Barreto 2011

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REVIEW
Nanomaterials: Applications in Cancer Imaging

and Therapy
José A. Barreto, William O’Malley, Manja Kubeil, Bim Graham,* Holger Stephan,*
and Leone Spiccia*
the capacity to combine multiple modalities
The application of nanomaterials (NMs) in biomedicine is increasing rapidly on one probe, enabling higher sensitivity
and offers excellent prospects for the development of new non-invasive strat- to be achieved and deeper insight gained
into in vivo processes. NMs are also ide-
egies for the diagnosis and treatment of cancer. In this review, we provide a
ally suited to be applied as drug-delivery
brief description of cancer pathology and the characteristics that are impor- systems, making the development of a
tant for tumor-targeted NM design, followed by an overview of the different new generation of theranostics possible.
types of NMs explored to date, covering synthetic aspects and approaches The combination of molecular imaging
explored for their application in unimodal and multimodal imaging, diagnosis and local treatment of lesions is unique
and therapy. Significant synthetic advances now allow for the preparation of for nano-objects and has the potential to
change the current medical paradigm of
NMs with highly controlled geometry, surface charge, physicochemical prop-
“see and treat” to “detect and prevent”.[1]
erties, and the decoration of their surfaces with polymers and bioactive mol- NMs used as diagnostic/therapeutic tools
ecules in order to improve biocompatibility and to achieve active targeting. encompass a wide range of substances, both
This is stimulating the development of a diverse range of nanometer-sized organic (e.g., liposomes, natural and syn-
objects that can recognize cancer tissue, enabling visualization of tumors, thetic polymers including dendrimers, and
carbon nanotubes) and inorganic materials
delivery of anti-cancer drugs and/or the destruction of tumors by different
(e.g., quantum dots (QDs), metallic nanos-
therapeutic techniques. tructures, and metal oxides (particularly
magnetic iron oxides, up-converting nano-
phosphors, and zeolites)). Decorated with
1. Introduction special functionalities, NMs allow the application of different
molecular imaging techniques, such as computed tomography
The development of new nanomaterials (NMs) for the diagnosis (CT), magnetic resonance imaging (MRI), single-photon emis-
and/or treatment of different diseases has been receiving greater sion tomography (SPECT), positron emission tomography (PET),
attention in recent years and has now become an important field ultrasound imaging, and optical imaging methods.[7] Their fasci-
in medical research. Dedicated NMs can be used to monitor the nating and unique properties are also exploitable across a range
progress of a therapy or disease, to determine the blood type of therapies, including chemotherapy, photodynamic therapy,
of patients requiring transfusion, or for tissue typing when a neutron capture therapy, thermal therapy, and magneto-therapy.
transplant is required.[1–6] One major advantage of NMs is their NMs may be engineered that permit a combination of these
potential to be used as non-invasive diagnostic tools. Another is therapies to be used, leading to synergetic medical effectiveness.
This review focuses on recent developments of NMs for
application in cancer diagnosis and treatment. A short descrip-
tion of tumor angiogenesis is given, and its importance for the
J. A. Barreto, Prof. L. Spiccia design of new NMs is discussed. A major goal of this review
School of Chemistry
Monash University Clayton is to unveil the emerging possibilities of nanovectors for thera-
VIC 3800, Australia peutic applications.
E-mail: leone.spiccia@monash.edu
W. O’Malley, Dr. B. Graham
Medicinal Chemistry and Drug Action 2. Cancer Pathology
Monash Institute of Pharmaceutical Sciences
Monash University Cancer is a generic group of diseases that can affect different
Parkville, VIC 3052, Australia parts of the body. According to the World Health Organiza-
E-mail: bim.graham@monash.edu tion, cancer accounted for 7.9 million deaths in 2007 (13% of
M. Kubeil, Dr. H. Stephan all deaths), and this number is expected to rise to 12 million by
Institute of Radiopharmacy
Helmholtz-Zentrum Dresden-Rossendorf
2030. Cancer occurs because of mutations in genes that control
PF 510119 Dresden, 01314, Germany cell cycles.[8] Four major characteristics of cancer cells are
E-mail: h.stephan@hzdr.de uncontrolled growth (uncontrolled division), invasion of adja-
cent tissue, metastasis (spreading to other locations in the body),
DOI: 10.1002/adma.201100140 and immortality (protection against programmed cell death).
H18 wileyonlinelibrary.com © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2011, 23, H18–H40
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Practically all cancer cells show irregular cell-cycle control.[8]
REVIEW
When the tumor has grown larger than ca. 1–2 mm, it develops José A. Barreto, born in Bogotá, Colombia,
new blood vessels (angiogenesis) by stimulation from sub- received a Bachelor of Chemistry (Honours)
stances released into the tumor microenvironment. Tumor ves- from the National University of Colombia
sels are abnormal, presenting spaces between endothelial cells, (Universidad Nacional de Colombia) in
interruption of the basement membrane, and no smooth muscle 2006. From 2006 to 2008, he worked as a
within the capillary walls.[8] They possess a chaotic architecture, researcher at the Colombian Immunology
are tortuous and dilated, exhibit uneven diameter and exces- Foundation Institute (FIDIC) in the field
sive branching, and have a disorganized vasculature.[9,10] With of peptide synthesis. He is currently
respect to the walls, the vessels have numerous openings, such undertaking PhD studies in the School of Chemistry at Monash
as endothelial fenestrae, vesicles and transcellular holes, inter- University within the group of Professor Leone Spiccia. His
endothelial junctions, and a discontinuous basement. These research focusses on the development of novel iron oxide nano-
factors make the capillaries more permeable than normal ves- particles as imaging agents for multimodal detection of cancer
sels, allowing substances to pass more easily to and from the tumors by MRI and PET.
surrounding environment.[7,8] Vascular permeability depends
on the type of tumor and the organs within which it is located. Leone Spiccia obtained his PhD degree
from the University of Western Australia
2.1. Tumor Angiogenesis in Perth, Australia in 1984. He took up an
academic appointment in the Department
Angiogenesis refers to the growth of new blood vessels of Chemistry at Monash University in
from existing ones; this process is necessary for the growth of Melbourne, Australia in 1987, where he
multicellular organisms to transport oxygen and nutrients to is currently Professor of Chemistry. His
the new cells.[9] Angiogenesis is regulated by a balance between research interests include bioinspired water
pro- and anti-angiogenic molecules, the angiogenic switch. This oxidation catalysis, nanomaterials for water splitting devices and
switch is considered to be “off” when the effect between pro- dye-sensitized solar cells, metal-ion speciation aqueous envi-
and anti-angiogenic molecules is balanced, and “on” when the ronments, biosensors based on metal-complex bioconjugates,
balance is favorable for angiogenesis.[9,11,12] artificial nucleases and ribonucleases, therapeutic and diag-
A tumor typically grows as a cluster of cells at a rate that nostic applications of magnetic nanoparticles, and radiolabelled
depends on oxygen and nutrient diffusion, and can be benign bioconjugates.
or malignant (Figure 1). When the tumor reach a maximum
size (1–2 mm),[9,11,13,14] the inner cells are unable to grow and
proliferate because of a lack of nutrients and become quiescent Holger Stephan received his PhD degree
or necrotic, leading to the formation of a three-layered struc- from the Technical University Bergakademie
ture: a core of dead cells surrounded first by a layer of quies- Freiberg in 1989. He is currently leading
cent cells and then by a thin rim of proliferating cells.[11] The the “Nanoscalic Systems” group at the
tumor can exist in a state of dormancy where cell proliferation Helmholtz-Zentrum Dresden–Rossendorf.
