Biomedical Nanotechnology For Cancer

Med Clin N Am 91 (2007) 899–927
Biomedical Nanotechnology for Cancer

Amy Pope-Harman, MDa,*,
Mark Ming-Cheng Cheng, PhDb,c,
Fredika Robertson, PhDd, Jason Sakamoto, PhDb,e,
Mauro Ferrari, PhDb,c,d,e,f
a
Dorothy M. Davis Heart and Lung Research Institute, Division of Pulmonary, Critical Care,
Allergy, and Sleep Medicine, Department of Internal Medicine, The Ohio State University
College of Medicine and Public Health, 473 West 12th Avenue, Columbus, OH 43210, USA
b
Center for Nanomedicine, Institute of Molecular Medicine, The University of Texas
Health Science Center at Houston, Houston, TX 77030, USA
c
Biomedical Engineering, The University of Texas Health Science Center at Houston,
Houston, TX 77030, USA
d
Department of Experimental Therapeutics, The University of Texas MD Anderson
Cancer Center, Houston, TX 77030, USA
e
Alliance for NanoHealth, Houston, TX 77030, USA
f
Department of Bioengineering, Rice University, Houston, TX 77003, USA
Clinical medicine has seen tremendous improvements in the past several

decades. Despite the progress, however, many illnesses, especially cancer,
are as yet unable to be detected at the earliest, subclinical stages, before
the time that health care workers practically may prevent disease or mini-
mize its impact. Patients still are called on to endure toxic and uncomfort-
able whole-body chemotherapy and other treatments with the hope that
their cancers will succumb. There is expectation, however, that all of this
will change radically with the use of the nanotechnology discussed in this
review, allowing improvements in mortality and prevention of suffering
from cancer and other devastating diseases.
The worldwide scientific community has made great strides toward
understanding the basic mechanisms behind cancer and many other human
ailments. As scientists begin to understand the combination of innumerable
isolated relationships that define the complexities of inner biology [1], they
MCC and MF are grateful to the National Cancer Institute for funding under National
Institutes of Health Contract No. NO1-CO-12400.
* Corresponding author.
E-mail address: amy.pope-harman@osumc.edu (A. Pope-Harman).
0025-7125/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2007.05.008 medical.theclinics.com
900 POPE-HARMAN et al
will move ever closer to truly personalized and responsive care for individ-
uals. Nanotechnology provides the tools to progress toward personal med-
icine, allowing assessment of individual risk for certain disorders and
response to planned therapies using the presence of particular genetic poly-
morphisms or other markers of disease. The scientific community is in the
midst of the difficult process of developing methods to thoughtfully unite
the various and growing pieces of medical knowledge with practical means
to precisely apply it clinically. By working on a nanometer, molecular scale,
there is the potential to assess and intervene simultaneously assess and inter-
vene, with accuracy in space and, time, which is an ability that has never
before been available.
Recent advances in engineering, material science, chemistry, and physics
have resulted in the ability to create materials, devices, or functional compo-
nents of devices in nanoscale (1- to100-nm) proportions. The scale of these
nanomaterials and nanodevices allows their assembly into novel arrange-
ments that have unique physical and chemical properties, owing to their
size, that may be exploited for particular biologic uses. Nanomaterials
and nanodevices are alterable to serve specific purposes within biologic
systems. Because the size of these nanomaterials is similar to that of natu-
rally occurring components of cells, including surface receptors, organelles,
nucleic acids, and proteins, nanoscale materials can readily interface with
biologic molecules. The term, ‘‘nanotechnology,’’ in this context generally
is not applied to molecular biology alone but reserved for the science that
results in materials that are, at least in part, conceived and manufactured
by humans, with at least one component that is of sub–100 nanometers in
linear dimension. Having established this, however, the authors do believe
that function and philosophy hold greater importance than strict size defini-
tions and this review does not exclude mention of otherwise biologically
functional and medically useful devices that are beyond 100 nanometers.
The unique properties attendant to the nanoscale can be taken advantage
of to achieve multiple functions from a single platform. Nanotechnology
allows overcoming biologic barriers that have in the past hampered medical
efforts toward diagnosis or therapy. Nanotechnology can allow unprece-
dented localization of therapeutic interventions to diseased areas within
the body and improved control over temporal variables. All of these advan-
tages should result in the potential for significantly more effective and less
toxic or unpleasant interventions. This review discusses nanotechnology
as it is already used in many diagnostic and therapeutic applications for
cancer and theoretic and evolving uses of nanotechnology, including exam-
ples and explanations of technology, such as multifunctional nanoparticles
for imaging and therapy, nanochannel implants for controlled release of
drugs, nanoscale devices for evaluation of proteomics and genomics
(including nanowires, nanocantilevers, and nanostructured surfaces), and
diagnostic techniques that take advantage of physical changes in diseased
tissue.
NANOTECHNOLOGY FOR CANCER 901
Diagnosis, prognosis, and disease status

Diagnosis encompasses identification of risk for disease; recognition of
indicators, or markers, of disease states; various forms of imaging; localiza-
tion, staging, and quantification of disease; prognostics; and monitoring of
the progression of disease. It also is conceivable that, using the special capa-
bilities of nanotechnology, many techniques that have been used to localize
and identify a disease may also be applied toward targeting therapeutic in-
terventions. A disease state or risk for disease may be recognized or local-
ized by the identification of markers of disease. These may include any of
several potential biomolecular or physical clues. Proteins may manifest dis-
ease in the form of either completely abnormal proteins or peptides (chem-
icals that would not be present at all in a nondiseased state), chemical or
electrical changes that are encountered in places and at times where they
normally should not be located, or proteins that are processed abnormally.
Similarly, a disease state (or predisposition to it) may be predicted by the
presence of particular genes within an individual’s total genome or even
by localized genetic abnormalities. Abnormalities in the structure of genetic
material may come about as a result of local injury or other insult (struc-
tural genetic aberrations) or from abnormal alterations in patterns of gene
expression for given conditions. These changes in gene structure, in the func-
tion of genes, or in translation of mRNA to produce altered proteins may be
associated with particular diseases or may predispose to diseases such as
cancer. Disease markers may be present in exceedingly small amounts,
found only in relatively inaccessible anatomic locales, or be present in or
on only specific pathologic cells. Nanotechnology may permit less invasive,
less uncomfortable means of identifying and quantifying these markers, help
make cancer diagnoses, monitor cancer recurrence or metastasis, and define
the locations, biologic types, and behaviors of malignancies. Additionally,
nanotechnology methods may allow for improvement in the lower limits
of detection of disease and, thus, improve the likelihood of early diagnosis
and provide more accurate monitoring of therapeutic response or progres-
sion of disease [2].
There are targets that may be used to identify and localize cancerous le-
sions. Among the many, abnormal areas of endothelial growth factors may
be associated with (and provide a target against) metastasis [3]. Methylation
of p16INK4a, DAPK, MGMT, and FHIT is seen in lung epithelial tissue at
risk for the development of cancer [4,5]. The number of identifiable genetic
abnormalities seems to increase with progression from a precancerous risk
state through to cancer, and early reinstatement of absent or malfunctioning
genetic material may be effective in averting the conversion to malignancy
[6,7]. Early identification and intervention again is the key to success.
Concentration of markers that are present only in small amounts, either
by accumulation at a stationary binding site or by the binding of biomarkers
remotely onto particulates with subsequent harvesting of bound particulates
for query, can result in improved assay sensitivity. Identification of bio-

