30 Current Radiopharmaceuticals, 2008, 1, 30-36

Nanoparticles in Cancer

Kalevi Kairemo1,2, Paola Erba3, Kim Bergström2,4 and Ernest K.J. Pauwels*3,5
1
Helsinki University Central Hospital, Department of Oncology, Helsinki, Finland; 2Imanext Ltd, Helsinki, Finland; 3University of
Pisa Medical School, Department of Nuclear Medicine, Pisa, Italy; 4University of Helsinki, Laboratory of Radiochemistry, Helsinki,
Finland; 5Leiden University Medical Center, Department of Radiology, Leiden, The Netherlands

Abstract: Nano-engineered particles have been developed to reach specific molecular targets on diseased cells and have been used in
various experimental and clinical conditions. The medical application involves diagnostic and therapeutic applications and a large deal of
this research concerns malignant disease. Various approaches have been tried to effectively reach the cancer cell and PEGylated
liposomes have demonstrated targeting and controlled release of antineoplastic drugs. For cancer diagnostics nanoparticles have been
engineered to optimize magnetic resonance imaging, ultrasound imaging and nuclear medicine imaging. Radiolabeled nanoparticles can
also be used for therapeutic purposes when tagged with appropriate radionuclides. This article aims to provide an overview how
nanomedicine is presently influencing drug design and, more specifically, the development of radiopharmaceuticals for cancer
management.
Keywords: Nanoparticles, nanocarriers, oncology, therapy, imaging.

INTRODUCTION invasive) imaging has been effected already and the proof of the
principle has been delivered.
Cancer is on the increase in the developing world as well as in the
industrial world. The latest world cancer statistics report that the Summarizing, the following characteristics offer advantages over
number of new cancer cases will increase to more than 15 million in conventional pharmaceutical agents:
2020 [1]. It is evident that enormous challenges lie ahead for all those
Nanotechnology produces the smallest functional units by
that are involved in cancer research and patient management. It building groups of atoms.
should be mentioned that medical research has achieved ground-
breaking progress in the field of tumor biology and molecular
Nanoparticles are smaller than 100nm and are in the similar
genetics. This will undoubtedly lead to the development of new and size-range as biologicals like viruses, DNA and proteins.
more effective drug therapies in the foreseeable future. In parallel Nanoparticles developed on a platform of biotechnology,
with this progress, on the molecular scale, remarcable developments nanotechnology and information technology can be used to take part
in medical imaging have kept pace with the other advances. Cancer in molecular, biochemical and biological processes, e.g. genetics and
imaging (ultrasound, magnetic resonance, nuclear medicine and pharmacogenomics:
computer tomography) is now recognized as a major modality to
measure the effect of treatment. Both the field of drug design and
The surface of nanoparticles can be decorated with various
cancer imaging are going to gain from a development that is molecules in order to avoid being recognized by the immune
system, enabling them to reach their target more efficiently.
generally regarded as a fundamental breakthrough in medicine,
namely the introduction in nanotechnology.
Nanoparticles may be designed to overcome physiological
The integration of nanotechnology with biotechnology and barriers like the blood brain barrier and dermal tight junctions.
medicine means the ability to uncover the structure and function of
Due to the leaky constitution of neovasculature in malignant
biosystems, which intrinsically have an organizational level at the tumors, nanoparticles may penetrate the lesion.
nano-scale. In other words: nanotechnology provides the tools to
measure and understand biosystems [2]. More specifically,
Nanoparticles may carry drugs and be designed to release their
nanotechnology maybe translated into nanomedicine thereby contents at a site of disease.
referring to treatment and curing of diseases at a molecular scale.
Indeed, the use of nanoparticles (100 nm or smaller) for delivery and
Nanoparticles may consist of an inorganic core of
targeting of therapeutic and diagnostic agents is at the forefront of superparamagnetic materials coated with polymer such as
dextran. These particles are used as contrast agents in magnetic
projects in cancer medicine. The targeting and accumulation of drugs
to specific sights where the agent is released provides a means to resonance imaging for diagnostic applications and therapy
reach high drug concentration at a designated area with far less monitoring.
systemic side effects. Likewise, medical imaging may make a
More specific tissue targeting (“functionalizing”) can be
gigantic step forward with the use of nanoparticles with achieved by the conjugation of the nanoparticle with a ligand
superparamagnetic properties for magnetic resonance imaging (MRI). e.g. monoclonal antibodies.
These developments harbor favorable prospects for diagnostic and
therapeutic applications in oncology. This article presents an
overview of the possible applications of nanoparticles in medicine, DRUG DELIVERY WITH NANOPARTICLES
highlighting its utilization in oncology as far as therapeutics and Various drug delivery and drug targeting systems are currently
imaging is concerned. applied or under development. Drug carriers include synthetic
polymers, microcapsules, liposomes, dendrimers and many others
and have one thing in common, namely the increased drug
GENERAL FEATURES OF NANOPARTICLES
bio-availability and increased accumulation at the pathological site.
The pharmaceutical perspectives of nanotechnology are This is especially important for anticancer drugs, which should
tremendous. Its medical use as drug delivery system and for (non preferably be delivered locally with minimal or no effect onto normal
tissue. Drug containing nanoparticles can be made slowly
*Address correspondence to this author at the 3University of Pisa Medical School, biodegradable, thus delivering their pay-load at a controlled rate.
Department of Nuclear Medicine, Pisa, Italy; 5Leiden University Medical Center,
Department of Radiology, Leiden, P.O. Box 9600, The Netherlands; Tel: +31715269111; Furthermore, nanocarriers are ideal entities to deliver poorly
E-mail: [email protected] water-soluble agents at the desired site [3]. These factors may

