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review article
Current Concepts
Nanomedicine
Betty Y.S. Kim, M.D., Ph.D., James T. Rutka, M.D., Ph.D.,
and Warren C.W. Chan, Ph.D.
From the Institute of Biomaterials and
Biomedical Engineering (B.Y.S.K., W.C.W.C.),
Terrence Donnelly Centre for Cellular and
Biomolecular Research (B.Y.S.K., W.C.W.C.),
the Department of Materials Science and
Engineering (W.C.W.C.), and the Depart-
ment of Chemical Engineering (W.C.W.C.),
University of Toronto (B.Y.S.K., J.T.R.,
W.C.W.C.); and the Division of Neurosur-
gery (B.Y.S.K., J.T.R.) and the Arthur and
Sonia Labatt Brain Tumour Research
Centre (J.T.R.), Hospital for Sick Children
(B.Y.S.K., J.T.R.) — both in Toronto. Ad-
dress reprint requests to Dr. Chan at the
Institute of Biomaterials and Biomedical
Engineering, Donnelly Centre for Cellular
and Biomolecular Research, 164 College
St., 407, University of Toronto, Toronto, ON
M5S 3G9, Canada, or at warren.chan@
utoronto.ca.
N Engl J Med 2010;363:2434-43.
Copyright © 2010 Massachusetts Medical Society.
M
any diseases originate from alterations in biologic processes
at the molecular or nanoscale level. Mutated genes, misfolded proteins,
and infections caused by viruses or bacteria can lead to cell malfunction
or miscommunication, sometimes leading to life-threatening diseases. These mol-
ecules and infectious agents are nanometers in size and may be located in biologic
systems that are protected by nanometer-size barriers, such as nuclear pores 9 nm
in diameter. Their chemical properties, size, and shape appear to dictate the trans-
port of molecules to specific biologic compartments and the interactions between
molecules.
Nanotechnology is defined as the “intentional design, characterization, produc-
tion, and applications of materials, structures, devices, and systems by controlling
their size and shape in the nanoscale range (1 to 100 nm).”
1
Because nanomaterials
are similar in scale to biologic molecules and systems yet can be engineered to have
various functions, nanotechnology is potentially useful for medical applications.
The field of nanomedicine aims to use the properties and physical characteristics of
nanomaterials for the diagnosis and treatment of diseases at the molecular level.
Nanomaterials are now being designed to aid the transport of diagnostic or
therapeutic agents through biologic barriers; to gain access to molecules; to medi-
ate molecular interactions; and to detect molecular changes in a sensitive, high-
throughput manner. In contrast to atoms and macroscopic materials, nanomaterials
have a high ratio of surface area to volume as well as tunable optical, electronic,
magnetic, and biologic properties, and they can be engineered to have different
sizes, shapes, chemical compositions, surface chemical characteristics, and hollow
or solid structures.
2,3
These properties are being incorporated into new genera-
tions of drug-delivery vehicles, contrast agents, and diagnostic devices, some of
which are currently undergoing clinical investigation or have been approved by the
Food and Drug Administration (FDA) for use in humans. Examples of the nano-
materials most commonly used in medicine are provided in Figure 1 and Table 1. This
overview describes the properties of nanomaterials, their principal medical appli-
cations, and the future possibilities for this emerging field.
Properties of Nanomaterials
Over the past three decades, physical scientists have developed strategies to repro-
ducibly synthesize nanomaterials and to characterize their unique, size-dependent
properties.
2,3
An understanding of these fundamental physical and chemical prop-
erties is necessary for the optimal use of nanomaterials in medical applications.
Nanomaterials generally consist of metal atoms, nonmetal atoms, or a mixture
of metal and nonmetal atoms, commonly referred to as metallic, organic, or semi-
conducting particles, respectively. The surface of nanomaterials is usually coated with
polymers or biorecognition molecules for improved biocompatibility and selective
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current concepts
n engl j med 363;25 nejm.org december 16, 2010
2435
targeting of biologic molecules. The final size and
structure of nanomaterials depend on the salt and
surfactant additives, reactant concentrations, re-
action temperatures, and solvent conditions used
during their synthesis.
A common feature of all nanomaterials is their
large ratio of surface area to volume, which may be
orders of magnitude greater than that of macro-
scopic materials.