markers found in low concentrations may be improved through amplifica-
tion by cascade reactions or by tagging known biomarkers with indicators
that may be more detected easily. Imaging, or definition of the structure
and localization of abnormalities, may take advantage of the presence of
markers, the function or behavior of organs or tissues, or the architectural
structure of the tissue or organ. How nanotechnology is used in many of
these areas is discussed.
Nanotechnology in diagnostic assays

Nanostructured surfaces for proteomic analyses via mass spectrometry
and reverse phase microarrays
Mass spectrometry (MS) currently is the gold standard for profiling
protein expression in biologic fluids and tissues [8–10]. There is mounting
evidence that early detection and prognostic information regarding malig-
nant disease may be achieved through analysis of the low molecular weight
proteome (LMWP), comprising protein fragments at extremely low concen-
trations [11]. This task is complicated by the number of different biomolec-
ular species in the plasma proteome, which exceeds 300,000 (and could be as
high as 106), with perhaps 12 orders of magnitude difference between
relative abundances, dominated by large carrier proteins that likely are of
minimal diagnostic importance.
The physicochemical nanoscale modification (‘‘nanotexturing’’) of sur-
faces on a MS planar or micro- or nanoparticle substrate has been proposed
to provide size exclusion, elective capture, and resultant enrichment of
selected regions of the LMWP from body fluids and other biologic samples
[12,13]. In proof-of-principle validation experiments, silicon oxide nanopo-
rous particle substrates challenged with human plasma mixtures spiked with
peptide standards demonstrated, by matrix-assisted laser desorption/ioniza-
tion–time of flight, one type of MS analysis, that a signal can be detected
with peptide amounts as low as the ng/mL range, thus increasing the sensi-
tivity of MS analysis (by approximately 400-fold). This selective enrichment
achieved by the use of nanotextured surfaces with chemical or structural
modifications represents a powerful tool to improve the selectivity of
peptide harvesting and identification in the search for disease-related bio-
markers. Nanoscale surface modifications similarly may be used in reverse
phase protein microarrays, which enable high-throughput screening of post-
translational modifications of signaling proteins within diseased cells [14].
One difficulty with protein-based molecular profiling is the lack of
capability for polymerase chain reaction (PCR)-like intrinsic amplification
as is achievable with nucleic acids. This is vexing especially given the low
concentration of many potentially useful protein targets within patient tis-
sues. Quantum dots, nanoscale crystals with unique optical and electrical
properties owing to their small sizes, may be used as potential reporter
agents. Their ability to multiplex and their physical properties allow

unique methods of detection, providing the potential for significant in-
creases in sensitivity [15]. Silicon, which offers low intrinsic autofluorescence
compared with nitrocellulose glass slides, additionally shows promise as a
surface for microarrays by using semiconductor etching techniques and
chemical modifications to provide large surface areas with attached
bioreactive groups [16].
The bio-barcode assay

The bio-barcode assay (Fig. 1) is a powerful amplification and detection
system for nucleic acids and proteins found in biologic samples. This
technique uses two types of particles to bring about sample purification,
detection, and signal amplification [17–21]. The technique starts with
Fig. 1. Bio-barcode assay: a magnetic probe captures a target molecule using either monoclonal
antibody or complementary oligonucleotide. Target-specific gold nanoparticles sandwich the
target, thus identifying the target and amplifying the signal. The barcode oligonucleotides are
released and detected using the scanometric method. (The Verigene ID is a commercial instru-
ment of Nanosphere, Northbrook, Illinois.) (From Cheng MMC, Cuda G, Bunimovich YL,
et al. Nanotechnologies for biomolecular detection and medical diagnostics. Current Opin
Chem Biol 2006;10:14; with permission.)
a microparticle attached to a recognition agent. The recognition agent is an

oligonucleotide complementary to a unique region of a target nucleic acid or
a monoclonal antibody if the target is a protein [17,19]. The second particle
is a nanoparticle that is attached to a recognition agent that sandwiches the
target between the particles. This second recognition agent can be either
a polyclonal antibody in the case of a protein target or a complementary ol-
igonucleotide for a nucleic acid of interest. This nanoparticle carries with it,
additionally, hundreds of nonbinding oligonucleotides, referred to as barc-
odes. The barcodes typically are comprised of 15- to 20-mer oligonucleo-
tides, allowing formulation of a unique barcode for every conceivable
recognition agent: for 20-mer strands, there potentially are 420 unique
combinations. After the target is sandwiched, a magnetic field can separate
the complexed target from the sample solution. The barcodes then are re-
leased chemically or released by heat [20,22–24] and then identified with
a high-sensitivity detection system. The speed and high sensitivity of the
bio-barcode assay comes from three unique features: (1) very efficient, ho-
mogeneous target capture as opposed to slow surface capture on a plate;
even with weak target-binding antibodies, the equilibrium can be pushed
toward complexing by increasing the concentration of the particle probes;
(2) amplification through a high ratio of barcode-to-target recognition
element; and (3) high-sensitivity barcode sorting and sensing capabilities
through chip-based scanometric methods. At present, the barcode detection
system allows detection of nucleic acids with efficiency close to the sensitivity
of PCR without the need for complicated enzymatic processes and can be
viewed potentially as a more efficient alternative to PCR. Although alterna-
tives to PCR are important, the barcode assay likely will have its most
significant scientific and clinical impact in protein marker-based diagnostics.
It is up to 106 times more sensitive than enzyme-linked immunosorbent as-
say (ELISA)-based technology, offering researchers and clinicians at least
three major opportunities: (1) the ability to use new markers for diagnosing
many types of diseases that could not be identified with conventional tech-
nology because of a lack of sensitivity, (2) the ability to look at known dis-
ease markers via less invasive means, and (3) the ability to use existing
markers to evaluate disease recurrence. It currently is being evaluated as
a potential tool for studying recurrence in patients who have prostate can-
cer. The barcode assay would be able to identify a minimal rise in pros-
tate-specific antigen (PSA) secondary to recurrent disease well before
conventional tests, thereby increasing the efficacy and success of treatment
options. It is projected that the barcode assay and variations on it will rede-
fine several aspects of modern biodiagnostics for many types of cancer.
Nanowires: label-free electronic sensors of genes and proteins

