Tumor Ablation and Nanotechnology

reviews
Tumor Ablation and Nanotechnology
Rachel L. Manthe,† Susan P. Foy,† Nishanth Krishnamurthy,† Blanka Sharma,†

and Vinod Labhasetwar*,†,‡
Department of Biomedical Engineering, Lerner Research Institute, and Taussig Cancer
Institute, CleVeland Clinic, CleVeland, Ohio 44195
Received June 7, 2010; Revised Manuscript Received September 22, 2010; Accepted
September 24, 2010
Abstract: Next to surgical resection, tumor ablation is a commonly used intervention in the
treatment of solid tumors. Tumor ablation methods include thermal therapies, photodynamic
therapy, and reactive oxygen species (ROS) producing agents. Thermal therapies induce tumor
cell death via thermal energy and include radiofrequency, microwave, high intensity focused
ultrasound, and cryoablation. Photodynamic therapy and ROS producing agents cause increased
oxidative stress in tumor cells leading to apoptosis. While these therapies are safe and viable
alternatives when resection of malignancies is not feasible, they do have associated limitations
that prevent their widespread use in clinical applications. To improve the efficacy of these
treatments, nanoparticles are being studied in combination with nonsurgical ablation regimens.
In addition to better thermal effect on tumor ablation, nanoparticles can deliver anticancer
therapeutics that show a synergistic antitumor effect in the presence of heat and can also be
imaged to achieve precision in therapy. Understanding the molecular mechanism of nanoparticle-
mediated tumor ablation could further help engineer nanoparticles of appropriate composition
and properties to synergize the ablation effect. This review aims to explore the various types of
nonsurgical tumor ablation methods currently used in cancer treatment and potential improve-
ments by nanotechnology applications.
Keywords: Theranostic; microwave; radiofrequency; cryoablation; photodynamic therapy; high
intensity focused ultrasound; nanoparticles
Introduction energy X-rays and can have side effects such as structural
Surgical resection remains the standard treatment for many and functional morbidity, skin redness, cosmetic defects,
cancers. However, there are a large number of cases where vomiting, hair loss, and many others without guarantee of
surgical resection is not possible due to unfavorable location the tumor being fully eradicated.1-3
of the tumor, the presence of multiple tumors, or patient Nonsurgical tumor ablation methods have been developed
preference. Chemotherapy and radiation therapy are often with the precision and immediacy of surgery without the
used as substitutes for surgery, either alone or in combina- associated pain, potential morbidity, long hospitalization
tion.1 Nonetheless, typical chemotherapy regimens and time, and high cost.3,4 The term tumor ablation refers to the
radiation therapy require regular treatment for a number of
weeks with high doses of anticancer therapeutics or high (1) Jalali, R.; Munshi, A.; Arora, B. Curability of cancer by
radiotherapy and chemotherapy, including in neuraxial neo-
plasms. Neurol. India 2009, 57, 13–19.
* Author for correspondence. Mailing address: Department of (2) Durante, M.; Loeffler, J. S. Charged particles in radiation
Biomedical Engineering/ND-20, Lerner Research Institute, Cleve- oncology. Nat. ReV. Clin. Oncol. 2010, 7, 37–43.
land Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. Tel: (3) Triesscheijn, M.; Baas, P.; Schellens, J. H.; Stewart, F. A.
216/445-9364. Fax: 216/444-9198. E-mail: labhasv@ Photodynamic therapy in oncology. Oncologist 2006, 11, 1034–
ccf.org. 1044.
†
Department of Biomedical Engineering, Lerner Research Institute. (4) Kennedy, J. E. High-intensity focused ultrasound in the treatment
‡
Taussig Cancer Institute. of solid tumours. Nat. ReV. Cancer 2005, 5, 321–327.
1880 MOLECULAR PHARMACEUTICS VOL. 7, NO. 6, 1880–1898 10.1021/mp1001944  2010 American Chemical Society
Published on Web 09/24/2010
Tumor Ablation reviews
Table 1. A Summary of Current Tumor Ablation Therapies

treatment area of efficacy advantages disadvantages side effects
radiofrequency (RF) liver, lung, bone, minimal side effects, relatively small heating range, requires postablation syndrome, skin
breast, kidney, safe, inexpensive efficient grounding pads, heat sink burns
adrenals procedure effect
microwave (MW) liver, lung, bone, less heat sink effect, no local treatment, nonspecific postablation syndrome
breast, kidney, grounding pads, larger area
adrenals of ablation
cryoablation prostate, kidney, can be done with US, CT, heat-sink effect, recurrence cryo-shock
liver, lung, MRI guidance, same day more often than RF or MW
bone, breast procedure
photodynamic therapy head, neck, minimal long-term side painful procedure, skin prolonged light sensitivity
(PDT) esophagus, effects, superior healing, no photosensitivity, cannot treat
bladder, skin, scarring deeply set tumors
lung, brain
high intensity focused liver, kidney, confined accurate lesion, difficult to focus US wave, skin burns, organ system specific
ultrasound (HIFU) pancreas, completely noninvasive, expensive, long procedure side effects
breast, nontoxic time, difficult to maneuver
prostate, near air pockets, or bone
abdomen
chemotherapy/radiation all well-known, most used and recurrence, long procedure, hair loss, vomiting, cosmetic
therapy effective multiple dose regimen, defects, functional morbidity
many side effects
complete destruction of a tumor by the direct application of the tumor’s rapidly formed vasculature and the enhanced
chemical or thermal therapies while sparing nearby vital and permeability and retention (EPR) effect to help target and
healthy structures.5,6 The ablation area often includes treat- advance the efficiency of these treatments. The tumor tissue
ment of a 0.5-1 cm margin of normal tissues adjacent to is highly vascular, and the ill-formed blood vessels are highly
the lesion.7 Several local tumor ablation methods developed permeable to different macromolecules such as lipids, plasma
for the treatment of unresectable tumors in various organs proteins, and nanoparticles. The poor lymphatic clearance
include thermal therapies, photodynamic therapy (PDT), and causes the increased retention of these compounds within
agents that produce reactive oxygen species (ROS).3,8-10 the tumor tissue. This review will explore the various types
While nonsurgical tumor ablation therapies are minimally of nonsurgical tumor ablation methods currently in use. An
invasive options to conventional surgery, these therapies have overview of these methods and a summary of their advan-
their own challenges, such as achieving a balance between tages and disadvantages are listed in Table 1 and will be
accurate targeting and minimizing damage to surrounding discussed in greater detail throughout this review. For each
vital organs and structures. To eliminate some of the technology, the basic principle, methodology, and equipment
limitations and increase the efficacy of these ablative used will be explained, as well as the associated benefits
therapies for cancer treatment, nanomaterials, composed of and limitations. Improvements to these treatments through
metals, lipids, or polymers, have emerged with promising nanotechnology applications will also be analyzed and
applications and results.11 Nanoparticles take advantage of discussed. A brief overview of the mechanisms of tumor
ablation provided by various types of nanoparticles is
(5) Rybak, L. D. Fire and ice: thermal ablation of musculoskeletal included in Table 2.
tumors. Radiol. Clin. North Am. 2009, 47, 455–469.
(6) Cavaleri, M.; Riva, S.; Valagussa, A.; Guanci, M.; Colombo, Thermal Therapies
L.; Dowell, J.; Stogniew, M. Pharmacokinetics and excretion of
dalbavancin in the rat. J. Antimicrob. Chemother. 2005, 55 Thermal therapies use radiofrequency, microwaves, cryoa-
(Suppl. 2), ii31–ii35. blation, or focused ultrasound for the delivery of thermal
(7) Goldberg, S. N. Radiofrequency tumor ablation: principles and energy to destroy tumor tissue.8,9 All thermal therapies offer
techniques. Eur. J. Ultrasound 2001, 13, 129–147. the advantage of flexible, low cost treatment approaches
(8) McTaggart, R. A.; Dupuy, D. E. Thermal ablation of lung tumors. including percutaneous, laparoscopic, and open surgical
Tech. Vasc. InterV. Radiol. 2007, 10, 102–113. access.12 Thermal therapies are also minimally invasive
(9) O’Neal, D. P.; Hirsch, L. R.; Halas, N. J.; Payne, J. D.; West,
outpatient procedures with repeatability and reproducibility
J. L. Photo-thermal tumor ablation in mice using near infrared-
absorbing nanoparticles. Cancer Lett. 2004, 209, 171–176. of results between patients.8,9 These therapies have limited
(10) Wang, J.; Yi, J. Cancer cell killing via ROS: to increase or procedural pain with the patient usually under conscious
decrease, that is the question. Cancer Biol. Ther. 2008, 7, 1875–
1884. (12) Carrafiello, G.; Lagana, D.; Mangini, M.; Fontana, F.; Dionigi,
(11) Juzenas, P.; Chen, W.; Sun, Y. P.; Coelho, M. A.; Generalov, G.; Boni, L.; Rovera, F.; Cuffari, S.; Fugazzola, C. Microwave
R.; Generalova, N.; Christensen, I. L. Quantum dots and tumors ablation: principles, clinical applications and review of
nanoparticles for photodynamic and radiation therapies of cancer. preliminary experiences. Int. J. Surg. 2008, 6 (Suppl. 1), S65–
AdV. Drug DeliVery ReV. 2008, 60, 1600–1614. S69.
VOL. 7, NO. 6 MOLECULAR PHARMACEUTICS 1881
1882
Table 2. Nanoparticle Formulations and Mechanisms of Tumor Ablationa
nanoparticle characteristics agents encapsulated
reviews
mechanism of and additional