is balanced by cell death. Only through formation of new blood His research interests are the develop-
vessels (angiogenesis) can the tumor emerge from this state ment of radiometal complexes, including
of dormancy. Angiogenesis provides access to an increased functionalized nanoparticles for therapeutic
supply of oxygen and nutrients, thus allowing rapid growth of and diagnostic applications, dendrimer chemistry, coordination
the tumor. The more malignant tumors have the greatest ang- chemistry, and the themodynamics of liquid two-phase systems.
iogenic potential.[11] Different signals have been reported to
Bim Graham obtained his PhD degree
from Monash University in 1999. After
post-doctoral studies at the Max Planck
Institute for Chemistry, Mainz, Germany,
and the Commonwealth Scientific
and Industrial Research Organisation,
Molbourne, Australia he took up an aca-
demic post within the Monash Institute of
Pharmaceutical Sciences in 2006, where
he is now a senior lecturer in medicinal chemistry. His research
focusses on the development of luminescent metal complex- and
nanoparticle-based probes for imaging and assay applications, lan-
thanide tags for biomolecular NMR spectroscopy, metal complex
Figure 1. Types of tumors. In a benign tumor mutated cells remain con- bioconjugates for nucleic acid cleavage, and novel bioconjugation
tained within a single cluster, with a clear boundary separating them from reagents and strategies.
normal cells. In a malignant tumor, mutated cells are mixed with normal
cells, attempting to invade the surrounding tissue.
Adv. Mater. 2011, 23, H18–H40 © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com H19
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REVIEW
endothelial cells, and proteolysis of the base membrane stops

after the target tissue has been vascularized), in tumor angio-
genesis the angiogenic switch remains turned on due to the
continued production of angiogenic factors within the hypoxic
regions of the tumor. New capillaries continue to grow through
the tumor, leading to a non-mature, irregular, leaky and tor-
tuous vasculature that lacks a stable basement membrane.[11]
An important characteristic of tumors is their pH. Whereas
the intracellular pH of tumors and normal tissue is similar
(ca. 7.2),[21,22] the extracellular pH for tumors can be more
acidic (varying from 5.8 to 7.8, with an average of 7) compared
to that of extracellular fluid/blood in normal tissue (7.4). This
results from an accumulation of lactic acid and carbonic acid,
produced by aerobic/anaerobic glycolysis, glutaminolysis,
and ATP hydrolysis inside the cells. As the tumor has a high
metabolic rate and poor blood convective and/or diffusive
Figure 2. Key events during tumor angiogenesis: a) a tumor in a state drainage, H+ ions accumulate in the respective tissue.[23–25]
of dormancy near a blood vessel, b) the angiogenic switch is turned on,
causing dissolution of the basement membrane (black hole), followed
by migration and proliferation of endothelial cells in order to form new
blood vessels c) and d).
2.2. The Enhanced Permeability and Retention (EPR) Effect
The abnormalities present in the tumor tissue result in exten-

switch on the angiogenesis process, such as hypoxia,[9,11] low sive leakage of blood plasma components and other macro-
pH, hypoglycemia, mechanical stress, immune or inflamma- molecules.[26,27] The greater permeability of tumor vessels
tory responses, or genetic mutations.[11] to macromolecules compared with normal vessels, and the
The key events that result in the sprouting and growth of tumor impaired clearance of these macromolecules from the interstitial
vessels are similar to those involved in normal tissue angiogen- space of the tumor (contributing to longer retention of these mol-
esis (Figure 2). In quiescent endothelia, the rate of proliferation ecules), is called enhanced permeability and retention (EPR) effect
and migration is minimal (endothelial cells can, however, activate (Figure 3).[26–30] A consequence of the EPR effect is that macro-
these mechanisms very quickly if required),[11] while in tumors molecules can accumulate in the tumor at concentrations five to
endothelial cells are produced rapidly. The endothelial cells must ten times higher than in normal tissue within 1–2 days.[26,28]
be able to proliferate, degrade the extracellular matrix, change The EPR effect can be exploited to achieve passive targeting of
their adhesive properties, migrate to the new vascular vessels, tumors for imaging and/or drug release by using macromolecules
and finally differentiate and avoid apoptosis.[15] In tumor angio- and nanoparticles (NPs) instead of conventional small-molecule
genesis, three main events must occur for new vessel formation: drugs, which, unless they are bound to tumor specific molecules,
dissolution of the basement membrane, migration of endothelial can also interact with and affect normal tissue.[10,31] In order to
cells, and proliferation to provide new cells for vessel growth.[16] effectively exploit the EPR effect for both detection and treat-
Once the angiogenic switch has been turned on, induced by ment of cancer, a drug should have a molecular weight greater
the production of the vascular endothelial growth factor (VEGF) than 40 kDa.[31] Pore cut-off sizes for several tumor models range
and other angiogenic molecules,[11,17] the endothelial cells between 380 and 780 nm.[10,32] The ability of macromolecules
within the vessel start to lose contact with nearby cells due to and NPs to accumulate specifically in tumor tissue has been
the action of proteolytic enzymes produced by these cells. Two studied extensively since Maeda et al.[33] first described the EPR
main enzyme groups are responsible for proteolysis: the matrix effect twenty years ago. Nowadays, most drug delivery systems
metalloproteases (MMPs) and the plasminogen activator (PA)/ for cancer are being designed based on this principle.
plasmid system. The basement membrane is the first target of
these proteins.[11,18,19] After the endothelial basement membrane
has been disrupted, the endothelial cells are able to migrate,
while other endothelial cells fill the gap left in the membrane.[11]
Once the endothelial cells start moving away from the parent
vessel, they begin to form small sprouts, and more endothelial
cells are recruited, elongating the new vessels. These endothelial
cells also start creating a central lumen that will form the ini-
tial structure of the new vessels,[11,20] and rapid proliferation of
the endothelial cells begins to occur near to the sprout tips. The
sprouts initially grow and expand parallel to one another, until a Figure 3. The enhanced permeability and retention (EPR) effect. In
normal tissue, only small molecules can diffuse through blood vessel
certain point at which they turn towards other sprouts, leading to
walls (a), whilst in tumors, macromolecules and NPs can diffuse inside
the formation of closed loops necessary for blood circulation.[11] the tissue due to the leaky vasculature (b); NPs thus reside longer inside
In contrast to physiological angiogenesis (where the expres- the tumor blood vessels, allowing specific targeting of the tumors. This
sion of angiogenic factors, migration and proliferation of is the principle used in passive targeting of tumors.