Local chemical, electrical, or physical property changes in cells or tissues
may be monitored by means of nanometer scale tubes and wires in the form
of field effect transistors [25,26]. Expanding on this concept, nanowire

sensors operate on the basis that the change in chemical potential accompa-
nying a target-binding event, such as DNA hybridization [27], can act as
a field effect gate on the nanowire, thereby changing its conductance. The
ideal nanowire sensor is a lightly doped, high–aspect ratio, single-crystal
nanowire with a diameter between 10 and 20 nanometers. If the nanowire
is much smaller, it is too noisy a sensor, and if it is much larger, it is not
as sensitive. Because even exotic lithographic patterning methods cannot
produce such small-width, high–aspect ratio semiconductor structures
[28], new materials methods have been used to grow nanowires, which
then are assembled using various fluidics approaches into individual
devices.
One advantage of nanowire sensors is that the number and density of the
sensor elements is limited only by the ability to address electronically each of
the individual nanowires, which may be formed into dense circuits. Large-
scale circuits can, in principle, be constructed within very small (microflui-
dics) environments, creating very dense sensor libraries, thus enabling mea-
surements of many different genes and proteins from very small tissue
samples or even single cells [1]. Encoding the individual nanowires with
single-stranded DNA (ssDNA) molecules or protein-capture agents repre-
sents a serious challenge, however. Electrochemical methods [29] have
been applied successfully to encoding the surfaces of electronically selected
nanowires with proteins [30].
Cantilevers: nanomechanical detection of biologic molecules

Detecting biomolecular interactions by measuring nanomechanical forces
offers an exciting means to develop highly sensitive, miniature, and label-
free biologic sensors [31,32]. Molecular adsorption can cause measurable
mechanical forces. Micron-sized silicon cantilever beams bend subtly under
surface stresses when molecular adsorption occurs on one side of the canti-
lever. The cantilever beam manifests the forces involved in the adsorption
process or mass loading by nanometer scale displacement and by changes
in resonant frequency [33]. The adsorption-induced bending and frequency
variation can be measured simultaneously by using several techniques, such
as variations in optical beam deflection, piezoresistivity, piezoelectricity, and
capacitance. Micron and submicron cantilevers will require even more
sensitive techniques for measurement, such as electron tunneling. With
recent advances in lithographic technologies and micro- and nanofabrica-
tion techniques, these sensors can be mass manufactured on silicon wafers
and other materials in a cost-effective and modular fashion.
Selective chemical recognition on cantilevers is achieved by affinity bind-
ing reactions. The cantilever is coated on one side with self-assembled
monolayers, DNA probes, antibodies, or peptides. DNA hybridization on
cantilevers has been investigated extensively by several groups [34,35].
Thiol-modified ssDNA probes (20 mer) immobilized on one side of a canti-

lever over a vacuum-deposited gold layer demonstrated bending as a result
of hybridization with complementary ssDNA targets in a liquid environ-
ment. The extent of cantilever bending varied as a function of the length
of the complementary ssDNA. Detection of proteins by cantilever nanome-
chanics is a bit more challenging, mainly because of the lack of reproducible
and robust immobilization techniques for antibodies. PSA and biowarfare
agents, ricin and tularemia, however, have been detected successfully on
cantilevers using immobilized antibodies [36,37]. In tests using antibody-
immobilized cantilevers to bind specific proteins, the amplitude of the
bending is proportional to concentration of the antigen and time of expo-
sure. The biomolecular interaction-induced cantilever bending is irreversible
at room temperature.
Mechanical label-free detection, although still in its early stages, has the
potential as a platform for sensitive, multiplexed sensors for biomolecules.
Currently available micromachining technologies could be used to make
multitarget sensor arrays involving tens of cantilevers on a single chip.
Increasing the number of sensing elements in an array would lower signal-
to-noise ratio, increase selectivity, and enhance robustness. Simplicity,
low-power consumption, potential low cost, inherent compatibility with
array designs, and label-free detection make cantilever sensors appealing
for a variety of applications.
Imaging
As with many diseases, and cancer especially, it is crucial to provide pre-
cise bodily location, define its structure and biologic activities, and reliably
assess response to interventions. There are several modes of imaging in cur-
rent use, including magnetic resonance imaging (MRI), positron emission
tomography (PET), ultrasound, and optical imaging techniques. These can
be enhanced through the addition of nanotechnology components.
Maximizing the capabilities of current imaging techniques, iodinated
nanoparticles have localized successfully to lymph nodes after broncho-
scopic instillation and may be visualized precisely through the use of com-
puterized tomography (CT) [38]. PET scanning distinguishes metabolic
activity in diseased tissues versus that of normal tissue. The use of various
specific tracers allows evaluation of key metabolic events in many different
types of cancers. Nanotechnology enhancements will permit increased sen-
sitivity through amplification of these detected chemical changes or by in-
creasing their specificity, allowing improved differentiation between
‘‘normal’’ areas of increased metabolic activity and areas of true disease, po-
tentially even permitting discrimination among tumor types and determina-
tion of the biologic behavior of tumors. Contrast agents in the form of
superparamagnetic nanoparticles, usually iron oxide, serve to enhance the
contrast of images [39] and have been used for many years to improve the
diagnostic capabilities in MRI. Conjugation of folate and polyethylene gly-

col (PEG) onto superparamagnetic particles results in increased uptake in
cancer cells (Fig. 2) [40] and may be imaged by MRI. Areas of tumor het-
erogeneity can also be identified by contrast-enhanced MRI [41]. Other
nanoparticulates can aid in visualization of cancerous tissue and define its
characteristics. The reduction-oxidation state of specific biologic molecules
in living systems can be determined [42–44] and may provide clues as to
the vulnerabilities of tumor tissue and response to therapeutic interventions.
Mechanical differences between normal and diseased tissue may be iden-
tified through the use of specialized precision ultrastructural ultrasound
techniques [45]. Characterization-mode ultrasound allows a detailed mathe-
matic reconstruction of the material properties of cells/tissue to provide
quantifiable mechanical parameters (eg, density, mechanical moduli, and
attenuation coefficients) of a sample (Fig. 3) [46]. Standard industrial non-
destructive evaluation C-scan ultrasound technology also is under evalua-
tion for its usefulness in evaluation of tissue samples [47].
Fig. 2. Superparamagnetic nanoparticles: BT20 breast cancer cell line cellular uptake of (A) un-
modifed magnetite nanoparticles, (B) PEG-coated, and (C) folic acid–coated magnetite nano-
particles, independent of time in culture. (From Zhang Y, Kohler N, Zhang M. Surface
modification of superparamagnetic magnetite nanoparticles and their intracellular uptake.
Biomaterials 2002;23(7):1560; with permission.)
Fig. 3. Ultrastructural ultrasound: reflection spectra from normal breast tissue and malignant
breast tissue (invasive ductal carcinoma). N1, N2, and N3 are the reflection spectra from three
normal tissue sections; T1, T2, and T3 are those from three malignant tissue sections from the
same patient (ultrasound frequency range: 5 to 14 MHz). (From Liu J, Ferrari M. Mechanical
spectral signatures of malignant disease? A small-sample, comparative study of continuum ver-
sus nano-biomechanical data analyses. Dis Markers 2002;18(4):175–83; with permission.)
Ultrasound-identifiable malignant tissue characteristics may be enhanced