nanoparticle type tumor ablation sizeb zeta ζ properties system cell type ref
iron oxide NPs coated MW 30-50 nm targeting, folic acid; in vivo S180 mouse tumor sarcoma Nie et al.33
with polyaniline imaging, thermoacoustic
imaging
SWNTs MW hyperthermia d 1-2 nm × l 5-30 µm tissue mimicking mixtures Mashal et al.32
Fe3O4, Fe2O3 NPs MW hyperthermia 3.2-5.3 nm Janmaleki et al.162
AuNPs drug-NP-ROS 15 nm combination therapy: in vitro human MCF7 breast cancer and Ito et al.92
5-aminolevulinic acid + HepG2 hepatocellular
citrate AuNPs carcinoma
PVP coated AgNPs ROS 118-121 nm -21.8 mV in vitro BRL3A rat liver cells and rat Foldbjerg et al.83
alveolar macrophages
polymer nanosphere, drug-ROS 52-56 nm, (-7.9)-(-2.9) mV, drug: ferrocenyl tamoxifen in vitro human MELN (MCF 7 breast Nguyen et al.91
vesicular nanocapsules 130-180 nm (-57.8)-(-44.0) mV derivatives cancer)
mPEG-PCL polymer drug-ROS 87.5 nm -5.6 mV drug: resveratrol in vitro rat C6 glioma cells Shao et al.90
MOLECULAR PHARMACEUTICS VOL. 7, NO. 6

mPEG-PCL polymer drug-ROS 75.3 nm -6.1 mV drug: tetrandrine in vitro human colorectal cancer cells Li et al.89
(LOVO)
chitosan nanoparticles ROS 40-100 nm +50 mV in vitro, in vivo human hepatoma BEL7402 Qi et al.88
mesoporous silica NPs AO increase, 110 nm (-35.6)-(+27.5) mV promote tumor growth in vitro, in vivo A375 human malignant Huang et al.96
ROS depletion melanoma
silica NPs ROS 15-46 nm in vitro A549 human bronchoalveolar Lin et al.87
carcinomas
“liposils”: hollow ceramic MW, US 100 nm -40 mV encapsulate: congo red Steinberg34
silica spheres and other dyes
polystyrene nanospheres HIFU 100-200 nm encapsulate: dyes in vivo muscle Hancock55
temperature sensitive US hyperthermia 140 nm drug: doxorubicin in vivo human squamous cell carcinoma Kong et al.163
liposomes xenograft in mice
temperature sensitive HIFU hyperthermia, drug: doxorubicin in vitro, in vivo murine adenocarcinoma Dromi et al.28
liposomes ThermoDox RF, US phase I, II, III hepatocellular carcinoma, and ClinicalTrials.
clinical trials recurrent breast cancer at chest gov126,128
wall
liposomes HIFU 210 nm encapsulate: FITC Chen et al.51
aerosol OT (AOT)- PDT, ROS 62 nm -25.1 mV encapsulate, methylene in vitro drug resistant NCI/ADR RES Khdair et al.122
alginate nanoparticles blue; drug, doxorubicin
polyacrylamide, sol-gel PDT 20-30 nm, 190 nm, encapsulate: methylene blue in vitro rat C6 glioma cells Tang et al.118
silica, or organically 160 nm
modified silicate
(ORMOSIL)
gold nanoparticles in PDT Zn(II)-phthalocyanine in vivo amelanotic melanoma Camerin et al.119
Cremophor emulsion disulfide
ZnO nanoparticles PDT drug: daunorubicin in vitro drug resistant leukemia K562/A02 Guo et al.144
a
Abbreviations: AgNPs, silver nanoparticles; AO, antioxidant; AuNPs, gold nanoparticles; NPs, nanoparticles; mPEG-PCL, methoxy poly(ethylene glycol)-poly(caprolactone); PVP, poly
vinyl pyrrolidone; ZnO, zinc oxide. b Size may be core diameter determined by electron microscopy or hydrodynamic diameter determined by dynamic light scattering.
Manthe et al.
Figure 1. Comparison of monopolar wet RF (A) with bipolar wet RF (B). The bipolar method does not require a
grounding pad and has two saline infusions in the tissue which requires two separate probe insertions. Images
courtesy of Dr. Afshin Gangi.
sedation; however, if pain persists, general anesthetic can a high frequency (375-500 kHz) alternating current, creating
be administered.8 The major disadvantage of thermal thera- a voltage between the tip of the probe and one or more
pies is that they are local treatments and cannot be used to grounding pads placed on the patient within the vicinity of
treat systemic ailments. the treatment site (Figure 1A).5 RF ablation initially produces
Radiofrequency. Radiofrequency (RF) ablation is cur- a heating zone through the friction caused by rapid oscillation
rently the most popular and widely used thermal therapy for of ions present within the tissue. The heat from the friction
the treatment of solid malignancies of the liver, lung, bone, then dissipates further out from the focal point at the probe
breast, kidney, and adrenals.13-20 Radiofrequency works by tip via thermal conduction. The initial active heating zone
creating a complete electrical circuit through the body of can produce an effective and uniform ablation zone. How-
the patient.5,20 An RF probe is inserted directly into the ever, thermal conduction is inversely proportional to distance,
treatment area using image-guided ultrasound (US), com- and as you move further from the active heat produced from
puted tomography (CT), magnetic resonance imaging (MRI), friction, lower temperatures result.
or general surgical techniques. An RF generator then delivers Ideally, the temperature achieved during RF ablation is
around 60 °C, as temperatures in the range of 50-60 °C
(13) Belfiore, G.; Tedeschi, E.; Ronza, F. M.; Belfiore, M. P.; Della induce cellular death via coagulation necrosis, and temper-
Volpe, T.; Zeppetella, G.; Rotondo, A. Radiofrequency ablation atures in excess of 60 °C cause instantaneous cell death.7,20
of bone metastases induces long-lasting palliation in patients with Temperatures above 100 °C result in tissue boiling and
untreatable cancer. Singapore Med. J. 2008, 49, 565–570. charring, which actually decreases the ablation area.7,21 The
(14) Breen, D. J.; Rutherford, E. E.; Stedman, B.; Roy-Choudhury,
boiling and charring of the tissue causes an increase in the
S. H.; Cast, J. E.; Hayes, M. C.; Smart, C. J. Management of
renal tumors by image-guided radiofrequency ablation: experi- thermal resistance of the tissue, which reduces the amount
ence in 105 tumors. CardioVasc. InterVent. Radiol. 2007, 30, of heat dissipated through the charred tissue. Therefore, in
936–942. order to maximize the results of RF, it is important to
(15) Dupuy, D. E.; Goldberg, S. N. Image-guided radiofrequency maintain an appropriate temperature level throughout the
tumor ablation: challenges and opportunities--part II. J. Vasc. procedure. The power deposition in the ablation zone is
InterV. Radiol. 2001, 12, 1135–1148. strongly dependent on the electrical conductivity of the target
(16) Oura, S.; Tamaki, T.; Hirai, I.; Yoshimasu, T.; Ohta, F.;
tissue.7 By increasing the ions present in the target tissue it
Nakamura, R.; Okamura, Y. Radiofrequency ablation therapy
in patients with breast cancers two centimeters or less in size. is possible to increase the area of the ablation zone. Several
Breast Cancer 2007, 14, 48–54. techniques, such as injecting saline into the tissue prior to
(17) Salmi, A.; Turrini, R.; Lanzani, G.; Savio, A.; Anglani, L. or during the RF procedure, can cause increased electrical
Efficacy of radiofrequency ablation of hepatocellular carcinoma conductivity and a larger active heating area.
associated with chronic liver disease without cirrhosis. Int. The efficacy of RF ablation is also highly dependent on
J. Med. Sci. 2008, 5, 327–332. the probe design. Each RF probe usually comprises a metal
(18) Thanos, L.; Mylona, S.; Pomoni, M.; Athanassiadi, K.; Theakos,
shaft that is insulated except for an exposed conductive tip,
N.; Zoganas, L.; Batakis, N. Percutaneous radiofrequency thermal
ablation of primary and metastatic lung tumors. Eur. J. Cardio- which is in direct electrical contact with the desired target
thorac. Surg. 2006, 30, 797–800. tissue.7 Probes can range from single-tip monopolar probes
(19) Wong, J.; Lee, K. F.; Lee, P. S.; Ho, S. S.; Yu, S. C.; Ng, W. W.; to more complex multipolar cluster arrays, and include
Cheung, Y. S.; Tsang, Y. Y.; Ling, E.; Lai, P. B. Radiofrequency designs such as multitoned expandable probes, needle
ablation for 110 malignant liver tumours: preliminary results on
percutaneous and surgical approaches. Asian J. Surg. 2009, 32, (21) Goldberg, S. N.; Gazelle, G. S.; Halpern, E. F.; Rittman, W. J.;
13–20. Mueller, P. R.; Rosenthal, D. I. Radiofrequency tissue ablation:
(20) Brace, C. L. Radiofrequency and microwave ablation of the liver, importance of local temperature along the electrode tip exposure
lung, kidney, and bone: what are the differences. Curr. Probl. in determining lesion shape and size. Acad. Radiol. 1996, 3, 212–
Diagn. Radiol. 2009, 38, 135–143. 218.
reviews Manthe et al.
perfusion probes, and cool-tip probes. In general, monopolar