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3. Important Characteristics of Nanomaterials ways: i) a change of the opsonins from an inactivated state to
Used for Cancer Imaging and Therapy an activated state (by conformational changes) that can be rec-
ognized by phagocytes using specific receptors on their surface;
Although the EPR effect is the major effect that is exploited ii) non-specific association of phagocytes with the opsonins on
for the diagnosis and treatment of cancer using NMs, other the particle surface; iii) activation of the complement system.[47,49]
properties apart from size also influence the biodistribution After recognition, the phagocytes ingest the particle by endocy-
and clearance of NMs from the body and are thus important tocis and degrade it by producing enzymes and other oxidative-
considerations in NM design. These include shape, composi- reactive chemical factors. If not biodegradable, depending on its
tion, hydrophilic-lipophilic balance, and surface charge of the size and molecular weight, the particle will be removed by the
NMs.[34–36] Most NPs are easily cleared by the reticuloendothe- renal system or stored in one of the RES organs.[47]
lial system (RES) or mononuclear phagocytic system (MPS).[37]
3.1. Nanomaterial Size 3.2. Hydrophobicity/Hydrophilicity and Surface Charge
The RES is part of the immune system and consists of phago- Opsonization is influenced by the hydrophilic–lipophilic bal-
cytic cells like monocytes and macrophages that are located in ance of nanomaterials. This process is faster when the particles
the spleen, lymph nodes, and Kupffer cells in the liver. The are more hydrophobic due to the enhanced “adsorbability” of
main functions of the RES are to remove senescent cells from blood serum proteins onto their surface.[34,47,50,51] The NP sur-
the bloodstream and to produce phagocytic cells for immune face charge can also influence its uptake by the RES, uptake
and inflammatory responses.[38] In particular, larger NMs are being favored for NPs bearing low or neutral charge.[37,40,41,47]
easily cleared by the RES (Figure 4);[39–41] the smaller the nano- Positively charged particles can cause nonspecific sticking to
objects, the longer their retention time in the bloodstream.[40] cells, while negatively charged particles can be taken up by
NPs smaller than 100 nm in diameter have been suggested to scavenger endothelial cells in the liver.[37,44] NPs with a zeta
be ideal for cancer therapy[42,43] because of their favorable bio- potential higher than (+/−) 30 mV have been shown to be stable
distribution and clearance/accumulation behavior.[44] Since the in suspension, as their surface charge prevents aggregation.[52]
kidney is the first site where NPs can be eliminated, a lower-
size threshold has been established based on the glomerular
filtration of particles; particles smaller than 6 nm will be filtered 3.3. PEGylation of Nanoparticles to Avoid Clearance by the RES
and cleared from the blood, while particles bigger than 8 nm
will not.[45] Also, as the normal endothelium has an average In order to reduce the electrostatic and hydrophobic interac-
effective pore size of ca. 5 nm, particles smaller than this will tions between NPs (agglomeration) and clearance by opsoniza-
rapidly extravasate across the endothelium.[45] The renal excretion, shielding groups have been introduced onto their surface.
tion cut-off size has been established to be around 5.5 nm.[41–46] PEGylation is one preferred method for avoiding premature clear-
The mechanism used by the body to recognize and clear ance of NPs by the RES.[37,47,53,54] PEGylation refers to the process
NPs involves three steps: opsonization, phagocytosis and clear- of covering the NPs with polyethylene glycol (PEG) or its deriva-
ance.[47] In opsonization, a foreign organism or particle is envel- tives by grafting, entrapping, adsorbing or covalently binding
oped by proteins called opsonins, which allows recognition of the these molecules to the NP surface.[47,55,56] For example, Thierry
particles by phagocytic cells and subsequent clearance from the et al.[57] were able to stabilize silica NPs (126 nm diameter) by
bloodstream.[47,48] Recognition and attachment of phagocytes to covering the surface with a polyethyleneimine-polyethyleneglycol
the surface-bound opsonins can occur in one of three different (PEI-PEG) copolymer (PEG Mw = 3400 or 5000) via electrostatic
interactions with the silica surface without significantly affecting
the particle size (PEI-PEG 3400, 134 nm; PEI-PEG 5000,
139 nm). The resulting NPs were resistant to nonspecific adsorp-
tion of proteins onto their surface. Prencipe et al.[58] prepared
different polymers based on poly(γ-glutamic acid) (PGA) and
poly(maleic anhydride-alt-1-octadecene) (PMHC18), with PEG
grafted for stabilization of gold NPs and gold nanorods. The
NP suspensions were stable over a wide pH range, at high tem-
peratures, and when mixed with serum. The most remarkable
result from this study was the long circulation times found for
the nanorods grafted with PEG polymers (t1/2 ≈ 22 h for PGA-
PEG-nanorods, and 19 h for PMHC18-PEG-nanorods).
Covalent linking of PEG to the NPs avoids desorption of
the PEG chains and biodegradation of the NPs.[10,47] Zhang
et al.[59–61] covalently attached PEG to iron oxide NPs by conju-
Figure 4. Clearance of NPs by the reticuloendothelial system (RES). When
larger NPs are injected into the blood stream, a group of proteins called
gating PEG-dicarboxylate (Mw ≈ 600) with triethoxypropylami-
opsonins cover their surface (opsonization), enabling phagocytic cells in the nosilane (APTES). Coating of the NPs was achieved by hydrol-
blood stream to recognize the NPs and remove them by degradation, renal ysis (ligand exchange) of the silane-modified PEG molecules
excretion or accumulation in one of the RES organs (liver, spleen, etc.). over their surface. In the initial study,[59] the NPs were coated
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with PEG, followed by conjugating folic acid to the ends of the to increase in all the cases. Rapid elimination of the smallest
PEG chains. In a subsequent study,[60] NPs were modified with dendrimers (PEG200) into the urine was found, but low uptake
PEG-APTES conjugated to chlorotoxin, a glioma tumor tar- by the RES was also found, whereas the biggest dendrimers
geting molecule, and the fluorescent molecule, Cy5.5. The pref- (Lys16(PEG2000)32) showed no uptake by the RES and very little
erential uptake of the modified NPs by glioma cells was probed renal clearance. The effect of PEG length on the biodistribu-
by confocal fluorescence microscopy, which showed a signifi- tion of coated QDs was also assessed by fluorescence spectros-
cantly higher degree of internalization of the NPs containing copy in a study by Daou et al.[64] Notably, the QDs coated with
both chlorotoxin and Cy5.5 compared to those with only Cy5.5. PEGs of lower molecular weight (2750 and 4000 Da) accumu-
Zhang et al.[61] also demonstrated that PEGylation increases the lated in the liver faster than those coated with higher MW PEGs
uptake of NPs by breast cancer cells, probably due to the per- (12000 to 22000 Da), which circulated for longer periods in the
meability of PEG in the cellular membrane. bloodstream.