further by using nanoscale contrast agents in the form of monoclonal anti-
bodies conjugated to superparamagnetic iron oxide nanoparticles (approxi-
mately100 nm) [46]. In this strategy, the material properties of nanoparticles
provide contrast for imaging via ultrasound or other means, such as MRI
[46,48–50]. This approach using Herceptin, the commercially available hu-
manized monoclonal antibody directed against the Herceptin (HER-2)/neu
oncogene conjugated to iron oxide nanoparticles demonstrated 87.5%
sensitivity and 96.8% specificity for distinguishing the degree of HER-2/neu
positivity by conventional histologic staining and pathologist evaluation
and, even more encouragingly, 100% sensitivity in distinguishing between
malignant and normal tissue (Fig. 4) [46]. This approach also may permit
multifunctionality: nanoparticles so targeted to features on or in cancer cells
may serve not only as contrast agents but also as potentiators for thermal
ablation of malignant tissue via radiofrequency (RF), microwave, or focused
ultrasound [51–53].
Electron paramagnetic resonance is an evolving imaging technique that
may allow an even greater understanding of the regional metabolic activity
within diseased tissues and also may be enhanced through administration of
nanometer-scale contrast agents in the form of gadolinium nanoparticles
(folate and PEG coated). This technique also may be useful for imaging
and treatment through neutron capture therapy. The particles are demon-
strated to localize to tumors in vivo [54,55].
There is a continued need for development of new contrast agents that
not only will provide improved sensitivity for these imaging modalities
Fig. 4. Ultrasound combined with antibody-conjugated nanoparticles: each of these images

represents consecutively cut tissue sections originating from the same breast tissue block sam-
ple. The top row indicates by the colored circles ‘‘regions of interest’’ by ultrasound image of
breast cancer tissue sections, which have been processed in the following manners: (1) Her-
Con: iron oxide particle conjugated with Herceptin; (2) Herceptin: Herceptin-positive control;
(3) ISO-Con (negative control): iron oxide particle conjugated with an isotype-matched anti-
body; and (4) no treatment. The corresponding histology on the bottom row has been stained
(DAKO Autostainer) for HER-2/neu expression and determined to be 2þ for HER-2/neu ex-
pression by an experienced pathologist. (From Sakamoto JH, Smith BR, Xie B, et al. The mo-
lecular analysis of breast cancer using targeted nanoparticle based ultrasound contrast agents.
Technol Cancer Res Treat 2005;4(6):627–36; with permission.)
but will also allow identification of early genomic and proteomic changes as-
sociated with diseases, such as cancer, at time points well before gross phys-
ical changes can be detected. Recent developments in the field of magnetic
nanoprobe technology have allowed detection of molecular interactions in
live cells using an approach defined as magnetism-based interaction capture
(MAGIC) [39]. This technique uses induced movement of superparamag-
netic nanoparticles within living cells to identify specific molecular targets.
Superparamagnetic nanoparticles are coated with molecules of interest. Cel-
lular uptake is followed; the location of the particles is directed by the mag-
netic field. As an example, this approach has been used in genome-wide
expression screening that yielded multiple protein targets of a drug. Other
demonstrated uses of MAGIC include monitoring of alterations in proteins
that occurs after signal transduction and in the identification of protein-
protein interactions. These are few of the types of nanoplatforms that
currently are under development that ultimately will lead to the ability to
image changes at cellular and subcellular levels with unprecedented
sensitivity.
Disease-related abnormalities that may not be identifiable directly and
visually can be made manifest through the use of color- or fluorescent-
contrast agents or even expression of indicator genes that are targeted to
the diseased tissue of interest [56]. One recently developed approach has
used nanoparticles, called quantum dots, for imaging. Quantum dots are
semiconductor nanocrystals that are stabilized and protected within a shell,

fluorescing within specific wavelengths according to their size. These nano-
crystals can be conjugated or linked to antibodies or other markers that
allow them to bind to specific receptors or antigens on the surface of cells
or to organelles within cells. Used in combination with microscopy or other
instruments that can detect the fluorescent signal, quantum dots can allow
imaging of specific cell populations. As an example of the wide number of
uses of these quantum dots, studies have been performed to observe the
diffusion of individual receptors in living cells and to identify lymph nodes
in live animals using near-infrared emission during surgery [57]. Quantum
dots also may be targeted to protein markers in the lung endothelium and
to cancers [56]. Although the chemical composition of quantum dots in
current use does not allow these nanoparticles to be used in humans as
yet, this approach shows promise. Given the rapid advances in nanotechnol-
ogy and material sciences, similar nanoparticles that are biocompatible no
doubt will be available soon for use in vivo imaging of patients, may have
potential in such applications as intraoperative detection of sentinel lymph
nodes that contain metastatic tumor cells, and may have greater capability
to target tumors and tumor-associated vasculature. Experimentally, nano-
crystal technology may allow resolution at the level of single molecules
within living cells, which would yield insight into regulatory pathways
that are not yet fully described.
The properties of superparamagnetic iron oxide nanoparticles have been
combined with those of nanocrystals to create magnetic nanocrystals, which
have been used for in vivo MRI imaging and for in vitro and in vivo fluo-
rescent detection of human breast tumor cells grown in mice [58]. Although
these are initial studies, they suggest that the magnetic nanocrystals may
provide a platform for multimodality imaging of human tumors and, fur-
thermore, indicate that this approach may be useful for development of
nanoprobes that are well defined, with appropriate size and biocompatibil-
ity. This nanoplatform can be functionalized for targeting to appropriate re-
ceptors and may be useful for further development of new contrast agents
for MRI and other clinically relevant noninvasive imaging methods.
Therapeutic nanotechnology for cancer