probes allow for a larger heating zone around the probe and
limited invasiveness, while multipolar arrays have more
localized and effective heating in the area between the probes
and no need for grounding pads (Figure 1B).20 Multipolar
arrays require additional probe insertions and often saline
infusion to improve results.20 Overall, the choice of the probe
depends largely on the size of the tissue to be ablated and
the proximity to vital organs and structures. The size of the
area heated is affected by the overall length and size of the
probe tip; therefore, it is vital to use the correct probe for
each procedure.5 Figure 2. A 54-year-old man with colon cancer. A CT
RF is an effective and safe treatment for tumor ablation, scan obtained 3 months after right hepatectomy (left)
but there are potential side effects. The grounding pads shows hepatic 3 cm diameter metastasis (arrow). A CT
required to complete the electrical circuit through the patient scan obtained at the same level 2 months after
can cause skin burns. Patients can exhibit postablation radiofrequency ablation of tumor (right) shows hypodense
syndrome, characterized by flulike symptoms including low- “scar.” The scarred area is completely covering the site of
the metastasis. Reprinted with permission from ref 161.
grade fever, depression, nausea, and/or vomiting that can last
Copyright 2000 Journal of Roentgenology.
up to two weeks after the procedure. RF technology is also
limited by the requirement for invasive needle placement, also cause damage to surrounding tissues. Because the heat
accuracy of image-guidance, and ablation size limits due to diffuses so rapidly, it is difficult to target a concentrated area
probe designs.22 Moreover, RF is a relatively nonspecific and have it be large enough to eradicate the entire malig-
treatment. Although the RF probe is positioned into the target nancy. Furthermore, it requires invasive needle placement
ablation zone, the range of heating cannot be controlled and to reach deeply set tumors. Also, tumors need to be treated
thermal damage occurs in both malignant and normal cells to within 0.5-1 mm of the periphery to ensure that
surrounding the RF probe. The other issue that arises with retreatment is not necessary, and often this is not feasible
RF ablation is its power dissipation with distance away from due to the heating range of a standard needle probe.25
the probe. Although it is possible to heat the target zone for Nanoparticles provide unique characteristics that can be
long enough to destroy all malignant cells, because of the combined with the existing effects of RF treatments. Gold
rapid dispersion of heat and lack of concentration, to destroy nanoparticles and single-walled carbon nanotubes (SWNTs)
all malignant cells in one area a margin beyond that area is generate heat in excess of 50 °C when subjected to RF
also affected. This may not destroy the cells within that radiation. It is possible that the high aspect ratio and resistive
margin; however, the damage can still leave a scar (Figure conductivity of these particles contributes to their acute
2). This method of passive heating faces the same common heating capabilities.22,26 This excess heat can be used in the
problem that is associated with many thermal therapies same manner as a traditional RF treatment to cause coagula-
known as the heat-sink effect. The heat sink effect is tissue tion necrosis in tumor tissues. Nanoparticles also do not
cooling by nearby vessels that carry away heat via thermal require an electrical circuit to function. The nanoparticles
convection. This cooling effect of blood flow is most produce heat by converting the energy from RF waves, rather
prominent within zones of conductive heat transfer as seen than by friction in the tissue.5,22 In addition, nanoparticles
in RF.23 Overall, the heat sink effect is detrimental to the have the ability to be targeted to specific organs and even
RF procedure because it inhibits the dissipation of heat tissues with different receptors, ligands, and antibodies.27
through the tissue and adequate ablation of perivascular
tissue.24 (25) Goldberg, S. N.; Gazelle, G. S.; Solbiati, L.; Livraghi, T.; Tanabe,
Coagulation necrosis via RF treatment is the most widely K. K.; Hahn, P. F.; Mueller, P. R. Ablation of liver tumors using
accepted thermal ablative method currently in practice. percutaneous RF therapy. Am. J. Roentgenol. 1998, 170, 1023–
Although it is useful to treat unresectable tumors, it is limited 1028.
(26) Gannon, C. J.; Patra, C. R.; Bhattacharya, R.; Mukherjee, P.;
by its inability to eliminate larger malignancies, and it can Curley, S. A. Intracellular gold nanoparticles enhance non-
invasive radiofrequency thermal destruction of human gas-
(22) Cardinal, J.; Klune, J. R.; Chory, E.; Jeyabalan, G.; Kanzius, trointestinal cancer cells. J. Nanobiotechnol. 2008, 6, 2.
J. S.; Nalesnik, M.; Geller, D. A. Noninvasive radiofrequency (27) Paciotti, G. F.; Myer, L.; Weinreich, D.; Goia, D.; Pavel, N.;
ablation of cancer targeted by gold nanoparticles. Surgery 2008, McLaughlin, R. E.; Tamarkin, L. Colloidal gold: a novel
144, 125–132. nanoparticle vector for tumor directed drug delivery. Drug
(23) Liang, P.; Wang, Y. Microwave ablation of hepatocellular DeliVery 2004, 11, 169–183.
carcinoma. Oncology 2007, 72 Suppl 1, 124–131. (28) Dromi, S.; Frenkel, V.; Luk, A.; Traughber, B.; Angstadt, M.;
(24) Lu, D. S.; Raman, S. S.; Vodopich, D. J.; Wang, M.; Sayre, J.; Bur, M.; Poff, J.; Xie, J.; Libutti, S. K.; Li, K. C.; Wood, B. J.
Lassman, C. Effect of vessel size on creation of hepatic Pulsed-high intensity focused ultrasound and low temperature-
radiofrequency lesions in pigs: assessment of the “heat sink” sensitive liposomes for enhanced targeted drug delivery and
effect. Am. J. Roentgenol. 2002, 178, 47–51. antitumor effect. Clin. Cancer Res. 2007, 13, 2722–2727.
1884 MOLECULAR PHARMACEUTICS VOL. 7, NO. 6
Combining these two qualities, nanoparticle formulations can