Covering the surface of NPs with PEG prevents their clear-
ance from the body as opsonins are not able to efficiently cover
their surface, thereby hindering phagocytosis.[47] One explana- 3.4. Passive and Active Targeting of Tumors
tion for this observation is based on the conformation of the
PEG molecules on the NP surface. In solution, PEG chains NPs and other delivery systems can be classified as first, second
adopt extended conformations due to their flexibility and (passive) or third (active) generation, depending on their ability
hydrophilicity. They become compressed when an opsonin is to locate and deliver a drug to the site/target of interest in the
attracted to the surface by Van der Waals forces (or other forces). body.[39,65] First generation systems deliver substances when
This increases the energy state of PEG molecules, creating a applied near the site of action.[65] Second generation NPs can
force that repels the opsonin away from the surface.[47] PEGyla- locate the site of interest and/or deliver the drug by virtue of
tion may also reduce RES clearance by shielding the surface specific (intrinsic) properties of the carrier and/or those of
charge of NPs and increasing their hydrophilicity (Figure 5).[53] the associated drug.[40,49,65] As previously noted, passive tar-
The optimal chain length of surface-bound PEG molecules geting can be achieved by taking advantage of the EPR effect,
necessary to avoid RES clearance has been proposed to corre- which allows NPs to access tumors by way of their leaky vas-
spond to PEG with Mw ≥ 2000.[47] Recently, Choi et al.[62] studied culature.[43,66,67] Another passive targeting method exploits the
the biodistribution of near-infrared (NIR) fluorescent InAs (ZnS) tumor microenvironment (pH and redox potential);[66] here,
QDs (3.2 nm) as a function of the length of the PEG used for pH- or redox-responsive pro-drugs are converted into an active
coating. QDs were coated with dihydrolipoic acid (DHLA) con- drug when they reach the acidic, hypoxic microenvironment of
jugated to PEG chains of different lengths (n = 2, 3, 4, 8, 14, 22). the tumor target. Direct local application into the tumor can
The PEGylated QDs were stable in rat serum, while QDs avoid widespread circulation of the pro-drug in the body.[66]
coated only with DHLA were enveloped by serum proteins Third generation NPs used for active targeting are capable of
and increased in hydrodynamic diameter. For n = 2, the NPs specifically recognizing their target. The delivery system is
accumulated in the liver, whereas NPs with n = 3 accumu- equipped with a “homing device” capable of guiding the carrier
lated in the kidneys and bladder. The NPs with n = 8 (and to to the intended target. These NMs exploit specific properties
a lesser extent n = 14) tended to accumulate in the pancreas, of the tumor cells, such as the presence of unique or overex-
while those with n = 22 remained in the bloodstream for at pressed receptors on their surface. Small molecules, peptides,
least four hours post-injection. Kaminskas et al.[63] synthe- proteins, aptamers, and antibodies that interact with receptors
sized poly L-lysine dendrimers (generation 3 and 4) surrounded are commonly attached to NPs for active tumor targeting.[68]
by PEG molecules with different lengths (Mw = 200, 570 NP internalization can then occur by receptor-mediated endo-
and 2000, with n = 3, 10, or 42 ethylene glycol units, respec- cytosis, after which they may remain intact or be degraded
tively), and their biodistribution was studied after labeling with (Figure 6). In this way, anti-cancer drugs and other substances
tritium (3H). PEGylation significantly reduced plasma clear- can be delivered into cells via incorporation into NPs. The
ance of the dendrimers and the plasma half-life was found main targets for active tumor targeting with NPs are listed in
Table 1.[69–72]
4. Types of Nanomaterials Currently Applied in

Cancer Imaging and/or Drug Delivery
A wide range of NPs has been designed to reach tumors,
including liposomes, QDs, polymers/dendrimers, metals and
metal oxides (Figure 7).[42,67,73–76] (For a recent comprehensive
review on inorganic NPs as materials for cancer therapy, the
reader is referred to Minelli et al.)[77] Although all of these types
of NPs have been studied for cancer diagnosis and tumor drug
delivery and release, each type of NP can exhibit different and
Figure 5. Representation of how PEGylation avoids clearance of NPs by sometimes unique properties, which make them useful for dif-
the RES. ferent applications.
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REVIEW
Figure 7. Examples of NPs used for cancer treatment and diagnosis.
a) polymeric nanoparticles, b) liposomes, c) QDs, which usually posses
a CdSe core, d) gold NPs, e) zeolite L, f) magnetic NPs, traditionally iron
oxide, g) dendrimers, h) nanotubes, i) upconverting nanophosphors.
Based on their structural features, polymeric NPs can be fur-

ther classified into nanocapsules and nanospheres (Figure 8).[81]
In nanocapsules the shells are usually filled with an aqueous or
oil solution, which can contain a solubilized drug. Nanospheres
consist of a solid mass, which may be impregnated with an anti-
cancer agent.[78,80–83] Other classes of polymeric NPs include
polymeric micelles, which consist of amphiphilic block copoly-
mers that self-assemble into micelles in aqueous solutions,[67,80]
and dendrimers, which will be treated later in this review.
Polymeric NPs can be synthesized either by polymerization of
monomer units or from a preformed polymer.[84] Monomer poly-
merization may be achieved using emulsion (aqueous or organic)
Figure 6. Schematic sequence showing the receptor-mediated endocy- or interfacial methods.[84] In the former, an emulsion of the
tosis mechanism for uptake of targeted NPs by cancer cells. a) NPs flowing polymer is formed and the polymer then isolated by precipitation
around the cell interact with cell receptors; b), c), d) the particle is internal- or gelation.[81] Interfacial polymerization occurs at the interface of
ized by formation of an endosome; e) the drug is released, triggered by
two non-miscible phases, with different monomers dissolved in
enzymes or the lower pH inside the endosome; f) the NP is degraded while
the drug distributes in the cell; g) and h) the cell receptor is recycled. each phase.[81] One-step procedures, based on the spontaneous
formation of the polymer or self-assembly of the macromolecules,
are used to form nanogels or polyelectrolyte complexes.[81]
Table 1. Common targets in tumors for active targeting with NPs.[69–72]
Angiogenesis-associated targets Cell proliferation markers
4.1.2. Polymeric Nanoparticles for Drug Delivery
Vascular endothelial growth factor (VEGF) Human epidermal growth recep-
receptors[69,71] tors (HER):[69,72] TGF-α, EGF-R Drugs can be loaded into polymeric NPs by physical entrap-
αvβ3-Integrin cell adhesion Transferrin receptors[69,72] ment or chemical conjugation.[79] In nanocapsules, the drug
receptors[69–70,71] can be physically loaded in the interior if soluble in the liquid
Vascular cell adhesion molecule Folate receptors[69,72] phase contained in the nanocapsule, or via conjugation to the
1 (VCAM-1)[69,71] polymer chains. In nanospheres, the drug can also be dis-
Matrix metalloproteinases[69] Lectin receptors[72]
persed or covalently bound to the polymer matrix, while in
micelles, hydrophobic drugs are generally encapsulated in their
hydrophobic interior. Four types of covalent drug–polymer
4.1. Polymeric Nanoparticles conjugates have been described for potential combination
therapies (two or more drugs administered simultaneously or
use of a combination of two types of therapy): i) a polymer–
4.1.1. General Characteristics and Synthetic Aspects
drug conjugate plus non-conjugated free drug; ii) a polymer–
Natural polymers such as chitosan, albumin, heparin, dextran, drug conjugate plus a second polymer–drug conjugate; iii)
gelatin, alginate, and collagen as well as synthetic polymers, a single polymeric carrier of a combination of drugs; and
such as PEG, polyglutamic acid (PGA), polylactic acid (PLA),
polycarprolactone (PCL), poly-d,l-lactide-co-glycolide (PLGA)
and N-(2-hydroxypropyl)-methacrylamide copolymer (HPMA)
have been widely used to prepare NPs and encapsulate drugs
for cancer therapy.[67,78–80] In many cases the polymeric NPs
are comprised of a hydrophobic core containing the anticancer
agent and a hydrophilic surface layer for the stabilization of the
NPs in aqueous environment.[79] Figure 8. Main types of polymeric NPs.