Nanotechnology will offer significant and increasing improvements in
options for therapeutic interventions against malignancies. Ultimately,
nanotechnology will allow researchers and physicians to overcome many
of the difficulties encountered in the treatment of cancer and other diseases.
The nature of nanotechnology, in its ability to implement strategies on an
intimate scale, permits researchers to conceive of interventions built on en-
tirely different concepts than those treatment modalities developed in the
past that utilized single or multiple cytotoxic agents. Nanotechnology will
allow multifunctionalities that will enable surmounting of the problem
sequential biologic barriers. Selective targeted therapy will be enhanced

through the use of multimodal targeting, in which therapeutics are localized
physically by more than one mechanism (Fig. 5) [2]. Nanotechnologic pack-
aging of therapeutics will provide the ability to co-localize delivery of mul-
tiple and complimentary therapeutic agents. Additionally, materials that
now require injection potentially could be inhaled or swallowed using nano-
engineered delivery devices, thus improving patient comfort and compliance
[59,60]. Even through-the-skin administration of some agents, such as vac-
cines, can be made more comfortable, by using multitudes of micro- or
nanometer-scale needles, to which human nerves are insensitive, rather
than a painful injection [61]. Compliance may be improved further with lon-
ger dosing intervals [62], which are possible with the use of nanoparticulate
and other delivery systems. Nanoparticulates also may allow increases in the
amount of drug that reaches abnormal cells. This site-specific (and poten-
tially metabolism-specific) targeting and nanoparticle-induced cloaking of
potentially toxic therapies and, theoretically, the requirement for less total
amount of therapeutic agents may allow the safe use of some drugs that
are effective but otherwise have unacceptable toxicity profiles. Also,
Fig. 5. Multifunctional nanoparticle illustrating the ability to carry one or more therapeutic
agents, biomolecular targeting through one or more conjugated antibodies or other recognition
agents, imaging signal amplification by way of coencapsulated contrast agents, and biobarrier
avoidance exemplified by an endothelial tight-junction opening permeation enhancer and by
PEG for the avoidance of macrophage uptake. (From Ferrari M. Cancer nanotechnology:
opportunities and challenges. Nature Reviews Cancer 2005;5:161–71; with permission.)
activation of devices or release of drug may be made dependent on a site- or

tissue-specific second stimulus, via mechanical means, as in the localized appli-
cation of heat, ultrasound, or a magnetic field, or may, in the case of delivery
devices, be programmable or controlled externally by patients or health care
workers. Examples of many of these strategies are discussed in this section.
Drug delivery devices with nanoscale features

Nanometer-scale features may allow the practical construction and use of
fully implantable and controllable drug delivery devices. The authors’ nano-
technology research group is developing implantable nanochannel drug
delivery devices that can provide control and optimization of pharma-
codynamics, allowing prolonged steady-state drug release without poten-
tially injurious peaks, controlled start/stop of drug administration,
adjustment in level of dosing, or pulsatile release, all tailored to the require-
ments for a particular therapeutic agent. These devices are designed to serve
as an interface between a protected internal reservoir containing the thera-
peutic agent and the site of drug release within patients. The internal struc-
ture of the device contains multiple channels of nanometer dimension
through which a therapeutic agent must pass to gain release into the
body. Flow of medication is controlled by channel dimension and manipu-
lation of the microdelectrical environment within and across the device. De-
livery and subsequent biologic activity of interferon alpha a-2 (IFN-a2a)
against a human melanoma cell line has been demonstrated (Fig. 6)
[63,64]. Mathematic modeling gives precise predictions of the rate of drug
release over time [65]. The design of these devices should allow control
from outside the patient (via telemetry) or integration into a feedback
loop system using incorporated or associated diagnostics and monitoring.
Particulates for drug delivery

Liposomes
Liposomes in many sizes and compositions are already in fairly common
use as drug delivery devices in cosmetic and medical applications. Lipo-
somes work by encapsulating therapeutic agents in a one- or two-layer
lipid-containing membrane. This provides several potential advantages, in-
cluding improving the distribution and safety of poorly soluble agents, slow-
ing the rate of release and clearance of the therapeutic agents, and increasing
the time of circulation to allow efflux at areas of abnormality, which often
are associated with hyperpermeability of vasculature endothelium. Encapsu-
lation of drugs in liposomes often has demonstrated improved therapeutic
efficacy, after administration by any of multiple routes, over that of the
drug alone. Ongoing liposome refinements are aimed at overcoming early
problems related to variability in particle size, amount of medication incor-
porated into the particles, integrity of payload encapsulation, and targeting
diseased tissue and organs.
Fig. 6. Nanochannel drug delivery device: (A) cross-sectional view of the nanochannel delivery
system; (B) en face view of the bottommost of the two silicon layers; and (C) atomic force mi-
croscopy (AFM) image of a 100-nm step in bottom substrate, which creates the nanochannels
(scan size: 3.679 mm; scan rate: 1.001 Hz). (From Lesinski GB, Sharma S, Varker KA, et al. Re-
lease of biologically functional interferon-alpha from a nanochannel delivery system. Biomed
Microdevices 2005;7(1):71–9; with permission.)
Current use of liposomes, followed by mention of several more advanced