be made that selectively treat tumor cells without the need
for invasive procedures or multiple treatments. Destruction
of malignant cells in combination with RF therapy can be
further enhanced with temperature responsive liposomes that
carry various cytotoxic drugs.28 Such nanoparticles in
combination with RF and hyperthermia are currently being
evaluated in phase I-III clinical trials for the treatment of
both hepatocellular carcinomas and recurrent breast cancer
at the chest wall. Combinations of drug and heat can destroy
the entire tumor limiting cytotoxic effects to other tissue or
organs.
Nanoparticles are a novel and developing subject in the
research field. Their functionality can greatly enhance the
Figure 3. Heating pattern around a microwave antennae
efficacy of RF treatment. Nevertheless, they still have some
probe where the active heating range extends almost to
problems. When entering the body, the nanoparticles need
2 cm in diameter. A larger active heating range
to make it to the target site to be effective. In most cases
provides a more effective tumor kill, as well as greater
though, they are cleared by the reticuloendothelial system efficacy near vasculature. Reprinted with permission
(RES) before they can reach the target site.29 Lack of from ref 20. Copyright 2009 Elsevier.
clearance can also be an issue in nanoparticles that build up
with multiple treatments, e.g. long-term effects of residual Conversely, the transmission of MW in tissue does not rely
gold particles are not known. Overall the enhancements that on the conduction of electricity and consequently is not
nanoparticles provide to the existing RF method make it a reliant on thermal conduction (Figure 3).20,31 Microwave
very viable treatment option. ablation uses an active heating method as its primary means
Microwaves. Microwave (MW) ablation is a thermal of thermal ablation, so there is a more uniform heating pattern
therapy for numerous malignancies. Similar to RF ablation, allowing for a larger heating zone. Electromagnetic waves
MW ablation induces cellular death via coagulation necrosis target polar ions such as water in the tissue, so grounding
by generating heat. Conversely, while RF employs radio- pads are not required to create a circuit as in RF treatments.
frequency current to generate this heat, MW ablation Nevertheless, MW ablation is only a local treatment and has
produces an electromagnetic wave that is emitted from a 14.5 side effects including postablation syndrome and pleural
gauge microwave antenna placed directly within the treat- effusions.23 MW ablation is less affected by the perfusion-
ment site. The electromagnetic wave produces 60 W of mediated “heat sink” effect commonly observed in RF.30,31
power at a frequency ranging from 900 to 2450 MHz, which Since MW ablation produces zones of active heating rather
generates frictional heat from the agitation of polar water than conduction zones, MW ablation greatly eliminates the
molecules.8,23,30 As the electromagnetic wave passes through potential for the heat sink effect. As a result, MW therapy
the tissue, it causes polar water molecules to rapidly change may also allow for more uniform and complete tumor kill
their orientation in accordance with the magnetic field. The in areas next to large vessels.23,31
efficiency of MW therapy also depends heavily on the
There are multiple methods that can employ MW heating
antenna design. Ablation zones need to extend 5-10 mm
for enhancing nanoparticle tumor ablation, from selectively
beyond the tumor.23 Thus, designs with longer antenna
increasing the heating at the site of the tumor to promoting
lengths capable of producing larger coagulation diameters
drug release through deformations in nanoparticle capsules
are preferable.
(Figure 4). Nanoparticles are just beginning to be used in
Radiofrequency and microwave ablation share the benefits combination with MW as an ablation technique. Nanopar-
common to thermal therapies; however, MW ablation offers ticles such as SWNTs and iron oxide formulations have the
significant improvements over RF.31 The most important
distinction between these two techniques is that RF heating
(32) Mashal, A.; Sitharaman, B.; Li, X.; Avti, P. K.; Sahakian, A. V.;
is primarily passive and generally only produces an active
Booske, J. H.; Hagness, S. C. Toward carbon-nanotube-based
heating zone of several millimeters around the probe tip.20,30 theranostic agents for microwave detection and treatment of
breast cancer: enhanced dielectric and heating response of tissue-
(29) Brannon-Peppas, L.; Blanchette, J. O. Nanoparticle and targeted mimicking materials. IEEE Trans. Biomed. Eng. 2010, 57, 1831–
systems for cancer therapy. AdV. Drug DeliVery ReV. 2004, 56, 1834.
1649–1659. (33) Nie, L.; Ou, Z.; Yang, S.; Xing, D. Thermoacoustic molecular
(30) Simon, C. J.; Dupuy, D. E.; Mayo-Smith, W. W. Microwave tomography with magnetic nanoparticle contrast agents for
ablation: principles and applications. Radiographics. 2005, 25 targeted tumor detection. Med. Phys. 2010, 37, 4193–4200.
(Suppl. 1), S69–S83. (34) Steinberg, Y.; Schroeder, A.; Talmon, Y.; Schmidt, J.; Khalfin,
(31) Wright, A. S.; Sampson, L. A.; Warner, T. F.; Mahvi, D. M.; R. L.; Cohen, Y.; Devoisselle, J. M.; Begu, S.; Avnir, D.
Lee, F. T. Radiofrequency versus microwave ablation in a hepatic Triggered release of aqueous content from liposome-derived sol-
porcine model. Radiology 2005, 236, 132–139. gel nanocapsules. Langmuir 2007, 23, 12024–12031.
Figure 4. Illustration of nanoparticle-mediated tumor ablation. Nanoparticles containing drug or dye (1) are
intravenously injected and extravasate into tumor tissue through the leaky vasculature by the EPR effect (2).
Photoirradiation or hyperthermia (3) generates singlet oxygen or facilitates drug release from nanoparticles within the
tumor (4) leading to tumor apoptosis and necrosis (5). Radiofrequency (RF), microwave (MW), high intensity focused
ultrasound (HIFU), reactive oxygen species (ROS).
advantages of generating additional heat and can be imaged causing the temperature within the focus site to elevate above
to simultaneously guide and monitor the hyperthermia within 60 °C.42 As a result, HIFU induces cellular death by thermal
malignant tissue. Active targeting with folic acid can further necrosis, apoptosis, and acoustic cavitation.42,44 Acoustic
enhance the signal of iron oxide nanoparticles by up to 5-fold cavitation occurs when ultrasonic waves form small cavities
within the tumor compared to nontargeted particles, increas-
ing the local thermoacoustic signal and thus temperature.32,33 (35) Huber, P. E.; Jenne, J. W.; Rastert, R.; Simiantonakis, I.; Sinn,
Non-metal-based formulations can also provide additional H. P.; Strittmatter, H. J.; von Fournier, D.; Wannenmacher, M. F.;
therapies with MW application through modification of the Debus, J. A new noninvasive approach in breast cancer therapy
particles with MW frequencies. Liposils, i.e. 100 nm silica using magnetic resonance imaging-guided focused ultrasound
shells (∼10 nm thick) synthesized around intact liposomes, surgery. Cancer Res. 2001, 61, 8441–8447.
(36) Kim, Y. S.; Rhim, H.; Choi, M. J.; Lim, H. K.; Choi, D. High-
do not release their payload at temperatures below 260 °C,
intensity focused ultrasound therapy: an overview for radiologists.
but triggered release occurs with short (<30 s) MW applica- Korean J. Radiol. 2008, 9, 291–302.
tion possibly through fissures forming in the surface of the (37) Li, J. J.; Xu, G. L.; Gu, M. F.; Luo, G. Y.; Rong, Z.; Wu, P. H.;
particles through steam buildup.34 These liposils, which are Xia, J. C. Complications of high intensity focused ultrasound in
also coated with PEG phospholipids to reduce their aggrega- patients with recurrent and metastatic abdominal tumors. World
tion, may better evade RES uptake in ViVo and prevent J. Gastroenterol. 2007, 13, 2747–2751.
systemic toxicity by only releasing their contents when heated (38) Maestroni, U.; Ziveri, M.; Azzolini, N.; Dinale, F.; Ziglioli, F.;