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iv) polymer-directed enzyme prodrug therapy.[85–87] Listings of

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4.1.3. Polymeric Nanoparticles for Imaging

polymer–drug and polymer–protein conjugates and micelles
Polymeric NPs have been loaded with gadolinium complexes or
that are on the market or in clinical phases have been previ-
magnetic NPs in order to image cancer by MRI. Traditionally
ously published.[79,87–89]
magnetic NPs (magnetite) have been encapsulated in the core of
Recently, Grinstaff et al.[90,91] developed expansile polymeric
polymeric micelles. For example, Gao et al.[100,101] encapsulated
NPs, which release drugs by expanding in response to a change
magnetic NPs together with doxorubicin in micelles formed
in pH. The hydrophobic crosslinked NPs are based on a mono-
from amphiphilic block copolymers of maleimide-terminated
mer containing a 2,4,6-trimethoxybenzaldehyde protecting
poly(ethyleneglycol)-block-poly(D,L-lactide) and methoxy-
group, which is stable at neutral pH but can be hydrolyzed at
terminated poly-(ethylene glycol)-block-poly(D,L-lactide)
pH 5. The protecting groups are cleaved at low pH (5 in the
copolymer. These micelles were functionalized with agents such
endosome), causing the NP to change from hydrophobic to
as cRGD or a lung-cancer targeting peptide (LCP) for active tar-
hydrophilic in character and to expand from nanometer to
geting. Sohn et al.[102] recently designed magneto-fluorescent
micrometer size. The NPs were loaded with paclitaxel, a non-
polymeric NPs based on glycol chitosan conjugated to N-acetyl
water soluble anticancer drug. Testing against Lewis lung car-
histidine and bombesin, for targeting GRPRs overexpressed in
cinoma in vivo showed that only NPs loaded with paclitaxel
prostate cancer cells. Magnetic NPs coated with oleic acid were
reduced the incidence of tumor growth and tumor burden.[90]
incorporated into the polymeric matrix, and the NPs labeled
Zhang et al.[92,93] incorporated a lipidic component into poly-
with the near infrared fluorophore, Cy5.5.
meric NPs in order to increase drug retention in the NP. A
Gadolinium, a positive magnetic resonance imaging (MRI) agent,
lipid layer of lecithin was introduced at the interface between
was recently incorporated into polymeric NPs as Gd metal organic
the hydrophobic polymeric core (consisting of PLGA) and the
frameworks (MOFs), constructed from Gd3+ ions and organic
NP hydrophilic shell (consisting of PEG), through the use of a
bridging ligands, such as 1,4-benzenedicarboxylic acid. This mate-
lecithin–PEG conjugate. This was found to slow down diffusion
rial offers exceptional MRI capabilities over traditional methods for
of the encapsulated drugs and to reduce water penetration into
incorporating gadolinium into NPs using Gd2O3, GdPO4, GdF3,
the core, enhancing the drug-encapsulation yield and slowing
etc. The surface of MOFs is modified by covalent attachment of
down drug release from the NPs by avoiding hydrolysis of the
polymer chains to obtain the polymeric carriers.[103,104]
PLGA chains. Two anticancer drugs, paclitaxel and docetaxel,
were loaded into the NPs, using A10 RNA and anti-CEA mono-
clonal antibodies as targeting ligands for the paclitaxel-loaded 4.2. Liposomes
and docetaxel-loaded NPs, respectively.
The past decade has seen increasing attention focussed
on the development of NMs capable of delivering short RNA 4.2.1. General Characteristics and Synthetic Aspects
duplexes, called small interfering RNA (siRNA), into the cyto- Liposomes are spherical vesicles that consist of one or more
plasm of tumor cells as a potential means of combating cancer. phospholipid bilayers encapsulating water in their inte-
Once inside a cell, one of the siRNA strands (the guide strand) rior.[39,66] The phospholipids are arranged so as to form a
is recruited by an exogenous multiprotein complex, called the closed sphere, shielding their hydrophobic tails from the
RNA-induced silencing complex (RISC), to initiate the catalytic water, thus leaving water in the liposome interior. Drugs can
cleavage of complimentary mRNA sequences. This process, be encapsulated within the liposomes, not only in the aqueous
known as RNA interference (RNAi), provides a powerful tool for volume but also within the bilayer, which allows drugs of dif-
suppressing gene expression and thereby halting the growth of ferent hydrophilicities to be carried (Figure 9).[39,105,106] Three
tumor cells. Since siRNAs are highly negatively charged, how- types of liposomes have been described: i) multilamellar vesi-
ever, modification with and/or linkage to other molecules or cles (MLVs) composed of a number of concentric bilayers;
small particles that promote cellular uptake is necessary to affect ii) multivesicular vesicles (MVVs) consisting of many small,
RNAi.[94,95] A variety of polymeric materials have been explored non-concentric vesicles inside one lipid bilayer; and iii) small
for this purpose. For example, Davis[96] has reviewed the and large unilamellar vesicles (ULVs), which posses only a
development of a polymer-based delivery system (CALAA-01), single lipid bilayer.[107–109]
which consists of a cyclodextrin-containing polymer (CDP), Traditionally, liposomes have been synthesized by hydration
PEG, and human transferrin (Tf) as a targeting agent. This is of a thin film of a phospholipid mixture with a solution con-
the first ever NP-based siRNA delivery system to enter a phase taining the desired drug and/or a chelating ligand for radiola-
I clinical trial. Katas et al.[97] designed a delivery system for beling applications. The chelating ligand can also be incorpo-
siRNA based on chitosan polysaccharide NPs and studied the rated into the phospholipid mixture that will assemble into the
association of siRNA to chitosan using methods such as simple liposome membrane. After vortexing, the mixture is extruded
complexation, ionic gelation (entrapment), and adsorption onto under high pressure or sonicated, forming the unilamellar
the surface of preformed chitosan NPs. Entrapment of siRNA liposomes that can be purified by either column chromatog-
in the NPs was found to give the best in vitro gene silencing raphy or ultracentrifugation.[110] Other methods for synthesis
activities, probably because of protection of the siRNA mole- of liposomes include the Mozafari method, which avoids the
cules from degradation by nucleases. Self-assembled polymeric use of organic solvents and hazardous substances. This method
NPs and micelles have also been used to encapsulate siRNA involves hydration of the liposome components in an aqueous
and shown to be effective for transporting the siRNA across media, followed by heating of the mixture in the presence of
cellular membranes.[98,99] glycerol.[107,111]
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temperature,[138,139] redox reactions,[140] and the action of
REVIEW
enzymes on the liposome surface.[141,142] For example, Mallik
et al.[143–145] studied the cleavage and release of the contents of
liposome formulations by the matrix metalloproteinase, MMP-9,
which is found in high levels in metastatic tumors. Liposomes
incorporating a cleavage site for MMP-9 were prepared and
shown to release their contents after exposure to MMP-9. Wu et
al.[146] have developed liposomes that are sensitive to NIR light.
The liposomes incorporate hollow gold NPs (HGNs) as NIR
absorbing entities, which are either encapsulated or tethered
to the liposome membrane. The liposomes were shown to
release their contents within seconds when exposed to pulses
of NIR light due to collapse of transient vapor bubbles formed
during collapse of the HGNs into gold NPs. While the gold NPs
Figure 9. Structure of a carrier liposome. Hydrophilic drugs and NPs can
reached their melting temperature, the temperature increase
be loaded in the liposome interior, while hydrophobic drugs can be loaded observed in the surroundings was less than 1 °C.
between the hydrocarbon tails of the phospholipids.