applications of liposomes that are in various stages of anticancer testing, is
discussed. The use of liposomal formulations of toxic azole antifungal
medications is well established in human clinical use. Aside from these per-
haps better-known azole antifungals, several liposomal formulations are
approved by the United States Food and Drug Administration (FDA) for
use in cancer chemotherapy. These include doxorubicin hydrochloride en-
capsulated in STEALTH liposomes (DOXIL), that incorporates PEG,
a molecule that allows further evasion of uptake and removal by the retic-
uloendothelial system. The therapeutic approach of liposomal encapsulation
of doxorubicin has been approved for treatment of patients with AIDS-
related Kaposi’s sarcoma that has worsened on combination chemotherapy,
patients who are intolerant to other therapy, and patients who have meta-
static ovarian cancer refractory to platinum and paclitaxel-based therapies.
Liposomal cytarabine is approved for intrathecal administration in lympho-
matous meningitis. Daunorubicin in liposomal form is FDA approved as
a first line for treatment of AIDS-related Kaposi’s sarcoma. Clinical trials
currently underway use liposomally encapsulated medications, especially
doxorubicin, in combination with other conventional chemotherapeutic
agents against several types and stages of cancers. Additionally, liposomal
vincristine is in clinical trials, as is a liposomal camptothecin analog studied
under the name OSI-211.
Additional liposomal formulations are under evaluation in humans for
the treatment of cancer. Interleukin (IL) 2 has been in use for many years
to combat several types of cancer. Its administration, usually intravenous
or subcutaneous, as is true of many other immunologically based biologic
therapies, often is complicated by uncomfortable and occasionally life-
threatening, infection-like symptoms. Liposome-encapsulated IL-2 given
via inhalation was tested with promising results in animal models of several
cancers [66]. Subsequently, in a phase I study of nine patients, an inhalable
liposomal formulation of IL-2 for pulmonary metastatic disease showed no
measurable toxicities [67]. Liposome particulate delivery devices with PEG
outer coatings, which may increase the time of circulation and provide the
ability to add additional biologic surface treatment functionalities, have
performed favorably in human trials. Doxorubicin in such a vehicle for
metastatic or locally advanced lung cancer had no undue toxicities [68].
The STEALTH liposome in a phase II study using cisplatin as a payload
for stage IIIB and IV lung cancer (after failure of other therapy), however,
did not result in any increased survival in the small group of patients in
which it was studied [69]. This also was the case a trial of patients who
had doxorubicin-resistant breast cancer, using annamycin in liposomal
form [70]. The topoisomerase 1 inhibitor, 9-nitrocamptothecin, in liposomes
administered by inhalation, however, did show benefit in some patients who
had advanced pulmonary malignancies [71].
Many liposomally packaged chemotherapeutic agents or biologic agents
directed against malignancies still are in animal testing. Inhaled liposomal
IFN-g resulted in increased tumoricidal macrophage activity in a mouse
model [72]. L-arginyl-6-aminohexanoic acid is a mimetic of RGD (arginine–
glycine–aspartic acid sequence) peptides. When present in high amounts
near primary tumors, these peptides have prevented metastasis in animal
models. Such peptides generally are broken down quickly by the body’s met-
abolic machinery shortly after their introduction into the body and, therefore,
have not, up to now, been practical for therapeutic use. When enclosed in
liposomes and injected into mice that have malignant melanoma, however,
the result was an apparent inhibition of lung colonization by metastatic tumor
cells [73]. A 5’-O-dipalmitoylphosphatidyl derivative of 2’–C-cyano-2’-
deoxyl-1-beta-D-arabina-pentofuranosylcytosine, which causes cell cycle
arrest at G2, similarly resulted in a reduction in lung tumor colonization in
a murine model of melanoma [74]. When packaged in liposomes, RU
58,668 demonstrated increased efficacy over drug alone in mice that had
multiple myeloma [75]. There seems to be hope on the horizon through the
use of many of these formulations.
Newer versions of liposomes allow the potential to localize the delivery of
payload to a chosen site of biologic abnormality, among other enhanced
functionalities [76]. Fragment antigen binding antibody fragments directed
against beta-1 integrins, which are expressed on human non–small cell
lung cancer, when conjugated to sterically stabilized liposomes containing
doxorubicin, demonstrated binding to and internalization into tumor, sup-
pression of tumor growth in established lung metastases, prevention of
spread to liver and adrenals, and increased survival in a mouse model
[77]. Breast cancer in a rat model was targeted successfully, toxicity was min-
imized, and even cures were established through the use of doxorubicin
packaged in sterically stabilized liposomes directed to the tumor site by
anti-HER-2/neu monoclonal antibodies [78–80]. Similarly, a strategy was
devised to take advantage of the frequent overexpression by lung cancers
of the hyaluronan receptors, CD44 and receptor for hyaluronan acid-medi-
ated motility (RHAMM). When doxorubicin was packaged in high-Mr hya-
luronan nanoliposomes, there was greater accumulation of doxorubicin in
tumor tissue, along with decreased tumor progression and metastatic burden
and increased survival in a murine model [81]. Even strategies such as alter-
ation of the electrical charge of the liposomal particles may allow tumor tar-
geting. Negatively charged tripalmitin nanoparticles encapsulating etoposide,
when tested in a mouse model of Dalton’s lymphoma, showed improved
bodily distribution and increased tumor uptake over that of drug alone [82].
Among the more exciting uses of liposomes in cancer therapeutics is in
the area of gene delivery. Given the frustrating difficulties with viral vectors
for introduction of therapeutic nucleic acid constructs, many genetically
based therapies wherein the genetic material is introduced instead via lipo-
somes are under investigation, and the results are encouraging [83]. Several
centers are particularly active on this front. Researchers at University of
Texas MD Anderson Cancer Center have developed a cationic liposome
(DOTAP) for the delivery of genetic material that may be tailored to the
specific requirements of the clinical situation. They have demonstrated
that a version of their liposomes is taken up into tumor cells without any
other specific targeting and brings about increased and prolonged transgene
expression in tumor over normal cells along with a favorable immunologic

response profile [84,85]. Using these lipid particulate delivery devices, they
have optimized the formulation for transfection of the tumor suppressor
p53 gene in a mouse model of lung cancer, resulting in prevention of lung
tumor growth and prolonged survival [86,87]. Another group further refined
the p53 delivery strategy through antitransferrin receptor scFv (single-chain
variable fragment/singlechain Fv antibody/single-chain variable antibody
fragment) targeting [88]. The MD Anderson group also has demonstrated
successful transfection and resultant tumor response using the cationic lipid
device for delivery of the proapoptotic gene, bik, and the fus1 gene in mu-
rine models of breast and lung cancer, respectively [89,90]. Plasmids coding
for endostatin, an angiogenesis inhibitor, were introduced via cationic lipo-
somes in a rat model of osteosarcoma. This resulted in a delay in tumor
growth and prevention of lung metastasis [91]. At the University of Pitts-
burgh, researchers have used liposomes to deliver genetic constructs that
may provide protection against time-limited injuries, such as radiation ther-
apy. They have demonstrated expression of the antioxidant manganese
superoxide dismutase, in the esophagus with resultant protection from
radiation-induced apoptosis and improvement in survival in a murine tho-
racic tumor model associated with continued efficacy of radiation against
the tumor [92–94]. Strategies using small interfering RNA (siRNA) encased
in antibody-targeted liposomes have demonstrated successful intracellular
delivery of the intact RNA constructs and hold promise in creating interfer-
ence with essential tumor metabolism [95]. This group has contributed
further to the field of cancer treatment via targeted liposomal transfection
of tumor cells in the successful inclusion of a synthetic pH-sensitive histidy-
lated oligolysine, K[K(H)KKK]5-K(H)KKC (HoKC), designed to improve
transfection efficiency [96]. Using a lipopolypex of the DOTAP, cholesterol
cationic liposomes with protamine sulfate and noncoding bacterial plasmids
that stimulate the Th-1 immune response against lung metastases in a mouse,
Whitmore and colleagues showed reduction in tumor burden [97]. Another
approach to capturing the antitumor effect of IL-2 places complementary
DNA plasmids encoding the cytokine into cationic liposomes for infusion
into a dog model of metastatic osteosarcoma. This resulted in evidence of
appropriate immune activation, transgene expression in lungs, tumor regres-
sion in 3 of 20 animals, and increased survival over historical controls [98].
In an intriguing approach, Karara and colleagues delivered a suicide gene,
pCMVtk, via subcutaneously injected liposomes in a murine adenocarci-
noma model. This administration was followed by gancyclovir, an antiviral
directed against cytomegalovirus, to result in complete inhibition of tumor
growth in 80% of the animals they studied [99]. Other groups have liposo-
mally transfected the anti-angiogenic and anti-invasion proteins, angiosta-
tin, tissue inhibitor of metalloproteinase (TIMP) 2, and IFN-a, and IFN-b,
IFN-g, and a synthetic double-strand RNA that is a type I interferon in-
ducer, with positive antitumor results [100,101]. In an alternative approach,
administration of a liposomally packaged antisense oligonucleotide for the

