Noninvasive radiofrequency ablation

of cancer targeted by gold

nanoparticles
Jon Cardinal, MD,a John Robert Klune, BS,a Eamon Chory, BS,a Geetha Jeyabalan, MD,a
John S. Kanzius,b Michael Nalesnik, MD,a and David A. Geller, MD,a Erie and Pittsburgh, Penn

Introduction. Current radiofrequency ablation (RFA) techniques require invasive needle placement and
are limited by accuracy of targeting. The purpose of this study was to test a novel non invasive radiowave
machine that uses RF energy to thermally destroy tissue. Gold nanoparticles were designed and produced
to facilitate tissue heating by the radiowaves.
Methods. A solid state radiowave machine consisting of a power generator and transmitting/receiving
couplers which transmit radiowaves at 13.56 MHz was used. Gold nanoparticles were produced by
citrate reduction and exposed to the RF field either in solutions testing or after incubation with HepG2
cells. A rat hepatoma model using JM-1 cells and Fisher rats was employed using direct injection of
nanoparticles into the tumor to focus the radiowaves for select heating. Temperatures were measured
using a fiber-optic thermometer for real-time data.
Results. Solutions containing gold nanoparticles heated in a time- and power-dependent manner.
HepG2 liver cancer cells cultured in the presence of gold nanoparticles achieved adequate heating to
cause cell death upon exposure to the RF field with no cytotoxicity attributable to the gold nanoparticles
themselves. In vivo rat exposures at 35 W using direct gold nanoparticle injections resulted in signi-
ficant temperature increases and thermal injury at subcutaneous injection sites as compared to vehicle
(water) injected controls.
Discussion. These data show that non invasive radiowave thermal ablation of cancer cells is feasible
when facilitated by gold nanoparticles. Future studies will focus on tumor selective targeting of
nanoparticles for in vivo tumor destruction. (Surgery 2008;144:125-32.)

From the Starzl Transplant Institute, University of Pittsburgh Department of Surgery, Pittsburgh,a and Therm
Med LLC,b Erie, Penn

DESPITE A MYRIAD OF EFFORTS aimed at improving de- annually. While current therapeutic options for
tection and treatment, cancer continues to be the liver cancer (primary or metastatic) include hepa-
second leading cause of death among Americans. tic resection, liver transplantation, chemotherapy
Due to the high incidence of metastatic disease, (systemic or liver directed), or ablative techniques,
adjuvant therapies are an important component significant limitations exist. It is estimated that
in caring for patients with cancer. The liver is a fre- only 10–20% of patients with liver tumors are sur-
quent site of metastatic disease from many solid tu- gical candidates.1,2 In the remainder of cases,
mors. In fact, metastatic disease in the liver is more other modalities of treatment must be entertained
common than primary liver cancer in the Unites with radiofrequency ablation (RFA) having gained
States. Worldwide, however, primary hepatocellu- significant popularity in the last decade.
lar cancer (HCC) remains the fifth most common RF current, which has a frequency between 10
malignancy, and accounts for over 500,000 deaths kHz and 900 MHz, has been applied in medical
contexts for nearly a century in the form of electro-
Presented at the 3rd Annual Academic Surgical Congress, Hun- cautery. RFA results in thermal injury that occurs as a
tington Beach, California, February 2008. consequence of friction that is generated by the
Accepted for publication March 22, 2008. agitation of ions as they attempt to follow the
Reprint requests: David A. Geller, MD, Starzl Transplantation alternating current as it flows within tissue.3 RFA
Institute, 3459 Fifth Avenue, MUH 7 South, University of was limited to use in neurosurgical and cardiac pro-
Pittsburgh, Pittsburgh, PA 15213. E-mail: gellerda@upmc.edu. cedures until the early 1990s when two groups pro-
0039-6060/$ - see front matter posed it as an effective method for destroying
Ó 2008 Mosby, Inc. All rights reserved. unresectable, malignant liver tumors.4,5 Subsequent
doi:10.1016/j.surg.2008.03.036 animal and human trials suggested that RFA is safe