Campaniello, G.; Frattini, A.; Ferretti, S. High Intensity Focused
with MW at the tumor.
Ultrasound (HIFU): a useful alternative choice in prostate cancer
High Intensity Focused Ultrasound. High intensity focused treatment. Preliminary results. Acta Biomed. 2008, 79, 211–216.
ultrasound (HIFU), also commonly known as focused (39) Xiong, L. L.; Hwang, J. H.; Huang, X. B.; Yao, S. S.; He, C. J.;
ultrasound surgery, is a noninvasive treatment for deep Ge, X. H.; Ge, H. Y.; Wang, X. F. Early clinical experience
tumors of the liver, kidney, pancreas, breast, prostate, and using high intensity focused ultrasound for palliation of inoper-
abdomen.4,35-41 In this therapy, ultrasonic beams delivered able pancreatic cancer. J. Pancreas 2009, 10, 123–129.
from an extracorporeal source are focused into the target (40) Klatte, T.; Marberger, M. High-intensity focused ultrasound for
the treatment of renal masses: current status and future potential.
tissue.39,42 The ultrasound source ranges from single-element
Curr. Opin. Urol. 2009, 19, 188–191.
transducers to phased arrays, and can be focused either (41) Zhang, L.; Zhu, H.; Jin, C.; Zhou, K.; Li, K.; Su, H.; Chen, W.;
mechanically, using a focusing lens, or electronically by Bai, J.; Wang, Z. High-intensity focused ultrasound (HIFU):
phasing an array of transducers.43 As the HIFU beam is effective and safe therapy for hepatocellular carcinoma adjacent
focused into the target tissue, acoustic energy is absorbed, to major hepatic veins. Eur. Radiol. 2009, 19, 437–445.
within the tissue. Additional ultrasonic excitation leads to ability of HIFU and hinder treatment success.43,48,49 Thus,
volumetric pulsation of these cavities, also known as targeting is extremely important to the HIFU procedure and
bubbles.44 advances in using MR-imaging guidance can help eradicate
Acoustic intensities of HIFU are several orders of mag- some of these problems.36,50
nitude greater than those of diagnostic ultrasound.39 Diag- In addition to inducing local hyperthermia and acoustic
nostic ultrasound typically produces time averaged acoustic cavitation to cause tumor ablation, HIFU can also enhance
intensities around 100 mW/cm2, whereas HIFU can deliver drug release from drug delivery systems such as nanoparticles
intensities at focus that are over 10 kW/cm2.45 HIFU can and liposomes through their destruction or degradation.
produce peak compression pressures up to 30 MPa and peak Controlled drug release can be difficult when particles are
rarefaction pressures up to 10 MPa.39,45 By combining these in the nanometer size range, but this drug release can be
high acoustic intensities with the focused nature of HIFU, enhanced with HIFU in the MHz range. HIFU generates
the acoustic intensities are only high within the treatment fractures in the liposomes, resulting in rupture of liposomes
site.36,42 Outside the region the acoustic intensities remain >100 nm in size, or porelike defects in smaller liposomes
low, which minimizes damage to the surrounding healthy <100 nm in size, both of which lead to release of the
nanoparticle contents.51 In order to avoid rapid clearance,
tissue and helps preserve much of the tissue architecture.36,42
PEG is covalently attached to lipid liposomes. PEG and
This ability to generate a highly confined lesion is the main
oligo(ethylene glycol) surfactants further increase the sen-
advantage of HIFU.44 However, the tight focus and high
sitivity of the liposomal membrane to break up by ultrasound
pressures of HIFU also make adaptive focusing due to body
enhancing drug release up to 10-fold.52 Through sonopora-
movement extremely challenging and limit the wide applica-
tion, cavitation can further facilitate drug delivery, though
tion of this technology.44,46 Compared to the other thermal
this only occurs at the cellular level where the membrane is
therapies, HIFU is truly a noninvasive procedure, and open for seconds.53,54
therefore does not require an incision or percutaneous
Specially designed temperature sensitive particles can be
insertion of a probe.
synthesized to rapidly release their payload in response to
The noninvasiveness of the procedure allows HIFU to be small increases in temperature (4-5 °C) generated from
less toxic than other ablation therapies.45 Nevertheless, HIFU pulsed HIFU. Low temperature-sensitive liposomes stimu-
does have associated procedural complications, including lated to 42 °C for only 2 min can release 50% of their drug
skin burns, soft tissue damage in adjacent organs, and organ payload reducing tumor growth in murine adenocarcinomas,
system specific side effects.36,44 Other disadvantages of HIFU while no release is detected in non-thermosensitive liposomes
include long procedural time, difficulty in targeting and under the same conditions.28 Interestingly, pulsed HIFU for
monitoring moving organs, and relatively high procedural only 2 min can significantly enhance polystyrene nanoparticle
cost.36 uptake when injected up to 24 h post-treatment through
One major limitation of HIFU is that the presence of bones
and gas pockets in the region surrounding the ablation zone (48) Damianou, C. MRI monitoring of the effect of tissue interfaces
can lead to thermal damage due to the increase in delivered in the penetration of high intensity focused ultrasound in kidney
energy at the soft tissue boundaries with air or bone.43,47 in vivo. Ultrasound Med. Biol. 2004, 30, 1209–1215.
(49) Kennedy, J. E.; Ter Haar, G. R.; Cranston, D. High intensity
Both gas pockets and bone can interfere with the focusing
focused ultrasound: surgery of the future. Br. J. Radiol. 2003,
76, 590–599.
(42) Ji, X.; Bai, J. F.; Shen, G. F.; Chen, Y. Z. High-intensity focused (50) Mikami, K.; Murakami, T.; Okada, A.; Osuga, K.; Tomoda, K.;
ultrasound with large scale spherical phased array for the ablation Nakamura, H. Magnetic resonance imaging-guided focused
of deep tumors. J. Zhejiang UniV. Sci. B 2009, 10, 639–647. ultrasound ablation of uterine fibroids: early clinical experience.
(43) Zderic, V.; Foley, J.; Luo, W.; Vaezy, S. Prevention of post- Radiat. Med. 2008, 26, 198–205.
focal thermal damage by formation of bubbles at the focus during (51) Chen, D.; Wu, J. An in vitro feasibility study of controlled drug
high intensity focused ultrasound therapy. Med. Phys. 2008, 35, release from encapsulated nanometer liposomes using high
4292–4299. intensity focused ultrasound. Ultrasonics 2010, 50, 744–749.
(44) Barqawi, A. B.; Crawford, E. D. Emerging role of HIFU as a (52) Lin, H.-Y.; Thomas, J. L. PEG-Lipids and Oligo(ethylene glycol)
noninvasive ablative method to treat localized prostate cancer. Surfactants Enhance the Ultrasonic Permeabilizability of Lipo-
Oncology (Williston Park) 2008, 22, 123–129. somes. Langmuir 2003, 19, 1098–1105.
(45) Dubinsky, T. J.; Cuevas, C.; Dighe, M. K.; Kolokythas, O.; (53) O’Neill, B. E.; Vo, H.; Angstadt, M.; Li, K. P.; Quinn, T.;
Hwang, J. H. High-intensity focused ultrasound: current potential Frenkel, V. Pulsed high intensity focused ultrasound mediated
and oncologic applications. Am. J. Roentgenol. 2008, 190, 191– nanoparticle delivery: mechanisms and efficacy in murine
199. muscle. Ultrasound Med. Biol. 2009, 35, 416–424.
(46) Canney, M. S.; Bailey, M. R.; Crum, L. A.; Khokhlova, V. A.; (54) Deng, C. X.; Sieling, F.; Pan, H.; Cui, J. Ultrasound-induced cell
Sapozhnikov, O. A. Acoustic characterization of high intensity membrane porosity. Ultrasound Med. Biol. 2004, 30, 519–526.
focused ultrasound fields: a combined measurement and model- (55) Hancock, H. A.; Smith, L. H.; Cuesta, J.; Durrani, A. K.;
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(47) Myers, M. R. Transient temperature rise due to ultrasound tions into pulsed high-intensity focused ultrasound-enhanced
absorption at a bone/soft-tissue interface. J. Acoust. Soc. Am. delivery: preliminary evidence for a novel mechanism. Ultra-
2004, 115, 2887–2891. sound Med. Biol. 2009, 35, 1722–1736.
nondestructive reversible structural changes.53,55 Because