cell growth-inducer, Raf-1, resulted in inhibition of Raf-1 expression in tissue
and led to the enhancement of the activity of antitumor agents, doxorubicin or
paclitaxel, in animal models of breast and prostate cancer [102]. Using a similar
approach, another group used intratumor injection of liposomes containing
plasmids encoding anti-sense constructs of c-Met (mesenchymal epithelial
transition factor), a tyrosine kinase receptor that binds hepatocyte growth
factor and promotes tumorgenicity. The administration of c-Met antisense
decreased tumor growth and increased tumor apoptosis [103]. Similarly,
a liposomally delivered antisurvivin construct resulted in decreased prolifera-
tion and increased apoptosis in human lung carcinoma cells [104]. These are
exciting developments. Each of these approaches, none possible a decade
ago, deserves further exploration and study to define its use and potentials.
One advantage of nanotechnology in the treatment of cancer and other
complex diseases is the ability to co-enclose two or more therapeutic agents,
allowing one agent to prime for the other or to provide other complemen-
tary effects. To this end, dilauroylphosphatidylcholine liposomes containing
9-nitrocamptothecin with polyethleneimine-p53 DNA were used in a murine
model of malignant melanoma via aerosol or injection. Results of this study
demonstrated the ability of this approach inhibit growth of established lung
metastases and increase survival [105]. In another approach designed to
overcome some of the mechanisms of resistance to chemotherapy encoun-
tered in malignant tumors, doxorubicin was packaged together in liposomes
with antisense oligonucleotides targeted to multidrug resistance protein 1
(MRP1) messenger RNA (mRNA) (to suppress pump resistance) and anti-
sense to BCL2 mRNA (to suppress nonpump resistance). Chemotherapy-
resistant and nonresistant versions of human small cell lung cancer cells
were treated, demonstrating delivery of the nucloetides to cell nuclei and in-
hibition of MRP1 and BCL2 synthesis. This approach allowed the copack-
aged doxorubicin access to bring about caspase-dependent apoptosis of
tumor cells [106]. A phospholipid, cholesterol, and poly-L-lysine ‘‘nanoe-
mulsion’’ containing plasmid DNA with a pSV-b-Gal reporter was cultured
with a human SF-767 glioma cell line. Transfection increased with the addi-
tion of chloroquine, suggesting that endocytosis is a mechanism for uptake
for transfection [107]. At the Massachusetts Institute of Technology (MIT),
a group has developed a ‘‘nanocell,’’ comprised of a nuclear nanoparticle
within an extranuclear pegylated lipid envelope that is taken up by tumor
cells, enabling the cell initially to release an anti-angiogenic agent followed
by a contained chemotherapeutic agent [108].
Many strategies use a liposomal delivery strategy combined with a separate
intervention to bring about localized release of drug. Thermosensitive lipo-
somes have proved effective by several groups. In a rat model of breast cancer,
applying heat to the area of tumor after systemic administration of doxorubi-
cin-containing thermosensitive liposomes demonstrated localization of the li-
posomes to the site of tumor and release of their payload [109].
Thermosensitive liposomes containing doxorubicin in a hamster model of os-

teosarcoma were administered, followed by application of heat to the primary
tumor site. This resulted in inhibition of tumor growth and metastasis [110].
The same group used magnetic liposomes enveloping doxorubicin in a similar
osteosarcoma model. After intravenous injection, a magnetic field applied
over the affected limb brought about increased drug at the site, suppression
of primary tumor growth, and decreased lung metastasis [111].
Nonliposomal particulates
Many promising biodegradable nanoparticles for the purpose of therapeu-
tic agent delivery have been developed [112,113]. As with liposomes, nonlipid
nanoparticles may serve to localize drug delivery and to avoid first-pass me-
tabolism [114]. Certain nanoparticles may be able to evade the immediate rec-
ognition of the recipient immune system partially, allowing the potential for
a longer period of efficacy and improved arrival at target tissues [115]. As dis-
cussed in the following paragraphs, nonliposomal nanoparticulates may have
even greater functional flexibility than their lipid counterparts.
Nonliposomal nanoparticulates already have begun to prove their use
against cancer in humans. When tested in Phase I and II clinical trials in hu-
mans, polymer micels (NK911) containing doxorubicin were found to have
an acceptable toxicity profile and brought about a partial response in pa-
tients with metastatic pancreatic cancer [116]. This formulation is now un-
dergoing additional human studies. One of the particularly exciting stories
in the past few years has been that of Rexin G, a targeted delivery system
(TDS)-guided retroviral cytocidal gene injectable, which has demonstrated
acceptable safety in phase I human studies and probable efficacy against
metastatic pancreatic cancer. It now has FDA approval as an orphan
drug and testing is continuing in additional trials [117]. A micellar form
of paclitaxel complexed with polyglutamate also now is FDA approved
and undergoing further trials in combination with other therapeutic agents.
Additional nanoparticulate packaging systems are on the horizon. Poly
(D,L-lactide)-co-glycolide, a self-microemulsifying drug delivery system
containing paclitaxel, when used in a murine model of ovarian cancer,
shows enhanced antitumor activity over microemulsed drug alone [118].
Biodegradable copolymers coated with PEG enclosing the antiestrogen
RU 58,668 decreased tumor size in breast and uterine cancers in mice
[119]. Polymer microspheres formed by phase inversion encapsulation of
IL-2, IL-12, and granulocyte-macrophage colony-stimulating factor
(GMCSF) demonstrated release of the contained therapeutic agents over
30 days to 9 weeks [120].
One advantage of nanoparticulates as delivery devices is their potential to
target tumor in different ways. Nigavekar and colleagues have demonstrated
targeting of nanodendrimers, which may serve as drug delivery devices, to
tumors [121]. A group from Brussels took a unique approach to tumor tar-
geting: nanobodies (antibody fragments) directed against carcinoembryonic
antigen were conjugated to enterobacter cloacae b-lactamase. This was