1874-4710/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

Nanoparticles in Cancer Current Radiopharmaceuticals, 2008, Vol. 1, No. 1 31

contribute considerably to the drug performance and clinical [11, 12]. Nanocrystals are advantageous as an oral delivery system
acceptance. for various drugs as problems as poorly drug solubility are solved in
this way with no or virtually no potential toxicity. Effective treatment
with these type of carriers of gastrointestinal tract disorders has been
PASSIVE TARGETING BY NANOPARTICLES reported [13].
In order to acquire an efficacious therapeutic level of Carbon nanotubes are sheets of atoms in the form of tubes of
pharmaceuticals at a pathological site, nanoparticles should move which the size mimics the physical dimensions of nucleic acids [14].
from the circulation to the lesion. A prerequisite for this process is They are considered optimal vehicles for the delivery of genes,
that the blood carrier stays in the blood long enough to slowly peptides and proteins, but at this time only used under experimental
accumulate in the tissue of interest with affected and leaky conditions [15].
vasculature. In cancer, this process of passive targeting takes place in
a non-specific way through gaps into the tumor interstitial space. Liposomes are closed vehicles in which drug molecules are
These gaps between adjacent endothelial cells with a diameter up till entrapped in a central aqueous space surrounded by a membranous
800nm exist in neoangiogenic blood vessels which serve to supply lipid bilayer of phospholipids. The drug may also be intercalated into
the tumor with nutrients. Tumor tissues use permeability factors as the lipid bilayers, depending on the way of production. For already
vascular endothelial growth factor (VEGF) to increase the two decades these particles have proven their value in basic research
permeability of tumor blood vessels [4]. Nanoparticles, carrying and human application for drug delivery. A special modification is
encapsulated drugs, extravasate into the tumor interstitial space and the surface attachment of polyethylene glycol (PEG) to the bilayer,
passively target the tumor tissue. Once the drug is locally released the producing the so-called stealth liposomes, in order to alter the
local concentration becomes many times larger than after pharmacodynamic profile and improve the immunologic
conventional systemic intravenous administration. The altered biocompatibility [16]. These “Trojan Horses” have been shown of
lymphatic drainage of the tumor contributes to this effect [5]. This minimal systemic toxicity and specific designs prevent early
type of passive targeting is known as “enhanced permeation and degradation [17]. Liposomes are, up till now, the most used
retention” (EPR) [6]. nanocarriers for targeted drug delivery in the clinical setting [18].
Solid lipid nanoparticles are colloidal carriers consisting of a
monolayer of phospholipid coating around a solid hydrophobic core
ACTIVE TARGETING OF NANOPARTICLES containing the drug in a high melting fat matrix. The drug, being in a
Larger tumors show poor vascularization, especially inside the solid state, is released slowly from the particle and this delivery
necrotic areas, which prevents the localization of the nanoparticles system may offer advantageous in terms of biodegradation and
and makes local drug deposition impossible. tolerance [19].
Because of these inherent limitations the next generation of Polymeric nanoparticles typically consist of polylactic acid,
nanoparticle delivery systems, smart nanocarriers, is being developed. polyglycolic acid or acrylates. These colloidal carriers, prepared as
The ultimate goal is to deliver therapeutic agents and contrast agents nanospheres or nanocapsules, contain the drug in an entrapped or
to the single cancer cell. This can be achieved by conjugating the encapsulated form. Their design allows for the highly concentrated