hyperthermia and acoustic cavitation are transient phenom-
ena, this suggests that a third mechanism, such as weak
mechanical forces like radiation or shear forces, may also
play a role in HIFU tissue interaction to further enhance
nanoparticle uptake and drug delivery.55
Cryoablation. Cryoablation is used to treat benign and
malignant lesions of the prostate, kidney, liver, lung, bone,
and breast.56-61 The procedure can be performed either by
a laparoscopic or percutaneous approach under US, CT, or
MRI guidance.8,62 Cryoablation involves a number of
freeze-thaw-freeze cycles with argon and helium gas.8
Argon gas is used to remove heat from the target site, and
helium gas causes thawing.63 During the cryoablation
procedure, a probe is inserted into the tumor tissue under
image guidance and pressurized argon gas is released from
the probe tip causing a rapid drop in temperature. As the
tissue freezes, osmolarity increases and causes an imbalance
of solutes between the intracellular and extracellular environ-
ments.62 Cellular death initially occurs through cellular
dehydration and protein denaturation.62,63 During the thawing
process an “ice ball” is formed that further induces cell death
by causing vascular damage (Figure 5).63 To achieve
sufficient cell death, a temperature of less than -40 °C must
Figure 5. Multiple cryoablation probes create a uniform
be reached.5,63 Adjusting the length of time and rate of the
“ice-ball” for full tumor eradication. Illustration courtesy
thawing step can also dramatically impact the effectiveness of Endocare, Inc., Austin, TX; with permission.
of the treatment.64-66
The main advantage of cryoablation is that the ice ball
formation can be directly monitored with imaging (US, CT,
(56) El Hayek, O. R.; Alfer, W., Jr.; Reggio, E.; Pompeo, A. C.; Arap, MRI) throughout the procedure.62,63 This helps treat the
S.; Lucon, A. M.; Srougi, M. Prostate cryoablation: prospective tumor more effectively and diminishes the risk of healthy
analysis comparing high- and low-risk prostate cancer outcomes.
tissue damage.62,63 Compared to RF ablation, cryoablation
Urol. Int. 2008, 81, 186–190.
(57) Orlacchio, A.; Bazzocchi, G.; Pastorelli, D.; Bolacchi, F.; can be used to treat larger tumors (>3 cm), causes less
Angelico, M.; Almerighi, C.; Masala, S.; Simonetti, G. Percu- procedural pain, and does not require the use of grounding
taneous cryoablation of small hepatocellular carcinoma with US pads.8,63 The development of catheter-based cryoablation
guidance and CT monitoring: initial experience. CardioVasc. therapies leads to an obvious adoption into percutaneous
InterVent. Radiol. 2008, 31, 587–594. surgeries, and consequently cancer treatments. Yet, RF
(58) Pfleiderer, S. O.; Marx, C.; Camara, O.; Gajda, M.; Kaiser, W. A. therapy is still more effective in its degree of treatment and
Ultrasound-guided, percutaneous cryotherapy of small (< or )
effective disruption of cells.67 Cryoablation is hindered by
15 mm) breast cancers. InVest. Radiol. 2005, 40, 472–477.
(59) Silverman, S. G.; Tuncali, K.; vanSonnenberg, E.; Morrison, the same pitfalls experienced by RF and MW ablation; they
P. R.; Shankar, S.; Ramaiya, N.; Richie, J. P. Renal tumors: MR lack the specificity needed to not harm healthy tissue and
imaging-guided percutaneous cryotherapy--initial experience in are also hindered by the heat sink effect.68 Although
23 patients. Radiology 2005, 236, 716–724. cryoablation is much more effective near vasculature than
(60) Tuncali, K.; Morrison, P. R.; Winalski, C. S.; Carrino, J. A.; RF or MW, the heat-sink effect remains a problem.
Shankar, S.; Ready, J. E.; vanSonnenberg, E.; Silverman, S. G.
MRI-guided percutaneous cryotherapy for soft-tissue and bone (64) Baust, J. G.; Gage, A. A. The molecular basis of cryosurgery.
metastases: initial experience. Am. J. Roentgenol. 2007, 189, BJU Int. 2005, 95, 1187–1191.
232–239. (65) Finelli, A.; Rewcastle, J. C.; Jewett, M. A. Cryotherapy and
(61) Wang, H.; Littrup, P. J.; Duan, Y.; Zhang, Y.; Feng, H.; Nie, Z. radiofrequency ablation: pathophysiologic basis and laboratory
Thoracic masses treated with percutaneous cryotherapy: initial studies. Curr. Opin. Urol. 2003, 13, 187–191.
experience with more than 200 procedures. Radiology 2005, 235, (66) Hoffmann, N. E.; Bischof, J. C. The cryobiology of cryosurgical
289–298. injury. Urology 2002, 60, 40–49.
(62) Berger, A.; Kamoi, K.; Gill, I. S.; Aron, M. Cryoablation for (67) Dubuc, M.; Roy, D.; Thibault, B.; Ducharme, A.; Tardif, J. C.;
renal tumors: current status. Curr. Opin. Urol. 2009, 19, 138– Villemaire, C.; Leung, T. K.; Talajic, M. Transvenous catheter
142. ice mapping and cryoablation of the atrioventricular node in dogs.
(63) Uppot, R. N.; Silverman, S. G.; Zagoria, R. J.; Tuncali, K.; Pacing Clin. Electrophysiol. 1999, 22, 1488–1498.
Childs, D. D.; Gervais, D. A. Imaging-guided percutaneous (68) Skanes, A. C.; Klein, G.; Krahn, A.; Yee, R. Cryoablation:
ablation of renal cell carcinoma: a primer of how we do it. Am. J. potentials and pitfalls. J. CardioVasc. Electrophysiol. 2004, 15,
Roentgenol. 2009, 192, 1558–1570. S28–34.
Nanoparticles are used as an indirect method of enhancing exposure to an alternating magnetic field.72-74 The heat
cryoablation, e.g. using cytokines to cause different im- released by these methods can produce significant tumor
munological and inflammatory responses in the cell. As necrosis, making these methods promising therapies for
described previously nanoparticles have been effective minimally invasive tumor ablation.
methods of enhancing existing treatments to enable specific- Nanoparticles in the tissue produce heat strong enough
ity and increased range for RF and MW therapies. The for thermal ablation in both tumors and surrounding cells.
difference, though, is that RF and MW ablation generate heat Thus, it is critical to increase the intratumoral localization
and cause coagulation necrosis, whereas cryoablation uses of the nanoparticles to protect the surrounding tissue and so
extremely cold temperatures to stop cells from functioning. that there is sufficiently high concentration of particles
present to produce enough heat to effectively ablate the
The drug TNF-R increases neutrophil and cytokine local-
tumor. Alternate delivery methods, such as subcutaneous or
ization to induce an inflammatory response as well as direct
intratumoral injections, can increase the local concentration
endothelial injury in solid tumors playing an important part
of nanoparticles.74 These methods are not always possible
in enhancing cryotherapy.69,70 The increased damage to the with deep tissue tumors, so increasing the intratumoral
vascular region, or the periphery of the tumor, causes a localization of nanoparticles for thermal therapy can also be
synergistic response with the cryotherapy. This allows the achieved through antibody targeting, actively targeting a wide
ablation zone to reach closer to the edge of the tumor tissue variety of cancer specific markers.72,75,76 Antibody conju-
without harming surrounding tissues.68,70,71 Still, systemic gated nanoparticles increase the local nanoparticle concentra-
delivery of enough TNF-R to enhance therapies is a major tion; however, if the particles specifically target the surface
obstacle in its widespread use. The drug needs to be receptor, the particles may not be internalized. Without
effectively delivered to only the target tissue, as it has many internalization of the particles, the dissipation of heat through
harmful effects to normal tissue as well.71 Nanoparticles have thermal conduction is not enough to directly destroy the cells,
the unique ability to carry drugs, as well as targeting different though the radiated heat could destroy different adjacent
cell and tissue types. Gold nanoparticles are used to carry cellular structures consequently leading to cell death.76
TNF-R and target tumor cells with antibodies. By using There are limitations that prevent these nanoparticle
targeted nanoparticles for drug delivery, the systemic side therapies from providing a completely specific method of
effects of cryoablation can be significantly decreased.69 thermal ablation without any cytotoxic effects. SWNT
Cryoablation is an extremely promising method because ablation is limited by the penetration depth of the NIR
it allows for the real-time monitoring of the treatment. This wavelengths; the NIR spectrum does not penetrate deep
enough to effectively excite nanoparticles beyond the surface,
allows the surgeon to ensure that the entirety of the tumor
somewhat limiting this therapy to more superficial tumors.73,76
is removed with the ice-ball. In conjunction with the
However, in addition to applications in thermal therapy,
nanoparticle therapy described above, it is very possible to
SWNTs and MNPs can be used for drug delivery and
destroy a tumor fully without disruption to surrounding
visualized in different magnetic imaging systems. The
organs and tissue. However, the treatment can be rather multifunctional applications of these particles in tumor
painful and enduring, and the effects of the drug TNF-R are ablation through multiple mechanisms and the potential to
not fully understood in this setting. For these reasons, RF
and MW ablation are currently much more viable clinical
(72) Kam, N. W.; O’Connell, M.; Wisdom, J. A.; Dai, H. Carbon
options. nanotubes as multifunctional biological transporters and near-
Other Nanoparticle Thermal Therapies. Many nano- infrared agents for selective cancer cell destruction. Proc. Natl.
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Kanzius, J. S.; Kittrell, C.; Weisman, R. B.; Pasquali, M.;
HIFU pulses. Their ability to convert the energy they gain
Schmidt, H. K.; Smalley, R. E.; Curley, S. A. Carbon nanotube-
to thermal energy allows them to be used for thermal ablation enhanced thermal destruction of cancer cells in a noninvasive
separately from existing methods. Nanoparticles such as radiofrequency field. Cancer 2007, 110, 2654–2665.
SWNTs release heat with continuous exposure to NIR light, (74) Hilger, I.; Hiergeist, R.; Hergt, R.; Winnefeld, K.; Schubert, H.;
while magnetic nanoparticles (MNPs) produce heat after Kaiser, W. A. Thermal ablation of tumors using magnetic
nanoparticles: an in vivo feasibility study. InVest. Radiol. 2002,
37, 580–586.
(69) Goel, R.; Swanlund, D.; Coad, J.; Paciotti, G. F.; Bischof, J. C. (75) Lee, R. J.; Huang, L. Folate-targeted, anionic liposome-entrapped
TNF-alpha-based accentuation in cryoinjury--dose, delivery, and polylysine-condensed DNA for tumor cell-specific gene transfer.
response. Mol. Cancer Ther. 2007, 6, 2039–2047. J. Biol. Chem. 1996, 271, 8481–8487.
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induced by TNF-alpha augments cryosurgical injury on human R. D.; Cavicchi, R. E.; Avedisian, C. T.; Mitra, S.; Savla, R.;
prostate cancer. Cryobiology 2004, 49, 10–27. Wagner, P. D.; Srivastava, S.; He, H. Anti-HER2 IgY antibody-
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monitor their distribution and effect will likely provide wide The exact amount of ROS required to cause tumor cell
clinical application in the future. death is not exactly known. ROS are required by both cancer
ROS Inducing Agents. Oxidative stress is characterized and normal cells, and are essential for life because of their
by an imbalance in redox state resulting from excessive role in many vital processes such as signal transduction.78
production of ROS and a reduction in cellular antioxidant However, ROS can lead to carcinogenesis in healthy cells.10
agents.10,77 The role of oxidative stress in cancer initiation, Excessive apoptosis can also cause cardiovascular and
progression, and metastasis has been known for many neurodegenerative diseases, ischemia-reperfusion injury, and
years.78 Cancer itself is characterized by increased generation autoimmune disorders.10,78 Therefore, the primary concern
of ROS. If levels of ROS are high enough, there can be for using ROS inducing therapies is how to effectively and
significant cellular damage including damage to DNA, selectively kill cancer cells without producing toxic effects
proteins, and lipid membranes, as well as apoptosis.78 By in normal cells.10 Wang et al. describe a method to
taking advantage of the high amounts of ROS in tumor cells, discriminate between normal and malignant cells by their
further increasing these levels could provide an opportunity differential capabilities in maintaining redox homeostasis.10
to kill cancer cells.78 In general, mild increases in ROS cause cell proliferation,
Many nonsurgical methods currently used to treat cancer whereas large amounts of ROS induce the lethal effects
such as thermal therapies, PDT, and radiation already rely desired in cancer treatment.80 Some cancer cells do result
on the production of ROS to induce cellular death.10 ROS in growth arrest or death by eliminating ROS.10 In addition,