4.2.3. Liposomes for Radio-Imaging and Therapy
4.2.2. Liposomes for Drug Delivery Liposomes have also been studied as radionuclide carriers for
Liposomes are widely applied as delivery systems due to their tumor imaging and radiotherapy.[147–149] For imaging, labeling
ability to pass through cell membranes and lipid bilayers, their with 67Ga, 111In, 99mTc, and 64Cu(II) has usually been achieved
ease of preparation, biodegradability, and generally low tox- by conjugation of the radionuclide with an anchor molecule
icity.[110,112,113] Methods for loading drugs into the liposome present inside the cavity of the liposome or incorporated in
include formation of the liposome in a saturated solution of the the phospholipid bilayer.[122,123,150] For example, 64Cu(II) has
drug, use of organic solvents and solvent exchange mechanisms traditionally been loaded into liposomes by complexation with
for lipophilic drugs, and the use of pH gradient methods.[114] azamacrocycles, such as 1,4,8,11-tetraazacyclotetradecane-
Formulations produced by incorporating anticancer drugs such N,N’,N’’,N’’’-tetraacetic acid (TETA), which confers stability and
as doxorubicin into liposomes are in wide use.[115,116] Doxoru- avoids leakage of the radionuclide.[151,152] For radiotherapy, lipo-
bicin-loaded liposomes target tumors through passive accu- somes labeled with β-emitters, such as 32P, 90Y, 188Re, 67Cu, 131I,
mulation based on the EPR effect. Attempts to increase their α-emitters, such as 223Ra, 224Ra and 225Ac, and Auger electron
specificity have involved attaching targeting agents such as emitters can be utilized.[122] Nuclisomes, which are tumor-
folate derivatives, the RGD-peptide and anti-HER2 monoclonal targeting liposomes containing radionuclides coupled to DNA-
antibody fragments.[117] Other drugs loaded into liposomes intercalating molecules, are novel nanoobjects developed in
include daunorubicin (Leukemia treatment), lurtotecan (ovarian the last few years.[153,154] Fondell et al.[155] loaded liposomes
cancer), annamycin (doxorubicin-resitant tumors), platinum with a daunorubicin derivative labeled with 125I, an Auger elec-
compounds such as, and genes such as the E1A gene.[39,118–121] tron emitter. The liposomes target the epidermal growth factor
Due to their size and surface properties, traditional liposomes receptor (EGFR) expressed in cultured U-343MGaCl2:6 tumor
are usually cleared easily by the RES or accumulate in the liver cells. On internalization of the liposomes into cells, their contents
and spleen.[122] A new range of stealth liposomes, e.g., liposomes are released and the radionuclide-containing drug accumulates in
coated with PEG, avoid RES clearance and have prolonged cir- the cell nucleus, where it binds to DNA and causes double-strand
culation times compared to traditional liposomes.[123,124] breakage, leading to substantial inhibition of tumor cell growth.
Compounds other than anticancer drugs have been encap-
sulated in liposomes.[125] Recently, liposomes containing 4.3. Dendrimers
gadolinium in the lipid layer were developed for bimodal
imaging (labeling and imaging of HeLa cells by magnetic reso-
nance and fluorescence imaging).[126] A Gd-DOTA complex was
conjugated to N,N-distearylamidomethylamine, which forms Dendrimers are a class of polymeric macromolecules that
the lipidic layer of the liposome, and a fluorescent dye. Conjuga- consist of repeating branching units emanating from a cen-
tion of the gadolinium complex to the liposome avoided leakage tral core.[156–161] The unique properties of these almost mono-
of the metal complex before the site of action was reached. Iron disperse polymers reflect their compact, treelike molecular
oxide nanoparticles have also been incorporated into liposomes structure, providing an arrangement of inner and outer molec-
(magneto-liposomes), to prevent the interaction of iron oxide ular functionalities that is influenced by the solvent environ-
with biological media and leakage into the blood stream.[127–129] ment.[162] Dendrimers can be considered to comprise three
Magneto-liposomes can be used for magnetically induced tar- structural components: i) the core, which in larger dendrimers
geting of specific cells or organs, controlled release of certain is almost completely shielded from the outside by the den-
drugs, and in cancer treatment by hyperthermia.[130,131] dritic branch, ii) the outer shell, which possesses a well-defined
Drug release from liposome cavities can be achieved by microenvironment and is protected by (iii) the multivalent sur-
changes in pH,[132,133] mechanical stress,[134,135] light,[136,137] face, which usually bears a high number of reactive sites.
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REVIEW
Dendrimers are generally prepared via one of two main strat- etc.[184–187] 5-Fluorouracil, cisplatin, carboplatin, methotrexate,
egies. The first – divergent synthesis – begins from a multivalent doxorubicin, epirubicin and paclitaxel have all been covalently
core unit and involves the attachment of successive “layers” of attached to dendrimers using appropriate linkers. The thera-
branching units, each new layer producing a new generation of peutic index of such “dendritic drugs” can be significantly
dendrimer. The second – convergent synthesis – involves preas- higher than the drug alone. For active targeting, folate has been
sembly of the complete wedge-shaped branching units, fol- the most applied vector for the accumulation of dendrimer–
lowed by coupling of these to the central core moiety in the anticancer-drug conjugates in tumor tissue.[168,188] Dendrimers
final step. Dendrimers have also been synthesized applying functionalized with a variety of tumor targeting peptides, such
novel concepts such as the dual-convergent-divergent method, as RGD and neurotensin, are also gaining in importance due
“lego” chemistry, divergent click chemistry, solid-phase sup- to metabolic stabilization of the peptides as well as enhanced
ported pathways, and self-assembly of Janus dendrimers into affinity to cancer cells.[189–191]
uniform dendrimersomes.[163]
Depending on the generation, the type of branching unit,
4.3.3. Dendrimers for Imaging
and the moieties grafted onto their periphery, dendrimers can
be prepared with sizes ranging between 1 to 10 nm. Lower gen- Dendrimers have been widely studied as MRI contrast agents.