nanocarrier with biological recognition moieties which recognize cell drug delivery at a desired location, but the main obstacle for human
surface antigens or receptors. Experimental evidence suggests that use is their cytotoxicity for macrophages [20].
such a route may be successful. An example is the nanoparticle that Dendrimers are highly branched macromolecules with a
targets the folic acid receptor which is overexpressed in various controlled three-dimensional architecture [21]. The branches are
human carcinomas [7]. The nanoparticle conjugated with folic acid as structured around a designed central core and, like a tree, expand
a receptor seeker and containing methotrexate as a chemotherapeutic outward via polymerization reactions, which allow for exact shaping
agent has been demonstrated to enter the cancer cell and inhibit its of the nanoparticle. The branched structure makes it possible to attach
growth [8]. A widely investigated modality for the recognition of other molecules like drugs and contrast agents to the surface. Toxicity
cancer cells is the use of monoclonal antibodies. The recognition of is minimized by “hiding” the drug molecules in the interior of the
cell surface antigens has been successful in various instances, dendrimer. These carriers may be made as an uniform population of
especially in non-solid tumors as Non-Hodgkin’s Lymphoma [9]. molecules with a size ranging from 1 to 10 nm in diameter,
However, therapeutic antibodies target their intended cancer cells resembling that of biomolecules like proteins. Their low
only in the 0.01-0.001% range [10] and heterogeneity of antigenic immungenicity make in vivo applications within reach, especially for
expression, antigenic modulation and cross-reactivity with other targeting of tumors by transversion through vascular pores. The
tissues than the tumor present limitations which are difficult to abundant reactive sites provide numerous possibilities for surface
overcome. modification to improve targeting [22].
Viruses have the capacity to target cancer cells and deliver drugs
NANOPARTICLE ARCHITECTURE in both the cytosol and the cell nucleus. The functionality of several
Nanoparticles are designed as multifunctional diagnostic and nanocarriers can, at least theoretically, be improved by constructing
therapeutic devices. For pharmaceutical purposes and more hybrid virus nanoparticles which could use the targeting virus
specifically for cancer drug delivery and cancer imaging various characteristics to selectively invade cancer cells, using a similar
carrier types have been developed. Most of these nanoparticles are mechanism as proposed for gene therapy [23].
created in such a way that a variety of molecules (drug pay-loads) can
be attached to the surface or encapsuled in the interior of the particle.
For a better understanding of this exciting field, we provide a short CANCER IMAGING WITH NANOPARTICLES
overview of nanoparticles which appear to be important for cancer Optical Imaging with Quantum Dots
medicine (casu quo: drug treatment and imaging both in pre-clinical Nanocrystals possess unique properties which make them suitable
research and clinical practice). for optical imaging. Optical fluorescent imaging is achieved using
Nanocrystals consist of aggregates of around hundreds of drug these nanocrystals made of cadmium selenide, cadmium sulfide or
molecules combined in a single crystal with a thin coating as a cadmium telluride, surrounded by an inert polymer coating. These
surfactant. Nanocrystals are produced according to a technique called semiconductor crystals or quantum dots (“qdots”) are used as
nanonization using dispersion in an aqueous surfactant solution fluorescent labels of live cells, receptors and oncologic markers [24].
32 Current Radiopharmaceuticals, 2008, Vol. 1, No. 1 Kairemo et al.