4
Cutting a 1-cm cube into 10
21
cubes that are each 1 nm on a side will result in
the same overall volume and mass, but the surface
area will be increased by a factor of 10 million.
Thus, the advantage of using nanomaterials as car-
riers is that their surface can be coated with many
molecules.
Unique aspects of metal-containing materials
with at least one dimension that is smaller than
100 nm are their size, shape, and composition-
tunable electronic, magnetic, and optical proper-
ties. This relationship is a direct consequence of
the behavior of electrons in the nanomaterial. Elec-
trons have two important characteristics: their
spin and their ability to move in a quantized fash-
ion between specific energy levels. Electrons are
similar to tiny bar magnets, with a surrounding
magnetic field that corresponds to the electron
spin in an applied field. Also, after absorbing en-
ergy, electrons can generate light or heat when
they move between different energy levels (Fig. 2).
In macrostructures, electrons can spin in two
directions, in opposition or in alignment, and can
move among many energy levels. The behavior
of electrons in nanostructures is more constrained
and depends on the size or shape of the material
or on the electrons’ interactions with the surface
coating. The chemical composition of a nanoma-
terial determines whether one or both electron
characteristics (spin and energy transition) are
affected, as well as the extent of that effect. For
example, all electrons in iron oxide magnetic
nanoparticles (≤20 nm in diameter) spin in the
same direction, whereas electrons in iron oxide
macroparticles (>20 nm in diameter) spin in op-
posite directions (Fig. 2A).
5
When these spins are
aligned in the same direction, the field becomes
additive, but when the electrons spin in opposite
directions, the fields cancel each other out. Since
the overall magnetic-field strength of a material is
the sum of the magnetic fields of individual
electrons, these nanoparticles have a larger, local-
ized magnetic field as compared with that of
larger particles. This larger magnetic field can
increase the contrast on magnetic resonance im-
aging (MRI), since more protons interact in a
larger field.
In cadmium selenide semiconductor nano-
structures that are less than 10 nm in diameter
(known as CdSe quantum dots, or Qdots), the
electrons can transition between two energy lev-
els: a ground state, in which the electrons are at
rest, and an excited state, in which they are mo-
bile (Fig. 2B).
6
The difference between the ground
and excited energy levels dictates the color and
fluorescence emission of these nanostructures.
This energy difference is size-dependent and can
be observed under ultraviolet light by means of
the fluorescence emissions of Qdots of different
sizes. Furthermore, the magnetic and optical sig-
nals from these inorganic nanomaterials tend to
be stronger than their traditional molecular coun-
terparts because a larger number of electrons are
involved. To illustrate this point, the absorption
cross section of Qdots, a measure of the number
of electrons that transition from the ground to
the excited state, is at least 10 times that of or-
ganic fluorescent dye molecules.
6
Nanomaterials for in Vivo
Applications
A handful of nanomaterials are being studied in
clinical trials or have already been approved by the
FDA for use in humans,
3,7,8
and many proof-of-
concept studies of nanomaterials in cell-culture
and small-animal models for medical applications
are under way.
6,9,10
Many of these nanomaterials
are designed to target tumors in vivo and are in-
tended for use either as drug carriers for thera-
peutic applications or as contrast agents for diag-
nostic imaging (Fig. 3). Nanomaterials infused
into the bloodstream can accumulate in tumors
owing to the enhanced permeability and reten-
tion effect when the vasculature of immature tu-
mors has pores smaller than 200 nm, permitting
extravasation of nanoparticles from blood into tu-
mor tissue.
11
The infusion of antineoplastic drugs
with nanomaterials as carriers results in an in-
creased payload of drugs to the tumor, as com-
pared with conventional infusion. With nanoma-
terials, the high ratio of surface area to volume
permits high surface loading of therapeutic agents;
in the case of organic nanomaterials, their hollow
or porous core allows encapsulation of hundreds
of drug molecules within a single carrier particle.
When the carrier particle degrades, the drug mole-
cules are released, and the rate of degradation
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2436
can even be controlled and fine-tuned according
to the polymer composition. These nanomaterial
delivery vehicles can also be coated with polymers,
such as polyethylene glycol, to increase their half-
life in the blood circulation, prevent opsonizing
proteins from adhering to the nanomaterial sur-
face, and reduce rapid metabolism and clearance.