SURGERY 125
126 Cardinal et al Surgery
August 2008

and effective in the treatment of liver tumors.6-9 Lim- use in high electromagnetic environments (model
itations of current RFA technology include the re- getTemp-4, getSpec, Dresden, Germany).
quirement for invasive needle placement, accuracy Solutions testing. 13-nm citrate coated gold
of image-guidance, tumor size limits, operator de- nanoparticles (Au-NP) suspended in sterile water
pendence, and collateral damage to non-tumorous were a generous gift from David Waldeck, PhD
liver parenchyma and adjacent structures. In addi- (University of Pittsburgh, Department of Chemis-
tion, long-term follow-up studies have established try). Solution testing was performed on 0.5 mL of
that a learning curve exists,10 as well as the fact either gold nanoparticles or water placed in test
that local tumor recurrence rates are higher than tubes and suspended in the field in a constant
first reported, even in experienced hands.11,12 position while temperatures were measured con-
These studies reinforce that surgical resection re- tinuously. Field strengths as well as the lengths of
mains the ‘‘gold standard’’ for the treatment of liver exposure were adjusted.
tumors. However, the fact that the majority of liver Cell culture and in vitro exposures: HepG2 cells
cancer patients are inoperable at the time of (ATCC, Manassas, VA) were cultured on 6 cm
diagnosis, coupled with the limitations of conven- dishes in DMEM supplemented with 10% FBS
tional, invasive RFA procedures, is what provides along with 1% PS. Gold nanoparticles at a concen-
the impetus for developing a noninvasive manner tration of 4 nmol/L were added to the media of
in which RF current can be used for tumor ablation. cells in culture 4 hours prior to exposure to the
The use of nanoparticle technology in onco- field. Gold nanoparticle-free media was used as
logic applications has been the focus of recent control. The media on all cells was removed and
study.13 Specifically, gold nanoparticles have been replaced with fresh media with no nanoparticles
used to image tumor vasculature14 and can serve after the 4 hour incubation to remove any residual
as potential diagnostic markers for cancer.15 Fur- nanoparticles that had not been incorporated into
thermore, they have shown promise in targeting the cells. Cells were then exposed to the field at 35
and enhancing the uptake of chemotherapeutic W while temperatures were continuously recorded.
agents to cancer cells.16,17 One study has demon- After exposure, cells were reincubated at 37°C, 5%
strated the variable bioavailability of nanoparticles CO2 for 4 more hours. At that time, supernatants
to mouse tumor models based on their physical were collected and frozen and cells were scraped
properties.18 These studies highlight the potential into cold PBS and pelleted by centrifugation at
use of gold nanoparticles for specific targeting of 8000 rpm for 5 minutes.
cancer cells. Herein, we describe our initial experi- Cell viability assay: Cell viability was assessed
ence using a novel, noninvasive radiowave ma- using a lactate dehydrogenase assay kit (Roche
chine coupled with gold nanoparticle enhancer Diagnostics, Indianapolis, IN) according to the
solutions to thermally ablate tissue and cancer cells manufacturer’s recommendations.
in both in vitro and in vivo systems. Western blot analysis. Whole cell lysis of HepG2
cells was performed by resuspending the cell
MATERIALS AND METHODS pellets in an appropriate volume of 13 lysis buffer
Noninvasive RF generator/coupling system. A (CelLytic M, Sigma-Aldrich, St. Louis, MO) with
variable power (0--2 kW) RF signal (13.56 mega- 1 mmol/L PMSF for 30 minutes prior to high speed
hertz) generator was built to specification and centrifugation. Protein concentrations were deter-
donated as a kind gift by Therm Med LLC, Erie, mined using the bicinchonic acid protein assay kit
PA. This generator consists of a power source (Pierce, Rockford, IL). Supernatants from HepG2
coupled to a transmitting and receiving head cells incubated in the presence of gold nanopar-
whose separation distance is adjustable, as is the ticles alone or in combination with exposure to the
direction in which the field is generated. The RF field were collected, as were those from control
electromagnetic field strength generated between plates, and mixed with equal volumes of 33
the 2 heads was measured in a Faraday shielded Laemelli sample buffer. Samples were loaded into
room at low powers using an isotropic field mon- a 12% nondenaturing, acrylamide gel and electro-
itor and probe (models FM2004 and FP2000, phoresed prior to being transferred to nitro-
Amplifier Research Inc., Souderton, PA). A Hew- cellulose membranes. After blocking in 5% milk
lett-Packard Spectrum Analyzer (model 8566B; overnight, membranes were probed using antibody
Agilent, Santa Clara, CA) was connected to the for b-Actin (1:5000 in 1% milk overnight, Sigma
system to accurately measure transmitted power. Aldrich, St Louis, MO). Horseradish peroxidase
Temperature measurement was achieved using a tagged anti-rabbit secondary antibody (1:10,000 in
non-metallic fiber optic thermometer designed for 1% milk) was added for 1 hour after which
Surgery Cardinal et al 127
Volume 144, Number 2