molecules have unpaired electrons that make them highly some tumors utilize an enhanced antioxidant system to adapt
reactive when formed in ViVo via oxidation-reduction to increased oxidative stress that might be affected by a low
reactions and include free radicals such as hydroxyl (HO•) level of ROS in combination with another anticancer therapy
and superoxide radicals (•O2-), and nonradicals including instead. Both ROS elevating and depleting approaches are
hydrogen peroxide (H2O2) and singlet oxygen 1O2.79 There effective therapies, and therefore, the best strategy employed
are both endogenous and exogenous sources of ROS genera- will depend on the specific cell line.
tion including NADPH oxidase, P-450 metabolism, peroxi- Generally, nanoparticles can cause tumor ablation by
somes, activation of inflammatory cells, transition metals, several different mechanisms involving ROS. First, nano-
and radiation.77,78 Mitochondria are major producers of free particles themselves can generate ROS in the biological
radicals and superoxides, and are involved in cell death by environment; second, nanoparticles can be loaded with ROS
controlling apoptosis. Many ROS inducing agents work by promoting agents; and finally, nanoparticles can perturb the
targeting mitochondria and disrupting the electron transport normal oxidative stress levels by directly scavenging and
chain, which increases ROS production.80 Therefore, ROS depleting ROS or by scavenging antioxidants and enhancing
are not only inducers of cell death due to their high toxicity ROS production. Each of these mechanisms of nanoparticle
but they also act as signaling molecules in apoptosis.80 tumor ablation in combination with ROS is discussed below,
As an effective cancer treatment, ROS producing agents however, there are interesting limitations. Similar to the
can either directly induce the generation of ROS in tumor paradox of ROS both causing and acting as a therapeutic
cells or inhibit their antioxidative defense system.78 More- for cancer, nanoparticles can either decrease or promote
over, ROS producing agents can be used either alone or in tumor growth depending on the conditions and tumor type.
combination with anticancer drugs or therapies. Hydrogen It is therefore necessary to carefully examine the roles of
peroxide effectively induces ROS, but other agents and nanoparticles in various carcinomas to ensure that they act
treatments that stimulate ROS generation in tumor cells are as a therapeutic agent.
being investigated since hydrogen peroxide is extremely toxic One mechanism of ROS-mediated cytotoxicity is the direct
to humans. ROS producing agents used as a single anticancer production of ROS from nanoparticle interactions in the
drug include procarbazine, doxorubicin, buthionine sulfox- biological environment. Concern for human toxicity and
imine, motexafin gadolinium, and rituximab.10,81 Further- environmental impact of nanoparticles has grown in recent
more, the thioredoxin system and the glutathione system are years due to their widespread use for both consumer products
important targets in inhibiting cells’ antioxidative defense and industrial applications. There is a growing body of
system.10 literature examining the effects of nanoparticles composed
of TiO2, silver, silica, and other metal particles suggesting
(77) Franco, R.; Schoneveld, O.; Georgakilas, A. G.; Panayiotidis, that these nanoparticles generate ROS and deplete the
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healthy cells as plain silica and chitosan nanoparticles have ROS production that can affect tumor proliferation.92
recently been shown to induce ROS and LPO acting as tumor Finally, nanoparticles can perturb normal oxidative stress
suppressors in lung and liver carcinomas.87,88 levels by scavenging ROS directly. Endohedral metallo-
Nanoparticles can be loaded with ROS producing anti- fullerenol nanoparticles are a unique class of particles known
cancer agents to improve their bioavailability, or to act as “radical sponge” that directly scavenge ROS such as •O2-,
synergistically with an agent to produce ROS once in the HO•, and singlet oxygen (1O2).93 These particles, originally
tumor vicinity. Drugs conjugated to the surface of particles designed as an MRI contrast agent, encapsulate the transition
or loaded within particles are released via diffusion or medal gadolinium within a fullerene cage. Interestingly, the
degradation of the particles and can produce ROS. Block fullerene cage is not destroyed during metabolism or when
copolymers can entrap water insoluble drugs such as tetran- converting free radicals allowing the nanoparticles to con-
drine, resveratrol, or ferrocenyl tamoxifen derivatives within tinue to scavenge ROS.93,94 Scavenging ROS is an indirect
a hydrophobic polymer core, exposing a hydrophilic surface mechanism of tumor ablation, leading to significant tumor
to form a nanoparticle sized drug delivery system.89-91 Once inhibition in mouse hepatomas.93,95 Elevated levels of
released the drugs can enhance tumor effect by activating antioxidants detected in response to the tumors are further
returned to more normal levels after treatment.94
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illumination of the target tissue with a light source of an the first and most commonly used photosensitizing drug, is
appropriate wavelength (635-760 nm).103 For PDT to be used in thousands of patients and demonstrates the advan-
an effective treatment, a sufficient amount of molecular tages of PDT as a cancer treatment option. Depending on
oxygen (normally present in the tumor) is required.104 The the photosensitizing agent, it can be administered either
combined action of the photosensitizer and molecular oxygen topically or systemically.104
results in the formation of 1O2 that causes oxidative damage Over the past 20-25 years that PDT has been used
to cellular components.105 PDT also damages the vasculature clinically, no long-term side effects have emerged, and PDT
of the tumor thereby inducing cell death via hypoxia and can be used repeatedly without cumulative toxicity. However,
starvation.3 Inflammation responses that follow post-PDT PDT is a painful procedure for some patients and skin
further assist in removing any remaining tumor cells.3,105,106 photosensitivity can occur at the treatment site.3,104 To
In addition to cancer, PDT can treat nonmalignant diseases improve the efficacy of PDT and reduce the amount of
photosensitivity, new photosensitizing agents that incorporate
including macular degeneration and infections.107,108
more ideal properties and better target selectivity are in
The efficacy of PDT is affected by a number of factors development.3 Numerous formulations of drug-encapsulated
including photosensitizer type, photobleaching, light delivery, nanoparticles are also being studied as potential PDT
blood flow, oxygen availability, and tumor interstitial agents.110-112
pressure.3,109 The most important factor is the type of PDT is used only for superficial tumors and deeper tumors
photosensitizer used in the procedure. An ideal photosensi- accessible by endoscopies.113 PDT cannot treat systemic
tizer is easily synthesized, stable in water, activated with light diseases because an appropriate dose of the photosensitizing
of a longer wavelength, and nontoxic in the absence of light agent combined with whole body irradiation is not currently
exposure and has target specificity.3,103 Several drugs can feasible.104 Advancements in drug targeting, limiting light
be used for PDT with such characteristics. Porfimer sodium, delivery, and using combination regimens improves the
efficacy of this localized treatment.3,114 With the development
of lasers, light emitting diodes (LEDs), and optical fibers,
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this relatively new treatment. The efficacy of the treatment particle shell.121 To improve availability of 1O2, photosen-
as well as the inaccessibility of tumors deeper beneath the sitizers such as phthalocyanine can be attached as a
skin makes it less effective when compared to conventional monolayer coating on gold nanoparticles.117 When delivered
therapies.115 Also, the lack of specialization of the drug leads in a Cremophor emulsion, such nanoparticles generate more
to prolonged photosensitivity. The first two issues are less 1
O2 than free phthalocyanine for tumor ablation.117,119
of a problem and deal mainly with the popularity of the In addition to simply delivering photosensitizers to produce
1
treatment, which is set back only by the effectiveness of the O2, nanoparticles can simultaneously deliver chemothera-
treatment. If the efficacy of the treatment, determined by peutic agents or contain contrast agents for image guided
the efficiency of 1O2 production, and the specialization PDT. Nanoparticles with combination drug and photosen-
of the photosensitizer to the target site can be improved, then sitizers can significantly enhance ROS production and
the cost and standardization will become a nonissue.115 cytotoxicity compared to single drug treatment to overcome
Nanoparticles are emerging as a popular delivery method resistance in drug resistant tumor cells.122 Nanoparticles can
to address issues associated with photosensitizers including also be loaded with magnetic or fluorescent contrast agents
their hydrophobicity, cytotoxicity, and rapid degradation and to visualize tumor uptake of the therapy, and in some cases,
consequent inactivity under irradiation. A wide range of the photosensitizer itself can be excited and visualized for
nanoparticles are being used as vehicles for photosensitizers optically guided therapy.121 Quantum dots (QDs) are nano-
including polymeric nanoparticles, liposomes, silica, and gold size particles that act as a photosensitizer as well as a
nanoparticles.116-120 In addition to protecting the healthy fluorophore.79 QDs generate 1O2 at a much lower yield than
tissue from potential cytotoxicity from the photosensitizers, photosensitizers (1-5% compared to 30-50% respectively);
nanoparticles prevent the photosensitizer from leaking, however they may exert toxicity after irradiation via produc-
minimizing degradation and consequent inactivity of the tion of ROS other than 1O2.123-125
photosensitizer in the biological environment. The nanopar- Nanoparticle-Mediated Drug Delivery and Tumor
ticles are then able to localize to the tumor via the EPR effect Ablation. Although the various methods described above
or active targeting further improving bioavailability at the are used in practice for tumor ablation, each method has its
tumor compared to free photosensitizers. own problem and is not completely effective. These treat-
Photosensitizers do not have to be released from nano- ments are beginning to be increasingly effective with the
particles to generate 1O2 to cause cytotoxicity, unlike some help of nanoparticles, yet none have presented to be
nanoparticle drug carriers that must release their drug payload particularly better than chemotherapy or radiation therapy.
to effectively ablate the tumor.118,121 Singlet oxygen is In many cases, the potential side effects of these treatments
generated within the nanoparticle and diffuses out into the are overlooked due to their familiarity. Nanoparticles have
surrounding environment, though nanoparticles must be been developed to carry different drugs, dyes, or targeting
carefully designed to allow diffusion out through the nano- ligands. This unique ability allows the use of multiple
methods in conjugation to produce a synergistic effect.
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Drugs have the ability to suppress tumor growth and
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propylamino)ethyl methacrylate based nanoparticles for photo- formulations, and there are dozens of ongoing clinical trials
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Beeby, A.; Chambrier, I.; Cook, M. J.; Russell, D. A. Generation
treatment of many types of cancers.126 Nanoparticles can
of Cytotoxic Singlet Oxygen via Phthalocyanine-Stabilized Gold
Nanoparticles: A Potential Delivery Vehicle for Photodynamic target these drugs to prevent proliferation for tumor cells in
Therapy. Langmuir 2002, 18, 2985–2987. difficult to treat carcinomas, limiting the systemic cytotoxicity
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efficacy of phthalocyanine-nanoparticle conjugates for the pho- oxygen via the composites of water-soluble thiol-capped CdTe
todynamic therapy of amelanotic melanoma. Eur. J. Cancer quantum dots-sulfonated aluminum phthalocyanines. J. Phys.
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simultaneous in vivo imaging and photodynamic therapy. Bio- duction of reactive oxygen species for cancer cell annihilation.
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of the drug.127 With that advantage, a thermal or other