followed by administration of a cephalosporin nitrogen mustard prodrug,
which activated release of phenylenediamine mustard at the site of tumor
on interaction of the cephalosporin with the b-lactamase [122]. Even what
amounts to radiation therapy can be targeted precisely by using techniques
of nanotechnology, as demonstrated by a group at Memorial Sloan-Ketter-
ing Cancer Center: actinium-225, a high-energy transfer a-nanoparticle, was
coupled to internalizing monoclonal antibodies. In vitro, these particles
were demonstrated to kill leukemia, lymphoma, breast, ovarian, neuroblas-
toma, and prostate cell lines at nanocurie levels. When used in mice that had
implanted prostate cancer or disseminated lymphoma, the same technique
caused tumor regression and increased survival without any noted toxicity
[123]. These are just a few of the innovative and encouraging designs under
development.
Gene delivery through the use of nonlipid nanoparticulates also holds
great promise. Polymeric nanoparticles have been used to achieve gene
transfection within tumor cells [124]. Another group armed polyisobytylcya-
noacrylate nanocapsules (with an aqueous core) with phosphorothioate
oligonucleotides against EWS/Fli-1 chimeric RNA. When injected into the
site of tumor in a mouse model of Ewing’s sarcoma, they demonstrated in-
hibition of the tumor growth [125].
Nonliposomal nanoparticulates also may be activated by separate local
interventions. Nanocapsules with an oily core surrounded by poly(D,L-
lactic acid) (PLA) with PEG or poloxamer 188 (polox PLA) were loaded
with beta-tetra(hydroxyphenyl) chlorine. With optical fiber fluorimetry,
PEG-surrounded capsule-treated mice showed higher drug levels early, re-
tention of drug in tumors, and reduced liver uptake [126]. Injection of poly-
styrene nanoparticles loaded with 5-fluorouricil (5-FU) in a mouse model of
colon cancer followed by ultrasound resulted in complete tumor regression
[127]. Thermoresponsive, pH-responsive biodegradable nanoparticles, com-
posed of a poly(D,L-lactic acid)-graft-poly(N-isopropyl acrylamide-co-
methacrylic acid)(PLA-g-P[NIPAm-co-MAA]) core-shell structure with
contained 5-FU, after being taken up into a hepatocarcinoma cell line,
have resulted in release of the 5-FU intracellularly through localized heating
and manipulations in pH [128]. Self-assembled polyelectrolyte shells of 1-mm
diameter, when used to treat MCF-7 breast cancer cells, demonstrated cel-
lular uptake in the face of various electrostatic potentials. This was inhibited
by serum protein adsorption. The inhibition could be overcome by polyca-
tion coating with a polyethyleneimine-PEG copolymer, however [129]. We
are truly crossing into an exciting new era in cancer therapy.
Vaccines
Vaccines represent a promising area in which nanotechnology is likely to
have a high impact in the prevention and treatment of cancers. With
provision of the correct stimulus and associated circumstances, we can work

to bring a patient’s own immune system to bear against malignancy. Some
vaccines using nanotechnology components already have been studied in
human trials. BLP25 (a synthetic MUC1 peptide vaccine that incorporates
a 25-amino acid sequence of the MUC1 cancer mucin) in a liposome injec-
tion was studied in a phase IIb trial for patients who had stage IIIb and IV
non–small cell lung cancer after any first-line therapy. In this trial, there
were no significant toxicities, and survival increased 4.4 months. Although
this was not statistically significant in this small group of patients, it does
warrant further study, especially in the subgroup of patients who had
locoregional disease who seemed to have the greatest response [130]. A cat-
ionic lipid (TFL2-3) formulation enclosing a plasmid vector encoding
Epstein-Barr virus (EBV) oriP and EBV nuclear antigen with autologous tu-
mor cells plus IL-12 and IL-18 genes in a melanoma mouse model resulted
in tumor suppression associated with interferon production [131]. Archaeo-
somes, vesicles of ether glycerolipid (Methanobrevibacter smithii) containing
ovalbumin antigen as an immunostimulant in mouse models of melanoma
cells (both positive and negative for ova expression), showed decreased
tumor growth in ova-expressing tumors which was believed mediated by
cytotoxic T lymphocytes [132].
Theoretic applications of nanotechnology for cancer

There are other promising techniques using nanotechnology on the hori-
zon. Researchers at MIT have been able to accomplish precision-inductive
coupling of a radiofrequency (RF) magnetic field with metal nanocrystals
linked covalently to DNA, thus bringing about localized and reversible de-
naturation of DNA [133]. Delivery of magnetic micro- or nanoparticles may
be targeted to areas of disease by magnetizable wires receiving a perpendic-
ular external uniform background magnetic field [134]. Gold islands formed
by binding to silicon ‘‘seeds’’ absorb near-infrared radiation. Assuming
these may be targeted to cancer cells, they could kill the cells on a local level
without significant damage to surrounding tissues [135]. This principle has
been refined further by researchers at Rice University, who have character-
ized the optical properties of gold nanoshells of various sizes in tissue sim-
ulations [136] and also have indicated the potential for their use in
photothermal therapy. These are but several of the many potential nano-
technology-based applications from which we may benefit over the next
several years.
Summary
There is no doubt that nanotechnology will continue to have a profound
and positive impact on humanity. This article has reviewed a few of its many
applications in the fight against pain, suffering and death from cancer. Many
nanotechnology-based diagnostic and treatment modalities already are in

use, with many others at various stages of pre-clinical and clinical testing.
Several nanotechnology platforms hold great promise for diagnosis and
treatment of cancer. Nanotechnology assuredly will serve as a cornerstone
in this ongoing and noble endeavor.
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Biomedical Nanotechnology For Cancer

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Med Clin N Am 91 (2007) 899–927

Biomedical Nanotechnology for Cancer

Clinical medicine has seen tremendous improvements in the past several

Diagnosis, prognosis, and disease status

for query, can result in improved assay sensitivity. Identiﬁcation of bio-

Nanotechnology in diagnostic assays

agents. Their ability to multiplex and their physical properties allow

The bio-barcode assay

a microparticle attached to a recognition agent. The recognition agent is an

Nanowires: label-free electronic sensors of genes and proteins

of ﬁeld eﬀect transistors [25,26]. Expanding on this concept, nanowire

Cantilevers: nanomechanical detection of biologic molecules

Thiol-modiﬁed ssDNA probes (20 mer) immobilized on one side of a canti-

diagnostic capabilities in MRI. Conjugation of folate and polyethylene gly-

Ultrasound-identiﬁable malignant tissue characteristics may be enhanced

Fig. 4. Ultrasound combined with antibody-conjugated nanoparticles: each of these images

semiconductor nanocrystals that are stabilized and protected within a shell,

Therapeutic nanotechnology for cancer

sequential biologic barriers. Selective targeted therapy will be enhanced

activation of devices or release of drug may be made dependent on a site- or

Drug delivery devices with nanoscale features

Particulates for drug delivery

Current use of liposomes, followed by mention of several more advanced

expression in tumor over normal cells along with a favorable immunologic

administration of a liposomally packaged antisense oligonucleotide for the

Thermosensitive liposomes containing doxorubicin in a hamster model of os-

antigen were conjugated to enterobacter cloacae b-lactamase. This was

provision of the correct stimulus and associated circumstances, we can work

Theoretic applications of nanotechnology for cancer

nanotechnology-based diagnostic and treatment modalities already are in

[126] Bourdon O, Laville I, Carrez D, et al. Biodistribution of meta-tetra(hydroxyphenyl)chlorin

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