membranes were developed with the Super Signal

West Pico chemiluminescent kit (Pierce, Rockford,
IL) and exposed to film.
In vivo subcutaneous injections and exposures.
All animal experiments were carried out in accor-
dance with guidelines established by the University
of Pittsburgh’s Institutional Animal Care and Us-
age Committee. Male Buffalo rats weighing be-
tween 250--300 g (Charles River, Wilmington, MA)
were put to sleep in a CO2 chamber prior to being
given an intraperitoneal injection of pentobarbital
sodium (Ovation Pharmaceuticals, Deerfield, IL).
Once they were adequately anesthetized, a 0.5
mL subcutaneous injection of either sterile water
or gold nanoparticles at a concentration of 13
nmol/L was given into the shoulder. A tempera-
ture probe was placed into the injection site
through a small incision followed by exposure to
the RF field at a power of 35 W. Temperatures
were measured every minute for up to 7 minutes.
Forty-eight hours were allowed to pass prior to har-
vesting the tissue at the site of injection/exposure.
In vivo tumor model. JM-1 hepatoma cells were
cultured as described previously19 and provided as a
kind gift from George Michalopoulos, MD (Univer-
sity of Pittsburgh, Department of Pathology). After
adequate induction of anesthesia, 13106 cells sus-
pended in 0.5 mL of sterile PBS were injected subcu-
taneously into the shoulders of male Fisher rats
(Charles River, Wilmington, MA) weighing 300– Fig 1. Equipment and set up of novel radiofrequency
400 g. Fourteen days were allowed to pass before field generator. The RF field generator consists of a
the subcutaneous tumor nodules were directly in- power source connected to transmitting and receiving
jected with either 0.5 mL gold nanoparticles or an heads. Solutions, cells in culture, or animals can be
equal volume of sterile water prior to exposure in placed into the center of the field for exposure.
the RF field at 35 W for 13 minutes. Temperatures
at the injection site were measured every minute gold nanoparticles were capable of serving as
and 48 hours were allowed to pass prior to sacrificing enhancers of heating in the externally generated
the animals and harvesting the tumor nodules. RF field (Fig 1), solutions of citrate coated, colloi-
Histopathology. Formalin fixed, RF exposed dal gold nanoparticles were used. When exposed
subcutaneous injection site samples or tumor to the field at constant powers, nearly immediate
nodules were embedded in paraffin and cut to 6- heating was observed and temperatures continued
mm thick sections. Tissues were stained with hema- to increase over a short period (Fig 2, A). Previous
toxylin and eosin and slides were assessed by a liver studies have demonstrated that temperatures of
pathologist (MN), who was blinded to treatment approximately 50°C are required for thermally in-
group, for evidence of RF induced tissue damage. duced ablation. These temperatures were achieved
Statistical analysis: Results are expressed as the within the first minute of our gold nanoparticle so-
mean ± standard error of the mean. Group com- lutions tests. To determine the effect of RF field
parisons were performed using Student’s t test or power on heating, solutions were exposed to the
ANOVA. Differences were considered significant at RF field at variable powers (10–100 W) for 3 min-
P < .05. utes. Heating was observed in a power-dependent
manner in the nanoparticle-containing solutions
RESULTS with no significant heating in the nanoparticle-
Gold nanoparticle containing solutions heat in free solutions (Fig 2, B). This data demonstrates
time- and power-dependent manners when that gold nanoparticle-containing solutions can
exposed to the RF field. To begin testing whether be heated selectively and to a degree (>50°C)
128 Cardinal et al Surgery
August 2008