noninvasive therapy can be administered allowing for
destruction of the majority of the malignant cells. The drug
released can then prevent recurrence of the tumor by
preventing cell proliferation. However, there are only a
handful of clinical trials that currently combine nanoparticles
for drug delivery with thermal therapies such as RF and
HIFU.128
As combined therapies are enhanced with drugs, it
becomes necessary to ensure the proper delivery of nano-
particles and drugs to the appropriate tissue in the correct
dosage. To ensure delivery, visualization of nanoparticles
and the consequent treatments are necessary in ViVo, and
accurate diagnosis and translational data are needed to make
effective treatment regimens.
Nanoparticles and Imaging in Tumor Ablation. Many
nanoparticles can be visualized inherently, or through the
attachment of a fluorescent dye. As new tumor ablation
methods are being developed, it is necessary to determine
effective treatment regimens with accurate knowledge of the
tumor boundaries. Modifying contrast agents or dyes to
differentiate between malignant tissues and healthy tissues
before, during, and after treatment can enhance the clinical
application of therapies.
Magnetic resonance imaging and fluorescence imaging are
two very common methods of visualization each with their
own advantages. The use of MRI for presurgical and
diagnostic purposes is very common with all tumors. MRI Figure 6. (A) The F-127 magnetic nanoparticle
provides high resolution images that are very useful in formulation has the ability to be localized using a
determining size, location, and the shape of a tumor. Our magnetic field. F-127 Pluronic works to provide a
laboratory has created a formulation of nanoparticles that hydrophobic region to carry anticancer drugs while still
can be used for such purposes (Figure 6). The nanoparticles being dispersible in water. (B) The magnetic
are made of an iron oxide core, which is then coated with nanoparticles serve as an effective contrast agent in
oleic acid, and finally a layer of Pluronic F127. The coating delineating tumor margins in an MR image. Panel B is
reprinted with permission from ref 129. Copyright 2009
of Pluronic F127 makes the nanoparticle dispersible in water;
Elsevier.
however, it retains a hydrophobic region that can carry
different hydrophobic anticancer agents. We have shown that
this particle has the capability to delineate tumor margins, efficacy. The nanoparticle also can provide sustained drug
and serve as a prolonged contrast agent using MRI due to delivery of multiple drugs alone or in combination to allow
its iron oxide core.129 This is a very important advancement, for a synergistic effect with certain drugs.130 Further, particles
as it is necessary to monitor the tumor size and shape after can be used to induce hyperthermia to enhance the drug
delivery of any anticancer drug to determine the treatment effect.
The images provided through MRI enhance the ability of
(126) ClinicalTrials.gov [Internet]. Bethesday (MD): National Library
of Medicine (US). (September 13, 2010). Available from: http:// a surgeon to locate and remove the entire tumor. However,
www.clinicaltrials.gov/ct2/results?term)nanoparticle+cancer. this equipment can only be used as a reference, and cannot
(127) Murphy, E. A.; Majeti, B. K.; Barnes, L. A.; Makale, M.; Weis, be compared to what is actually seen in surgery. Nanopar-
S. M.; Lutu-Fuga, K.; Wrasidlo, W.; Cheresh, D. A. Nanopar- ticles can be targeted to specific tissues and carry a dye or
ticle-mediated drug delivery to tumor vasculature suppresses autofluoresce as described in many methods above. Using
metastasis. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9343–9348.
this ability and surgical probes, nanoparticles can delineate
(128) ClinicalTrials.gov [Internet]. Bethesday (MD): National Library
of Medicine (US). (September 13, 2010). Available from: http:// tumor margins intraoperatively.131 Since the same particles
www.clinicaltrials.gov/ct2/results?term)liposome+hyperthermia+ delineate the tumor margin in a preoperative MRI image and
cancer, http://www.clinicaltrials.gov/ct2/results?term)liposome+
radiofrequency.
(129) Jain, T. K.; Foy, S. P.; Erokwu, B.; Dimitrijevic, S.; Flask, C. A.; (130) Jain, T. K.; Richey, J.; Strand, M.; Leslie-Pelecky, D. L.; Flask,
Labhasetwar, V. Magnetic resonance imaging of multifunctional C. A.; Labhasetwar, V. Magnetic nanoparticles with dual
pluronic stabilized iron-oxide nanoparticles in tumor-bearing functional properties: Drug delivery and magnetic resonance
mice. Biomaterials 2009, 30, 6748–6756. imaging. Biomaterials 2008, 29, 4012–4021.
during surgery, these particles provide accurate visualization modalities. This section highlights some of the mechanisms
of tumor margins for effective removal of tumor tissue.132 by which nanoparticles affect cell functions, and how these
Alternatively, nanoparticles can be modified to increase may be applied to tumor ablation.
retention time and provide a much longer period to monitor Mechanisms of ROS Generation. The hydroxyl radical is
uptake by cells than common markers used for MRI.129 They considered the most toxic free radical, and is generated in
can also be used in determining the success of tumor biological systems primarily by the iron-catalyzed Haber-
therapies and surgeries postablation. The enhanced resolution Weiss reaction (also referred to as Fenton reaction).136 In
provided by using nanoparticles as a target specific contrast this reaction, hydroxyl radicals (•OH) are formed from
agent in MR images can ensure complete eradication of hydrogen peroxide (H2O2) and superoxide (•O2-) via the
following reactions:
tumors postsurgery. With treatments like RF ablation and
MW ablation where the only visualization of the tumor may
Fe3+ + •O2- f Fe2+ + O2
be through fluorescence or MRI, nanoparticles can provide
an accurate comparison of pre- to post-treatment images by (reduction of ferric iron to ferrous iron) (1)
eliminating variables such as autofluorescence, time, and
noise.133 In recent years, imaging with fluorescent dye has Fe2+ + H2O2 f Fe3+ + OH- + •OH (Fenton reaction)
progressed well and is useful particularly in monitoring the (2)
efficacy of treatment options for superficial cancers such as
•
breast, because dyes can be imaged ∼10 cm through tissue, O2- + H2O2 f •OH + OH- + O2 (net reaction)
an ideal penetration depth for breast cancer imaging.134 (3)
Magnetic nanoparticles can be simultaneously loaded with
Nanoparticles made from transition metals may break down
fluorophores in the NIR region to study the dynamics of
within the cell to provide the metal ions that catalyze ROS
biodistribution and targeting and as an intraoperative tech-
(hydroxyl radical) generation via the Haber-Weiss reaction.
nique to define tumor margins.133,135 Fluorescent images are
Iron oxide based nanoparticles are particularly well suited
thus useful in determining what should be resected during
for this mechanism. The coatings typically used on the
surgery and what tissue is healthy, determining the level of nanoparticles can be degraded by lysosomal enzymes,
tumor regression, and reducing the chance of recurrence. In exposing the redox-active iron oxide core. Copper, as well
general, nanoparticles with multifunctional properties such as other metals, may also be capable of ROS generation via
as drug delivery and imaging in combination with ablation the Fenton reaction.137-139
techniques could improve cancer treatment. Cancer cells are generally deficient in the antioxidative
Molecular Mechanisms of Nanoparticle-Mediated Tumor enzymes present in normal cells, making them particularly
Ablation. The properties of nanoparticles alone can impact vulnerable to an oxidative assault. In addition, differences
many biological processes within cells. Understanding the in iron metabolism between cancer cells and normal cells
molecular mechanisms of nanoparticle-mediated tumor in- suggest an iron-mediated oxidative assault may be a mech-
hibition will be important to further optimizing and control- anism for selectively targeting cancer cells while leaving
ling their properties, and identifying synergies with specific normal cells unharmed. In cells of the RES, iron oxide
drugs, ablation techniques, and other cancer treatment nanoparticles are broken down with the majority of iron
stored as ferritin and or hemosiderin,140 and excess iron is
then removed from these cells via ferroportin. The metabolic
(131) Kim, D. K.; Zhang, Y.; Kehr, J.; Klason, T.; Bjelke, B.;
Muhammed, M. Characterization and MRI study of surfactant- demands of cancer cells manifest in increased levels of
coated superparamagnetic nanoparticles administered into the rat transferrin receptors to facilitate iron uptake, and decreased
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Josephson, L. A multimodal nanoparticle for preoperative reflects the activity of free copper released from the oxidatively
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magnetic field targeting of magnetic nanoparticles in tumors. ACS in rats: implications for magnetic resonance imaging. Cell Tissue
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levels of ferroportin.141 Therefore, when iron levels are of filamin,142 decrease in focal adhesion complexes,145 and
increased in the blood as well as via direct uptake of iron- decreased levels of focal adhesion kinase signaling.146 These
oxide nanoparticles, this may result in acutely elevated observations were often dependent on dose, exposure time,
intracellular iron concentrations in cancer cells and subse- nanoparticle properties (size, roughness), and cell line. The
quent ROS generation via the Fenton reaction. accumulation of nanoparticles in the cytoplasm may result
Silver nanoparticles have been linked to ROS generation in physical interactions/interferences with the cytoskeleton,
via disruption of calcium homeostasis.142 Silver ions may or an increase in size and/or number of endosomes associated
act on the same sites as calcium ions, which could affect with nanoparticle uptake, and may cause rearrangement of
calcium flux into and out of the mitochondria. Consequently, cytoskeletal components in order to form new trafficking
mitochondrial membrane damage results in ROS production, routes.145,149 One study showed nanoparticle exposure caused
inhibition of ATP synthesis, and initiation of apoptotic a decrease in ECM production and changes in ECM
signaling pathways. Another mechanism by which some properties, which may also impact the cytoskeletal organiza-
nanoparticles can generate ROS is related to their semicon- tion of the cell.149 The morphological changes can subse-
ductor properties, as is the case with zinc oxide (ZnO) quently affect signaling pathways that lead to decreased
nanoparticles. Electrons and holes within the ZnO nanopar- proliferation. Normal cells could eventually recover from the
ticle can migrate to the particle surface and react with oxygen nanoparticle-mediated antiproliferative effects. As the cells
or with hydroxyl ions or water to form superoxide and divided, albeit at a slower rate, the nanoparticles redistributed
hydroxyl radicals, respectively.143 UV light further enhances among the daughter cells, thus reducing the intracellular
electron conduction and ROS generation. The combination concentration of nanoparticles. Interestingly, cancer cells
of ZnO nanoparticles and the anticancer drug daunorubicin were not able to recover and ceased to proliferate.142
with UV irradiation had synergistic cytotoxic effects on Facilitating the transport of nanoparticles from the cytoplasm
leukemia cells.144 to the nucleus of the cell may further enhance the antipro-
Nanoparticles Induce Cytoskeletal Alterations and Antipro- liferative effects. Gold nanoparticles tagged with nuclear
liferatiVe Effects. The presence or accumulation of nanopar- targeting ligands localized within the nucleus of cancer cells
ticles within cells may affect or interfere with cell functions. where they disrupted cytokinesis and prevented the comple-
Cellular uptake of nanoparticles results in changes to the tion of cell division, ultimately leading to apoptosis.150
cytoskeleton, which can affect numerous biological processes Altering the Tumor MicroenVironment. Tumors comprise
such as cell spreading and adhesion, cell growth, viability, not only the malignant cells but also the supporting stroma.
and ECM production. Iron oxide, gold, and silver nanopar- The tumor stroma includes fibroblasts, immune cells, vascular/
ticles alter the cellular cytoskeleton of various cell types, endothelial cells, and progenitor cells, which regulate the
including fibroblasts, endothelial cells, neural progenitor cells, tumor microenvironment and impact tumor growth and
and glioblastoma cells, which is correlated with a decrease disease progression. Increasing interest has developed in
in cell proliferation.142,145-148 After nanoparticle exposure, cancer therapies that target the tumor stroma in order to create
cells became condensed (decreased cell area) and more a less favorable microenvironment for cancer cells to thrive.
polarized (larger aspect ratio) and cell proliferation was This approach, in combination with other therapeutic agents,
reduced. Cytoskeletal changes included remodeling of mi- may be important for preventing recurrence and overcoming
crotubules,147 disruption of actin filaments,148 downregulation drug resistance. In addition to controlling the biochemical
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synergistic effects to prevent recurrence and enhance tumor MNP, magnetic nanoparticle; MRI, magnetic resonance
imaging for precision of treatment. Strategies to synergize imaging; MW, microwave; PDT, photodynamic therapy;
the ablation effect in combination with drugs, ROS generat- QDs, quantum dots; RF, radiofrequency; RES, reticuloen-
ing agents specifically in tumor cells, and optimal energy dothelial system; ROS, reactive oxygen species; SWNT,
source could further improve the outcome of ablation single-walled carbon nanotube; TAMs, tumor associated
techniques. In this regard, new nanomaterials that can macrophages; US, ultrasound.
potentiate the thermal effect and that possess imaging
capability could certainly play a critical role. Nonsurgical Acknowledgment. The study reported here from our
tumor ablation techniques with advancements in nanotech- laboratory is funded by Grant R01 EB005822 (to V.L.)
nology will continue to develop and thrive as an effective from the National Institute of Biomedical Imaging and
and preferred approach to treat local cancers over surgical Bioengineering of the National Institutes of Health. S.P.F.
resection or convention drug therapy. is a predoctoral student in Cleveland Clinic’s Molecular
Abbreviations Used Medicine Ph.D. Program, which is funded by the “Med
into Grad” initiative of the Howard Hughes Medical
CT, computed tomography; ECM, extracellular matrix;
Institute [http://www.lerner.ccf.org/molcmed/phd/].
EPR, enhanced permeability and retention; HIFU, high
intensity focused ultrasound; LED, light emitting diode; MP1001944

Tumor Ablation and Nanotechnology

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Tumor Ablation and Nanotechnology

Rachel L. Manthe,† Susan P. Foy,† Nishanth Krishnamurthy,† Blanka Sharma,†

Table 1. A Summary of Current Tumor Ablation Therapies

mechanism of and additional

MOLECULAR PHARMACEUTICS VOL. 7, NO. 6

perfusion probes, and cool-tip probes. In general, monopolar

Combining these two qualities, nanoparticle formulations can

nondestructive reversible structural changes.53,55 Because

of the drug.127 With that advantage, a thermal or other

1898 MOLECULAR PHARMACEUTICS VOL. 7, NO. 6

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