Moreover, the use of nanomaterials for drug de-
livery may minimize adverse effects by preventing
the nonspecific uptake of therapeutic agents into
healthy tissues.
12,13
Aurimmune (CytImmune Sciences), which con-
sists of 27-nm gold nanoparticles coated with re-
combinant human tumor necrosis factor alpha
(TNF-α) and polyethylene glycol, is under inves-
tigation in phase 2 clinical trials (ClinicalTrials
.gov numbers, NCT00356980 and NCT00436410)
for the treatment of patients with a variety of ad-
vanced or metastatic cancers who are no longer
responsive to conventional treatment. Histopatho-
logical studies have shown that these nanopar-
ticles are localized within or around the tumor,
with less uptake into healthy organs than is seen
with the direct injection of TNF-α. The toxic ef-
fects and nonspecific accumulation normally as-
sociated with direct injection of TNF-α are re-
duced when TNF-α is coated on the nanoparticle
surface. The use of cytokines such as TNF-α is
limited by the inflammatory responses they pro-
duce, especially when tissues are exposed to high
doses. With intravenous injection of Aurimmune,
patients are able to tolerate 20 times the usual
dose of TNF-α.
14,15
Another agent under investigation and now in a
phase 4 clinical trial (NCT00912639) is Genexol-
PM (Samyang), which consists of 20-nm to 50-nm
micelles formed by the self-assembly of polyeth-
ylene glycol and poly-d,l-lactide polymers. The
core of these micelles contains paclitaxel, the
chemotherapeutic mitotic inhibitor. The micelles
were injected into 21 patients with advanced solid
tumors that were refractory to conventional ther-
apies. The disease stabilized in 42% of patients,
and in 14% of patients, there were positive re-
sponses (e.g., a decrease in lung mass).
16
In both
these examples, the patients were able to tolerate
a higher drug dose owing to the altered pharma-
cokinetic behavior of the therapeutic agents with
the use of nanoparticles, with no apparent side
effects attributable to the nanoparticle carrier.
Nanoparticles are also attractive as sensitive
contrast agents for cancer imaging. On nanopar-
ticle-enhanced MRI, a contrast can be observed
between tissues with and those without super-
paramagnetic iron oxide nanoparticles (SPIONs),
owing to a difference in the precession frequen-
cy of the protons (see the Supplementary Appen-
dix, available with the full text of this article at
NEJM.org). In one study, dextran-coated SPIONs
were injected into patients with prostate cancer
to detect possible lymph-node metastases.
17
The
dextran coating increased the circulation time of
the nanoparticles, and because of their small size,
these particles could traverse the lymphatic ves-
sels to reach the lymph nodes and be taken up
by the resident macrophages. The use of SPIONs
with MRI, as compared with conventional MRI,
was associated with substantial increases in both
diagnostic sensitivity (90.5% vs. 35.4%) and spec-
ificity (97.9% vs. 90.4%) in the detection of meta-
static tumors.
In another study, SPIONs were injected into
patients with solid tumors. The SPIONs remained
in the tumors 24 hours after the injection, as
compared with 1 hour for gadolinium-chelate con-
trast agents.
18
The reason for this difference is
that the smaller nanoparticles are more easily
taken up by tumor cells and diffuse out of the
tumor more slowly.
19
As a result, the tumor mar-
gins can be distinguished on MRI for a longer
period. Magnetic nanoparticles are also being
studied in clinical trials for imaging of hyperpla-
Figure 1 (facing page). Nanomaterials Commonly Used
in Medicine.
Several nanomaterials are being studied in clinical tri-
als or have been approved by the Food and Drug Ad-
ministration (FDA) for use in humans; others are in the
proof-of-concept stage in research laboratories. Lipo-
somes contain amphiphilic molecules, which have hy-
drophobic and hydrophilic groups that self-assemble in
water. Dendrimers are branched nanostructures; each
terminus contains reactive chemical functional groups
that allow the addition of more monomers to increase
the size of the nanostructure. Gold nanoparticles are
solid metal particles that are conventionally coated
with drug molecules, proteins, or oligonucleotides.