Fig 2. Au-NP solutions are heated selectively and effi-

ciently in RF field. A, Solutions of Au-NP (squares) or
water (diamonds) were exposed to the RF field at 50
W and temperatures were measured over time. Results
reported are averages of 3 separate experiments. B, Solu-
tions of Au-NP (black) or water (white) were exposed to
Fig 3. In vitro cell culture demonstrates effective heating
the RF field at 10, 50, or 100 W and temperatures were
and cell death with Au-NP treated cells in the RF field. A,
measured after 3 minutes. Results reported are the aver-
Temperature of HepG2 cells exposed to 35 W in the RF
ages of 3 separate experiments.
field in the presence (squares) or absence (diamonds)
of Au-NP over a timecourse. Results reported are the av-
that is sufficient to induce cell death upon expo- erage of 3 separate experiments. B, Percent cell death as
sure to the externally generated RF field. assessed by LDH assay of HepG2 cells exposed to 35 W in
HepG2 cells cultured in the presence of gold the RF field for 3, 5 or 7 minutes in the presence (black)
nanoparticles achieve adequate heating to cause or absence (white) of Au-NP. Results reported are the
cell death upon exposure to the RF field. Given the average of 3 separate experiments. C, Western blot for
results of the solutions testing described above, we b-actin on the supernatants of HepG2 cells exposed to
set out to determine if a human liver cancer cell 35 W in the RF field in the presence or absence of Au-
line when cultured in the presence of gold nano- NP for 5 or 7 minutes.
particles and subsequently exposed to the RF field
could be heated enough to cause cell death. death were confirmed by Western blot analysis of
HepG2 cells cultured in the presence or absence the supernatants which demonstrated markedly in-
of gold nanoparticles as described in the methods creased b-actin release after 5 and 7 min of heating
section were exposed to the field at 35 W for up to (Fig 3, C) in the gold nanoparticle group. The
7 minutes. The presence of gold nanoparticles presence of gold nanoparticles alone were not di-
resulted in a time-dependent increase in heating rectly cytotoxic to our cell cultures, a finding that
(Fig 3, A). Cell death as assessed by LDH assay cor- is consistent with previous reports.20 Furthermore,
related with temperature increases, with approxi- primary rat hepatocytes incubated with gold nano-
mately 80% cell death achieved in the gold particles at 37°C for up to 12 hours did not experi-
nanoparticle treatment group after 7 min of heat- ence significant cell death compared to control
ing (Fig 3, B). Additionally, these findings of cell cells (data not shown).
Surgery Cardinal et al 129
Volume 144, Number 2

Fig 4. Au-NP injection focuses the RF field for effective tissue ablation in vivo. A, Male Buffalo rats were injected sub-
cutaneously in the shoulder with 0.5 mL of either sterile water (H2O) or Au-NP and were placed in the RF field at 35 W
for a duration of 7 minutes. Temperatures at the injection site were measured each minute. Results are reported as the
change in temperature from baseline at the site of injection. B, Histologic assessment of subcutaneous injection site in
sterile water injected animals reveals generally normal tissue architecture with no significant signs of inflammation. C,
Tissue from Au-NP injected animals treated in the RF field demonstrates loss of tissue architecture and infiltration of
inflammatory cells.

In vivo subcutaneous injections of gold we utilized a rat hepatoma model. 13106 JM-1 cells
nanoparticles result in tissue destruction upon were injected subcutaneously into the shoulders of
exposure to the RF field. Next, we aimed to Fisher rats. 14 days were allowed to pass for tumor
establish that our in vitro results with gold nanopar- nodules to grow at which time the tumors were di-
ticles could be duplicated in vivo. Male Buffalo rats rectly injected with either gold nanoparticles or
were injected subcutaneously in the shoulder with sterile water (vehicle). Upon exposure to the RF
gold nanoparticles and then exposed to the RF field at 35 W, greater temperature increases were
field at a power of 35 W. These animals experi- achieved in the gold nanoparticle-injected animals
enced significant increases in temperature at the as compared to controls (data not shown). Histo-
soft tissue injection site compared to control pathologic assessment of tumor nodules harvested
(H2O-injected) animals (Fig 4, A). Following RF 48 hours after exposure demonstrated widespread
exposure, tissue samples were obtained from injec- tumor cell disaggregation coupled with nuclear hy-
tion sites for histopathologic assessment. Tissue perchromatism, cytoplasmic retraction, and areas
taken from control animals demonstrated gener- of apoptosis and cell fragmentation (Fig 5). This
ally normal tissue architecture (Fig 4, B), while pattern of necrosis was histologically reminiscent
tissue from gold nanoparticle injected animals re- of thermal injury. A separate, patchy pattern of ad-
vealed evidence of tissue destruction as evidenced vanced confluent necrosis was also observed in
by loss of normal tissue architecture, loss of mem- both nanoparticle-injected and control water-in-
brane integrity, and infiltration of inflammatory jected tumors. Additional studies will be required
cells (Fig 4, C). to determine whether this latter change represents
In vivo gold nanoparticle injections result in local in vivo effects of water inoculation or whether
tumor ablation in a rat hepatoma model. In order it is a feature of the growth characteristics of this tu-
to achieve proof of principle that gold nanopar- mor model. The widespread thermal pattern of tu-
ticles could facilitate tumor ablation in the RF field, mor injury was not seen in control samples.
130 Cardinal et al Surgery
August 2008