eration dendrimers have a flat starfishlike shape. As the gen- Dendritic structures incorporating many paramagnetic centers
eration number increases, dendrimers become more spherical are ideally suited for medical use due to their appropriate
in shape. Importantly, in a physiological environment, higher pharmacokinetic properties in combination with shortening
generation dendrimers are stabilized as compact balls. Sixth of proton relaxation times and signal intensification. In the
generation polyamidoamine (PAMAM) dendrimers resemble main, PAMAM dendrimers have been functionalized with
proteins in size and shape.[156–163] Gd3+ complexes of diethylenetriamine pentaacetic acid (DTPA)
Due to the many variations possible in the basic framework and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
and the peripheral substituents, dendrimers can be tailor- (DOTA) derivatives.[192] Variation of the chelating agent does
made for numerous applications, which include diagnosis and not appear to affect the biodistribution of the dendritic Gd3+
therapeutic agents.[164–171] Thus, the development of new, high- complexes.[193] Such dendritic contrast agents have been used
resolution contrast agents, synthetic vaccines, and novel drug to visualize tumor tissue and sentinel lymph nodes with high
transport systems based on dendritic structures are in progress. resolution and to gain information about the state of angenio-
Moreover, dendrimers are intriguing as enzyme and liposome nesis.[194–196] A multigadolinium complex (24 Gd-DTPA units,
models with regard to the development of synthetic cells in Gadomer17, Schering) consisting of a polysine dendrimer with
molecular and cell biology. trimesic acid as the core element shows very fast and complete
renal elimination, allowing the visualization of peripheral arte-
rial deseases.[197]
4.3.2. Dendrimers for Drug Delivery
Dendrimers provide an ideal platform to realize agents
One very intriguing application of dendrimers is the encapsu- with dual/multimodality imaging capability combined with
lation and controlled release of drugs. This principle was first active targeting (Figure 10).[192,198] Pioneering work by Wiener
demonstrated by Meijer and co-workers using the so-called et al.[199] resulted in the development of folate-conjugated
dendritic box, which allows for shape-selective liberation of PAMAM dendrimers capable of both MRI and fluorescence
encapsulated guests.[172,173] Drugs are usually loaded into den- imaging. Boswell et al.[189] designed a PAMAM dendrimer con-
drimer structures by noncovalent interactions (of which ionic taining RGD peptides for interaction with the integrin recep-
interactions seem most appropriate for medical applications) tors of αvβ3-expressing tumor cells, which utilized Alexa Fluor
or by chemical conjugation to functional groups located on 594 dye molecules for fluorescence imaging and Gd3+ com-
the surface or at focal points of the dendritic carriers.[174–176] In plexes for MRI. A multimodal nanoprobe for radionuclide and
addition to influencing the rate of drug release, modification of five-color NIR optical lymphatic imaging based on a generation
the dendritic surface also allows the bio-distribution and phar- 6 PAMAM dendrimer has been developed to permit dual-
macokinetics of drug-loaded dendrimers to be tailored for spe- modality scintigraphic (111In) and optical imaging in mice.[200]
cific purposes. PEGylation of dendrimers is often utilized for Despite the fact that SPECT and PET provide convenient and
pharmaceutical applications.[174,177–179] Using this approach, broad information about biodistribution, pharmacokinetics, and
anticancer drugs, such as camptothecin, doxorubicin, dimeth- functional imaging, relatively few examples of radiolabeled den-
oxycurcumin, etoposide, 5-fluorouracil, and paclitaxel, have drimers have been reported so far. In this regard, 64Cu, 67Cu,
76
been transported by PEGylated dendrimers into cancerous Br, 99mTc and 111In have been used as radiolabels for dendritic
tissue. Another promising strategy is the encapsulation of drug structures.[190,200–205]
molecules into dendritic sugar-containing biohybrids.[180–182]
Recently, we showed that sugar-capped dendrimers can encap-
4.3.4. Dendrimers for Therapy
sulate and slowly release nanosized cluster molecules that selec-
tively inhibit an enzyme involved in cancerogenisis.[183] In the early-1990s, the potential of dendrimers to transport DNA
Drugs can be attached to dendrimer surfaces through hydro- building blocks into cells was recognized by Szoka and Kukowska-
lyzable (amide or ester bonds) or biodegradable linkages, which Latallo et al., triggering a fast-paced development of gene trans-
offers the opportunity to release the drug after reaching the fection agents.[206–209] The combination of artificial non-viral
site of action by means of enzymatic action, pH differences, dendritic carriers as pharmacologically active transfection agents
www.advmat.de
REVIEW
their unique topology and the arising possibilities to influence
solubility properties, pharmacokinetics and pharmacodynamics,
dendrimers may remarkably improve PDT. Induced endog-
enous formation of protoporphyrin IX (PpIX) by 5-aminolae-
vulinic acid (ALA) has been one of the most popular forms of
PDT. Higher tumor accumulation and enhanced PDT efficiency
have been obtained with ALA-containing dendritic carriers in
comparison to the free prodrug.[227–229] An immunoconjugate
of fullerene-cored dendrimers containing pyropheophorbide as
a photosensitizer was found to specifically bind to malignant
cells.[230] Both enhanced cellular uptake and PDT efficiency for
lung carcinoma cells have been obtained with Zn-porphyrin-
cored polybenzylether dendrimers.[231] The photocytotoxicity
was dramatically improved when applying supramolecular
assemblies of such anionic dendritic porphyrins and cationic
PEGylated polylysines.[232] PEGylated PAMAM and POPAM
Figure 10. Multifunctional dendritic carrier capable of acting as both an dendrimers are capable of encapsulating protoporpyrin IX and
imaging and therapeutic agent. transporting the photosensitizer to the mitochondria of HeLa
cells, where singlet oxygen is generated.[233] Enhanced photo-
dynamic cancer treatment has been achieved with dendritic
and appropriate transcriptionally targeted antitumor genes may
encapsulated phthalocyanines.[234] Other novel methodologies
create an efficacious gene medicine for the systemic treatment
to improve PDT effectiveness[235] include the use of dendritic
of tumors and their metastases. Dendrimers with a positively
two-photon-absorbing chromophores to allow for a more effi-
charged skeleton, e.g., polyamidoamino (POPAM), polypropylene
cient generation of singlet oxygen.[236,237]
amine (POPAM), and polylysine dendrimers, are predestined to
Photothermal therapy has been recognized to be a very effi-
form stable complexes with the negatively charged backbone of
cient and selective methodology to treat cancer.[237] By exposing
DNA, affording nanosized toroidal DNA/dendrimer associates
tumors to a NIR diode laser, the photothermal effect of gold
(dendriplex, 50–200 nm) capable of penetrating into cells, and
and silver NPs may be used to selectively destroy tumor tissue
to reach the cell nucleus.[210,211] Both the structure and genera-
with minimum damage to the surrounding healthy tissue. Very
tion of dendrimers influence transfection efficiency. Thus, high-
recently, dendrimers have been applied as targeting vectors for
generation PAMAM dendrimers show a significant enhancement
cancer tissue. PAMAM dendrimers containing folic acid form
in activity.[212] The same holds true when PEG units or cyclodextrin
stable associates with gold NPs and specifically target cancer
are grafted on the surface of dendrimers or when terminal amino
cells overexpressing folate receptors.[238]
groups are replaced by arginine, ornithine, or spermine.[213,214]
Dendrimer–antibody conjugates labeled with 90Y and 212Bi
Novel strategies, e.g., phototriggered gene transfection, developing
(emitting beta and alpha particles) have been reported as poten-
dendritic agents with vectors showing natural anti-cancer proper-
tial vehicles for use in radioimmunotherapy.[205] However,
ties, and manufacturing inorganic-organic hybrids consisting of
despite the potential for dendrimers to improve endoradionu-
magnetic NPs decorated with PAMAM dendrons, are being evalu-
clide therapy, e.g., through enhancement of specific activity,
ated to improve the effectiveness of gene medicine.[215–217]
selective targeting of tumor cells and improved stability of radi-
Dendrimers have been used for boron neutron capture therapy
onuclides by encapsulation, this area is still very much in its
(BNCT), unveiling the potential to non-invasively treat incur-
infancy. One reason may be the non-specific accumulation of
able forms of cancer. BNCT is based on the delivery of a high
larger dendritic ensembles in the RES. Smaller dendritic struc-
amount of the 10B isotope to tumor cells, which, when exposed
tures and pretargeting approaches can potentially circumvent
to thermal neutrons, emit short-range radiation capable of killing
this problem.[190,240–242]
cells.[218,219] Initial studies showed that up to 120 boron atoms can
be attached per dendrimer,[220,221] but pharmaceutical targeting
was poor. Meanwhile, many boronated-dendrimer–antibody con- 4.4. Quantum Dots
jugates have been developed for BNCT which can target tumor
vasculature by interacting with EGF/VEGF receptors.[222–225] Such
conjugates contain up to 1100 boron atoms, affording enhanced
tumor accumulation and improved effectiveness for BNCT, QDs are highly fluorescent semiconductor nanocrystals, which
cf. simple boronated dendrimers. NIR imaging using Cy5 dye typically range from 1 to 10 nm in size.[243–245] They are usually
molecules attached to boronated-VEGF–dendrimer conjugates composed of semiconductor elements from group II–VI, such
revealed internalization by receptor-mediated endocytosis and as CdSe, CdS, and CdTe, group IV–VI, such as PbS, PbSe, PbTe
localization in regions of active angiogenesis. and SnTe, or group III–V, such as InAs and InP.[246] QDs possess
Dendrimers are now being widely studied for photodynamic broad absorption and narrow emission spectra, and their emis-
therapy (PDT). PDT is based on the in situ formation of singlet sion maxima can be tuned between 450 to 850 nm by changing
oxygen when a photosensitizer is irradiated with light.[226] The their size (Figure 11). They are extremely bright due to their high
photosensitizer (drug) is ideally non-toxic under non-irradiating extinction coefficient in the visible spectrum (ε up to 106 M−1cm−1;
conditions, only becoming toxic when exposed to light. Due to 10–100 times greater than for organic fluorophores)[244,247,248]
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REVIEW
dominance of radiative carrier relaxation over energy transfer

to oxygen when the QD is photoactivated. Energy transfer from
a QD to a conjugated PS is a more efficient strategy for the
production of ROI, as QDs are excellent donors in fluorescence
(Förster) resonance energy transfer (FRET). Indirect photoac-
Figure 11. Quantum dots’ fluorescence emission properties can be mod- tivation of a PS conjugated to QDs enables prolonged imaging
ulated by changing their size.