Quantum dots consist of a core-and-shell structure
(e.g., CdSe [red] coated with zinc and sulfide [blue]
with a stabilizing molecule and a polymer layer coated
with a protein [yellow structures]). Fullerenes (typically
called “buckyballs” because they resemble Buckmin-
ster Fuller’s geodesic dome) and carbon nanotubes
have only carbon-to-carbon bonds. These nanostruc-
tures are commonly named according to the number of
carbon atoms that form the structure (e.g., a C60
fullerene has 60 carbons).
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current concepts
n engl j med 363;25 nejm.org december 16, 2010
2437
Baseball
Hair
Red cells
Bacteria
Virus
DNA
Glucose molecule
Water molecule
10
8
10
7
10
6
10
5
10
4
10
3
10
2
10
1
nm
1
10
–1
Liposome
Dendrimer
Gold nanoparticle
Gold nanorod
Quantum dot
Fullerene
Carbon nanotube
Nanomaterials in clinical
trials or FDA-approved
Nanomaterials in proof-of-
concept research stages
1
Campion
11/12/10
AUTHOR PLEASE NOTE:
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Author
Fig #
Title
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Artist
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Knoper
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2438
sia, adenoma, and more specifically, primary lung
cancer, in which a decrease in the function of the
reticuloendothelial system affects the amount of
nonspecific phagocytic uptake.
Nanomaterials for in Vitro
Diagnosis
The second key application of nanomaterials is
as a label for measuring molecules of interest in
biologic samples. Nanomaterials are used to ei-
ther simplify the readout or amplify the detection
threshold of the diagnostic device. Nanoparticles
are used in lateral-flow in vitro diagnostic assays
(LFA) (as described below), such as the urine preg-
nancy test for detecting protein markers (e.g., hu-
man chorionic gonadotropin [hCG]).
20
The hCG
molecule is introduced into a membrane strip,
which moves through the membrane by capillary
force and initially interacts with anti-hCG anti-
body–coated gold nanoparticles. On successful
binding, this complex moves through the mem-
brane until it recognizes a region that is also
coated with anti-hCG antibody. The complex be-
comes tethered to the membrane surface as a
result of the antigen–antibody interaction. The
Table 1. Examples of Nanomaterials in Clinical Use.*
Nanomaterial Trade Name Application Target Adverse Effects Manufacturer Current Status
Metallic
Iron oxide Feridex MRI contrast Liver Back pain, vaso-
dilatation
Bayer Schering FDA approved
Resovist MRI contrast Liver None Bayer Schering FDA approved
Combidex MRI contrast Lymph nodes None Advanced Magnetics In phase 3 clin-
ical trials
NanoTherm Cancer therapy Various forms Acute urinary
retention
MagForce In phase 3 clin-
ical trials
Gold Verigene In vitro diag-
nostics
Genetic Not applicable Nanosphere FDA approved
Aurimmune Cancer therapy Various forms Fever CytImmune Sciences In phase 2 clin-
ical trials
Nanoshells Auroshell Cancer therapy Head and neck Under investigation Nanospectra
Biosciences
In phase 1 clin-
ical trials
Semiconductor
Quantum dot Qdots, EviTags,
semiconductor
nanocrystals
Fluorescent con-
trast, in vitro
diag nostics
Tumors, cells,
tissues, and
molecular
sensing
structures
Not applicable Life Technologies,
eBioscience,
Nanoco,
CrystalPlex,
Cytodiagnostics
Research
use only
Organic
Protein Abraxane Cancer therapy Breast Cytopenia Abraxis Bioscience FDA approved
Liposome Doxil/Caelyx Cancer therapy Various forms Hand–foot syndrome,
stomatitis
Ortho Biotech FDA approved
Polymer Oncaspar Cancer therapy Acute lymphoblas-
tic leukemia
Urticaria, rash Rhône-Poulenc Rorer FDA approved
CALAA-01 Cancer therapy Various forms Mild renal toxicity Calando In phase 2 clin-
ical trials
Dendrimer VivaGel Microbicide Cervicovaginal Abdominal pain,
dysuria
Starpharma In phase 2 clin-
ical trials
Micelle Genexol-PM Cancer therapy Various forms Peripheral sensory
neuropathy,
neutropenia
Samyang For phase 4
clinical
trials
* MRI denotes magnetic resonance imaging.
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