Qdots absorb white light and re-emit the light a few nanoseconds disturb the magnetic field generated by the imaging device and
later. This light has a tunable wavelength, depending on the size and demonstrate signal drop-out on the MRI scan. The affected
nature of the nanocrystal, ranging from ultraviolet till far-infrared, lymphnodes, not accumulating the USPIOs, appear as bright areas as
including the visible spectrum. The particle can be functionalized they do not change the magnetic field homogeneity.
(“active targeting”) by way of molecular recognition systems like
monoclonal antibodies attached to the outer coating against a specific Commercial contrast agents do not have active targeting
target or via receptor interactions with specialized ligands. The characteristics and during recent years there has been an increasing
intrinsic limitation of qdots, however, is the low penetration depth of interest to functionalize the particles in order to enhance and widen its
light through tissues, which hampers external in vivo imaging. In an diagnostic utility. For active targeting a second generation of
attempt to overcome this disadvantage near-infrared fluorescent qdots superparamagnetic nanoparticles (also known as cross-linked iron
have recently been developed which enabled the visualization of e.g. oxides, CLIOs) have been generated. They can be conjugated to
lymph nodes in mice and xenografted tumors [25, 26]. Although these monoclonal antibodies or receptor-seeking agents. This principle of
refinements offer interesting possibilities for biological investiga- active targeting is well known in diagnostic and therapeutic nuclear
tions, including oncological research, human applications are not medicine [33] in which field radiolabeled biomolecules with unique
foreseeable because the visualization of deeper situated organs is not biological properties have found widespread applications. An
possible. example is the experimental study on the targeting ability of G-250
antibody conjugated to MRI contrast agents wrapped in an neutral
liposome against renal cell carcinoma [34]. Also, Herceptin®
Magnetic Resonance Imaging (MRI) conjugated MRI probes have been shown to allow the successful
monitoring of the in vivo behaviour of human cancer cells in a mouse
Whereas X-ray based modalities offer information on attenuation model [35]. Of particular interest would be active targeting with MRI
and blood flow, MRI offers a wealth of information on local biology contrast agents covalently linked to monoclonal antibodies
and pathology based on nuclear magnetic resonance signals, received recognizing epitopes with internalizing properties, thus allowing the
from hydrogen nuclei present in the organism under different (patho) magnetic labeling of specific cancer cells [36].
physiological conditions. MRI lends itself exquisitely to creating
three dimensional images of the body and can be used to characterize With an eye on the future, folate targeting is an interesting
many types of tissues. Tumors can be highlighted with contrast concept as it offers advantages over the use of monoclonal antibodies.
agents (e.g. gadolinium chelates) which help to enhance the image Various tumors, including ovarian, colorectal, and lung malignancies,
contrast for diagnosis and the assessment of treatment response. possess folate receptors since DNA methylation is dependent on
folate. In contrast to the large majority of antibodies, folate is not
For MRI much attention has been devoted to the development of immunogenic. Moreover the folate receptor is absent in most human
superparamagnetic nanoparticles for contrast enhancement. These normal tissues. Last but not least, nanoparticles decorated with folic
particles consist of an inorganic core of iron oxide (Fe2+ or Fe3+ salts), acid are internalized through receptor mediation [37-39].
often coated with polyethylene glycol or dextran. These nanoparticles
possess large magnetic moments and disturb a homogeneous
