bulk silver. Particles and shells of gold with dimensions on the order of10 nm are expected to exhibit a similar increase in resistivity due to increased
electron-surface scattering since the size of the metal is significantly smaller than the
mean free path of electrons in gold, which is on the order of 50 nm .If the heat
released is due to resistive (Ù) dissipation by gold, then the measured heat should
scale with Joule‘s law, P = I2R, where P is the power dissipated as heat, I is the
current, and R is the resistance. For a given volume fraction of gold nanoparticles, an
increase in the resistivity should lead to a commensurate increase in the amount of
heat generated by ohmic dissipation. As such, the observed doubling of the heating
rate for small gold nanoparticles and Nanoshells is consistent with the hypothesis that
gold nanoparticles are heating resistively under capacitive coupled RF fields.
The analysis presented here describes the models we haveconstructed, which
allow the theoretical prediction and comparison with laboratory data of the
temperatures in saline samplesexposed to high intensity E-fields. An expression for
bath temperature as a function of saline concentration is possible withconsideration ofthe 0.5mL bath geometry, physical materialproperties and their variation with
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CHAPTER 6
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