Fig 5. Effect of RF field exposure on subcutaneous JM-1 hepatoma nodules. The photomicrograph compares RF expo-
sure following injection of gold nanoparticles (A, B) or sterile water (C, D) into tumors. A, Low power photomicrograph
shows relatively uniform cellular appearance of tumor with surrounding soft tissue present in upper portion of image
(H&E, 1003). B, Closer view shows areas of tumor cell disaggregation, cell fragments, hyperchromatic nuclei, and re-
tracted cytoplasm. These features are compatible with thermal injury (H&E, 6003). C, Overview of control tumor shows
area of confluent necrosis in the lower left-hand portion of the photograph with a sheet of viable tumor cells comprising
the remainder of the image (H&E 3100). D, Interface of viable tumor area (upper right) and necrotic region (lower
left) (H&E 3600).

DISCUSSION nanoparticles were targeted to subcutaneous tu-

Our results demonstrate that gold nanoparticles mors via direct intra-tumoral injections. For this
coupled with a noninvasive radiofrequency gener- technology to be clinically applicable, nanopar-
ator are a potentially novel method for ablating ticles will have to be administered noninvasively
tumors. Our in vitro cell culture tests demonstrate and subsequently targeted toward cancer cells.
that colloidal gold nanoparticles are not directly There are studies regarding the highly selective
cytotoxic but can, upon exposure to the RF field, targeting of specific cells and tissues by nano-
be heated to a degree that results in cell death. particles through the modification of their physical
We correlated our promising in vitro results with properties.18 Recently, nanoparticle delivery sys-
in vivo models in which gold nanoparticle injec- tems (20–100 nm) capable of escaping phagocytic
tions resulted in ablation of either normal tissues clearance by the reticuloendothelial system have
or subcutaneous tumor nodules from a rat hepa- been investigated.21-23 Additionally, 33 nm polyeth-
toma model. The conceivable applications of this ylene glycol-coated gold nanoparticles have been
technology are broad and include the potential incorporated with TNFa to enhance thermal
treatment of patients with nonoperative tumors induced tumor growth delay in a murine colon
as well as the possibility of treating multiple tumors cancer model.24 Furthermore, 1.9 nm gold nano-
in a single treatment session. particles delivered by IV injection have been used
While the results of this study support further to enhance radiotherapy induced tumor ablation
investigations into the use of gold nanoparticles in in a mammary cancer model.25 These reports sug-
combination with the RF generator, there are a gest that research progress is rapidly being
number of questions that remain to be answered as achieved for targeted nanoparticle delivery to
well as technical obstacles to be overcome in future cancer cells.
studies. First and foremost, the aim of the project Glypican-3, a member of the glypican family of
is to develop a noninvasive method of ablating heparin sulfate proteoglycans, has been found to
tumors as an alternative to currently available RF be overexpressed in hepatocellular cancer.26 Fur-
probes. However, in our rat hepatoma model, gold thermore, epidermal growth factor receptor
Surgery Cardinal et al 131
Volume 144, Number 2

(EGFR), a transmembrane tyrosine kinase, is over- nanotubes.29 However, like our study, the ablation
expressed in the fibrolamellar variant of HCC as model consisted of direct tumor injection of nano-
well as other cancers for which RFA is commonly tubes, and thus selective, noninvasive cancer tar-
used including breast, gastric and colorectal.27 geting remains elusive. Nonetheless, taken
Anti-EGFR antibody conjugated gold nanoparticles together these studies provide proof-of-principle
have been described with applications including that noninvasive radiowave ablation of cancer is
real time vital optical imaging as well as selective la- technically feasible, particularly when facilitated
ser photo-thermal therapy. Therefore, future inves- by nanotechnologies. While this technology holds
tigations will likely focus on developing antibody exciting potential for broad applications, signifi-
coated gold nanoparticles for targeted delivery. cant further research is needed.
In addition to targeting gold nanoparticles to tu-
mors, the radiofrequency generator has the poten- We thank Dr. George Michalopoulos for providing the
tial to be modified in such a way that a more JM-1 cells and Dr. David Waldeck for providing the gold
focused field is applied to specific sites of interest nanoparticles. This work was supported in part by a
in a manner akin to cyberknife technology that is grant from Labor, HHS, and Education Appropriations,
as well as philanthropic contributions to the UPMC Liver
currently in clinical use for the delivery of targeted
Cancer Center Research Fund.
external beam radiation. Another limitation of the
current study is that it does not address the diffu-
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