magnetic field. The contrast enhancement is due to this effect which Nuclear Medicine Imaging and Therapy
results in signal reduction on T2-weighted images, also known as
“negative contrast”. Their size affects their plasma half life and To our knowledge the making of nanoparticles did not have a
biodistribution properties and on that basis they are usually large impact on the development of radiopharmaceuticals in the field
categorized in two groups: of diagnostic and therapeutic nuclear medicine. In a short review
Lucignani has summarized a number of relatively new technological
SPIOs (superparamagnetic iron oxides) with an average size approaches for the synthesis of radiotracers [40]. He points out that
greater than 50 nm and usually subjected to uptake by Kupffer cells micro-reactor technology in the use of radioactive tracer synthesis
(reticuloendothelial system). might lead to the use of smaller quantities of expensive chemical
precursors. This is of value for the production and quality control of
USPIOs (ultra small paramagnetic iron oxides) with an average the tumor-agent 18F-fluorodeoxyglucose and other agents like
size lower than 50 nm allowing longer circulation and final removal iodinated Annexin V as an apoptosis marker and iodinated
by the lymphatic system. doxorubicine for the study of the biodistribution of this anticancer
Commercially available SPIOs as MRI contrast enhancers drug. In the field of therapeutic nuclear medicine an interesting
include Lumirem® and Endorem®, respectively in clinical use for development comes from the synthesis of lanthanide nanoparticles in
imaging of the gastro intestinal tract and for liver and spleen tissue. In the form of clusters of 153Sm-atoms, meant for peptide mediated
the latter application the increased contrast between healthy and tumor treatment [41].
diseased tissue facilitates the detection of space occupying lesions Liposomes can be used to carry radioactive compounds as
like primary or secondary liver tumors [27]. radiotracers can be linked to multiple locations in liposomes. One
A commercially available USPIO is Sinerem® which can be used option is the hydrated compartment inside the liposome, another the
for bloodpool visualization with MRI. Experimental and clinical lipid core into which especially hydrophobic conjugates can be
tumor imaging may occur on the basis of neovascularization and attached, and the third option is the outer lipid leaflet where
discriminates tumor tissue from the surrounding normal tissue molecules can be bound by covalent linkage. Delivery of agents to
[28,29]. The selective extravasation at pathological sites requires the the reticuloendothelial system (RES) is easily achieved, since most
engineering of the surface characteristics of these particles to prolong conventional liposomes are trapped by the RES. For the purpose of
their circulation time also MRI contrast agents have been made delivery of agents to target organs other than RES, long-circulating
“invisible” to macrophages by surface coating with PEG [30,31]. liposomes have been developed by modifying the liposomal surface.
After intravenous interstitial administration USPIOs can be used for Understanding of the in vivo dynamics of liposome-carried agents is
the detection of lymph node diseases [32]. In this important required for the evaluation of the bioavailability of drugs
application the contrast agent is slowly transported to lymph nodes by encapsulated in liposomes [42].
way of the lymphatic vessels. Subsequently the contrast agent is Non-labeled peptide-targeted liposomes have been used in
internalized by macrophages. In this way the normal lymph nodes experimental cancer therapy, and augmented killing (approximately
accumulate the USPIOs, whereas areas invaded by tumor tissue do 4-fold) of U937 leukemia and HT1080 sarcoma cells was obtained by
not accumulate this contrast agent. The iron-containing nanoparticles the peptide-targeted delivery of doxorubicin-containing liposomes,
Nanoparticles in Cancer Current Radiopharmaceuticals, 2008, Vol. 1, No. 1 33

compared with control liposomes administered without the peptide For tumor imaging, attention has focused recently for design of
(43). Gamma camera imaging of an experimental tumor has been polymer nanostructures such as shell cross-linked nanoparticles
applied to double-labelled liposomes, which were coated with (SCKs) [48]. In a recent study were 64Cu-radiolabeled folate-conju-
99m
Tc-peptide and encapsulated with 125I-albumin. Targeting of gated SCKs evaluated as candidate agents to shuttle radionuclides
liposomes to the lungs of tumor-bearing mice indicated the existence and drugs into tumors, which are over expressing the folate receptor.
of non-visible lung micrometastases [44]. According to this study 64Cu labeled SCKs showed in mice that
functionalized SCKs are promising drug-delivery agents for imaging
In the drug development, the biodistribution and and therapy of early-stage solid tumors [49].
pharmacokinetics of 111In-DTPA-labeled PEGylated liposomes has
been studied in 17 patients with locally advanced cancers [45]. Applications using no-carrier added 64Cu (half-life = 12.7h) for
Positive tumor images were obtained in 15 of 17 studies (4 of 5 PET imaging and radiotherapy may have potential to deliver
breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of radionuclide to solid tumors together with cytotoxic drugs improving
1 cervix cancer). The levels of tumor liposome uptake estimated from the therapeutic efficacy and imaging at the same time [49].
regions of interest on gamma camera images were approximately For thermoablative cancer therapy monoclonal antibody (Mab)
0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake –linked iron oxide nanoparticles escaping into the extravascular space
were seen in the patients with head and neck cancers, 33.0 ± 15.8% binding to cancer cell membrane antigen were followed by In-111
ID/kg. A significant localization of the liposomes was seen in the labelling [50].
tissues of the reticuloendothelial system (liver, spleen, and bone
marrow). Samples of the tumor, adjacent normal mucosa, muscle, fat,
skin, and salivary tissue were obtained at operation. The levels of Penetration Through Blood-Brain-Barrier
tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor Penetration through blood-brain-barrier is a prerequisite in some
uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in malignant conditions, such as in treatment of gliomas and brain
skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat metastases. There is some experimental evidence, that convention
by 10.8:1. enhanced delivery method can be used in administration of
PEGylated liposomal doxorubicin in experimental brain tumor
Molecular imaging with radionuclides gives broad possibilities
model. The intrathecally administrated drug increased the survival
for drug development [46]. Radionuclides have been used in
time from 30 days up to 90 days [51]. Coated nanoparticles can be
nanoparticle related drug delivery research in a limited extent.
designed for penetrating through blood-brain-barrier (BBB),
Among nanocarriers for contrast agents, liposomes and micelles draw
apolipoprotein A-I on nanoparticle surface acts on scavenger receptor
a special attention because of their easily controlled properties and
B1 in the BBB [52].
good pharmacological characteristics. General approaches have been
used to prepare liposomes for gamma imaging where the signaling PEG-coated liposomal doxorubicin is known to penetrate the
metal atom is chelated into a soluble chelate and then included into BBB and have additive effects with vincristin and trastuzumab [53].
the interior of a liposome. Alternatively, DTPA or a similar chelating Radiolabelled PEG-coated liposomal doxorubicin was investi-
compound may be chemically derivatized by the incorporation of a gated in 15 patients who had glioblastoma multiforme (5 pts) or brain
hydrophobic group anchoring the chelating moiety onto the liposome metastases (10 pts). The drug concentration was 13-19-fold higher in
surface. 111In and 99mTc-liposomes have been prepared to try different brain tumor than in normal brain tissue and 7-13-fold higher in
chelates and hydrophobic groups [47]. metastases as compared to normal brain tissue [54].

Fig. (1). Mice injected with 123I-labelled peptide targeted PEGylated liposomes.
On the left the mouse was preinjected with large amount cold control peptide (displacement study), the tumor uptake is weak, whereas sufficient tumor uptakes are
seen in mice with no peptide blockade (in the middle, on the right).
34 Current Radiopharmaceuticals, 2008, Vol. 1, No. 1 Kairemo et al.

Ultrasonography nanocarriers as an idiosyncratic reaction is also mentioned as a

The growth of nanotechnology has opened the way to improve potential pitfall associated with the use of engineered particles in
the quality of ultrasound methods for medical diagnosis. Microbubble nanomedicine, presumably secondary to complement activation [67].
contrast agents are miniature gas bubbles, which can remain In summary, the toxicity-profile of nanoparticles needs special
suspended in the circulation for an extended period. During scanning attention and for each type and each application safety tests are
the energy produced by the ultrasound beam causes rapid contraction required [68]. At the same time it should be realized that
and expansion of the bubble leading to contrast enhancement. The nanoparticles open unexpected ways on research on microbiological
utilization of these microbubbles includes plaque detection [55, 56], level as well as for diagnosis and treatment for malignant disease.
the assessment of hepatic artery patency following liver Nanotechnology is presently neither a plague nor a panacea. The
transplantation [57] and the study of tumor angiogenesis [58]. challenge is to uncover the possibilities with an eye on the potential
However, ultrasound examinations suffer from operator dependency, risks.
which could influence the results, especially in longitudinal studies. Another way to go is the use of nanoparticles with hyperthermia.
Apart from gas-filled bubbles, also solid nanoparticles have been Already in the 1960’s hyperthermia was recognized as a means for
used to enhance the ultrasonic images. In an experimental setting Liu cancer therapy. These investigations have come so far as realizing the
et al [59] have shown that these particles allow the visualization of concept of intracellular hyperthermia inducing heat-controlled
mouse livers. Whether these solid particles dispersed in agarose have cellular necroses based on heat production by magnetic nanoparticles
a future for clinical ultrasound diagnosis is not certain. under an alternating magnetic field [69]. To achieve complete tumor
regression intracellular temperatures have to be higher than 44
TOXICITY OF NANOCARRIERS centigrades and Japanese researchers have achieved promising results
in this field [70-72].
A common concern with regard to the clinical use of these
elegant nanocarriers of all types is the biocompatibility of these
agents, which translates into short- and long- term toxicity. It is CONCLUSIONS
obvious that cytotoxicity depends for a great deal on the local Summarizing, biotechnical developmets have provided us with
concentration of the nanocarrier used as well as the degree of nanoparticles of different composition enabling the solubilization of
exposure of the agent during the cellular contact. Therefore, in vitro poorly soluble antocancer drugs and, at the same time, increasing
imitation of the physiological conditions is not sufficient and their bio-availability. Nanomedicine may help to increase drug
scientifically unsatifying. This is especially true for nanocarriers resistance to stomach acid and enzymes, allowing better uptake from
designed to overcome drug solubility, stability and drug-induced the small intestine. Specially designed carriers allow controlled
side-effects. These nanoparticles may cross the cellular membrane biodegradability facilitating drug release at pathological areas, which
and penetrate the nuclear envelope of the normal cell. Particle uptake can be reached via the so called enhanced permeability and retention
by normal endothelial cells [60], pulmonary epithelium [61] and effect due to leaky vasculature. More specific targeting to required
intestinal epithelium [62], as well as the uptake of nanoparticles by areas can be achieved by the attachment of ligand molecules to the
macrophages has been described, but a definite answer to the ultimate carrier surface. The folate receptor seeking ligand is a good example
fate of the nanocarriers themselves has not yet been given [63]. For and is applicable in cancer eventually better than large proteins as
non-biodegradable particles and their coating agents this question is monoclonal antibodies, which may limit access to tumors. In which
even more important: inherent to the cellular penetration and possible way this new technology will transform medicine is , however,
entrance into the cellular nucleus is the interference with the cellular difficult to predict as a number of obstacles still need to be taken. One
biochemistry and the possibility of altered gene expression. such an obstacle is the present limitation of nanovectors to be specific
Therefore, engineered polymeric compounds may have a number of enough to deliver their payload to the cancer lesions without
unexpected effects and severe consequences for normal molecular collateral effects on healthy tissue. As mentioned before, the
biology [64]. Toxicity issues are of even greater importance in the conjugation with monoclonal antibodies does not provide an optimal
search for non-viral gene-delivery vehicles which should overcome way of targeting and the efficacious aiming of nanoparticles needs
the severe immunogenic and genetic consequences of the random another approach. Another obstacle belongs to the class of
integration of nucleic acids in the host genome by viral vectors [65]. biophysical barriers: once a cancer lesion becomes larger the
Moghimi et al [66] have reviewed the health risks of the use of increased osmotic pressure results in the ejection of the drug.
nanoparticles in medicine. In their paper hypersensitivity to Therefore, not only the specific delivery but also the penetration,

Table 1. Summary of the Differences Between Imaging Modalities and their Possibilities for Nanoparticle Applications. The Method
Characteristics (Spatial Resolution, Depth Resolution, Temporal Resolution, Sensitivity, the Amount of Needed Molecular Probe are
Modified from the Data in the Literature [77]

Temporal Sensitivity Molecular Nanoparticle

Modality Spatial resolution Depth
resolution (mol/L) probe design

PET 1-2 mm No limit 10 s-min 10-11 - 10-12 ng Label outside, in the membrane, or inside (radionuclide)
SPECT 0.5-1 mm No limit min 10-10 - 10-11 ng Label outside, in the membrane, or inside(radionuclide)
Bio- Label inside (or outside),
3-5 mm 1-2 mm sec-min 10-15 - 10-17 g-mg
luminescence luminescent compound

Label outside or inside,

Fluorescence 2-3 mm <1 mm sec-min 10-9-10-12 g-mg
fluorescent compound
Label outside, in the membrane, or inside, paramagnetic
MRI 25-100
m No limit min-hrs 10-3-10-5 g-mg
atom, particles
Label inside (or outside),
CT 50-200
m No limit min 10-1-10-4 N/A
contrast media
Ultrasound 50-500
m mm-cm sec-min 10-1-10-4 g-mg Label inside, gas filled particles
Nanoparticles in Cancer Current Radiopharmaceuticals, 2008, Vol. 1, No. 1 35

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Received: September 15, 2007 Revised: October 04, 2007 Accepted: October 08, 2007