and PDT without photobleaching.[250,261–264] Photosensitizers
(e.g., metallo-phthalocyanines, Rose Bengal (RB) and Chlorin
and high quantum yields (typically >50%).[249] They are resistant
e6) and the chemotherapeutic drug, Merocyanine 540 (MC540),
to photobleaching and chemical degradation, and more stable
have been conjugated with QDs for PDT.[265–268] UV irradiation
than conventional organic fluorophores and fluorescent proteins.
of green and red CdTe QDs capped with mercaptopropionic acid
Additional attractive properties for imaging and PDT of cancer
generated ROS in human pancreatic carcinoma cells (PANC-1),
include a high surface area, a large two-photon absorption cross-
which was attenuated by the antioxidant NAC. Cytotoxicity of
section, and the possibility of NIR photoluminescence.[250,251]
these QDs increased with UV irradiation time, QD concentration,
There are concerns about the use of QDs for medical purposes
and post-exposure time.[269] Yang et al.[270] found a linear relation-
because of the high toxicity of cadmium and selenium and their
ship between radiation dose rate and number of visible photons
instability to photolysis and oxidative conditions, which could
generated from QD-Photofrin NPs excited by 6-MV X-rays. FRET
result in dissolution of the QD core. It should be noted, however,
from the QD to the PS increased, approaching 100% as the
that cytotoxicity has not been observed in several in vivo and in
number of conjugated Photofrin molecules was increased.
vitro studies of QDs coated with ZnS,[252] and that coating with
ZnS and other agents has been shown to reduce the cadmium
toxicity and the production of free radicals from photo- and air 4.4.3. Quantum Dots for Fluorescence Imaging and
oxidation.[253] Notwithstanding this, there has been considerable
Diagnostic Assays
research into the development of cadmium-free QDs, such as
CuInS2,[254] as safe and non-toxic probes for biological use. QDs have been widely studied for fluorescent imaging of cancer
The traditional synthesis of CdSe and other QDs uses trioctyl- and even proposed for personalized medicine.[271] For example,
phosphine oxide (TOPO) and trioctylphosphine (TOP) as coordi- Li et al.[272] have developed CdSe QDs coated with a generation
nating solvents to stabilize the particles and prevent agglomera- 4 PAMAM dendrimer conjugated to an aptamer (GBI-10), for
tion. A solution of organometallic precursors is injected into the the targeting and imaging of U251 glioblastoma cells in vitro.
solvents at temperatures from 290 to 350 °C. The reaction mixture Simultaneous imaging, therapy and sensing of the release of a
is left for the desired time, cooled, and the QDs are purified.[246] conjugated drug can be achieved by activation of the QD’s fluo-
In recent years, efforts have been made to avoid the use of toxic rescence. For example, a QD-aptamer(Apt)-doxorubicin (Dox)
heavy metals, such as cadmium, lead, and mercury in the syn- conjugate [QD-Apt(Dox)] was prepared for specific delivery of
thesis of QDs. Research has also been directed towards the use doxorubicin to prostate cancer cells.[273] The double-stranded
of group III–V semiconductors nano-crystals, which have a more A10 PSMA aptamer intercalates Dox but also recognizes the
robust structure due to the presence of covalent bonds within extracellular domain of the prostate specific membrane antigen
their matrix.[255–258] For example, InP and InAs QDs are being (PSMA). When Dox intercalated into the aptamer, quenching
developed into diagnostic agents for cancer and other diseases. of fluorescence from both the QD and Dox was found to occur
In order to protect QDs from degradation and oxidation, a via a Bi-FRET mechanism. Binding of Dox to the QD (donor–
thin shell (also a semiconductor, but with a higher band gap) is acceptor) diminished QD fluorescence, while the binding of Dox
formed around the QD core, which, as well as increasing their to the aptamer (donor–quencher) decreased Dox fluorescence.
stability, also enhances their photoluminescence. The quantum Release of Dox from the NPs by physical dissociation from the
yield of the nanocrystal core (typically 10%) can increase to ca. conjugate, or biodegradation of the PSMA aptamer by enzymes
80% after the high-bandgap-semiconductor shell is epitaxially present in lysosomes, induced recovery of fluorescence from
grown around it.[259] Traditionally, ZnS, and ZnSe have been both the QD and drug.[273] Aptamers are proving useful in the
used as protector shells. The shell is formed at a temperature active targeting of cancer cells as they are comparable to anti-
below that used to prepare the QDs in order to avoid nucleation bodies in terms of their specificity and affinity. Cheng et al.[274]
of the shell particles. The QDs obtained by this method are only have designed an aptamer-based assay with QD-based fluores-
soluble in non-polar solvents, making it necessary to further cence readout for detection of mucin 1 (MUC1), a cell surface-
modify their surface to achieve water-solubility. This is achieved associated glycoprotein expressed on most epithelial surfaces
by surface ligand exchange, where the coordinating ligands are that serves as a useful biomarker for early cancer diagnosis.
displaced by bifunctional ligands or silanes, or by coating with QDs have been used to develop multimodal imaging probes
amphiphilic polymers.[254,260] for detection of tumors via fluorescence-MRI, by conjugating a
ligand for Gd3+ complexation[275,276] or directly doping the QD
with Mn2+ (as CdSe/Zn1−xMnxS),[277] or via fluorescence-PET
4.4.2. Quantum Dots for Photodynamic Therapy
imaging, by conjugation of ligands for complexation of 64Cu[278,279]
Although QDs are poor photosensitizers (PS) for PDT, due to a and other radioactive elements. Manganese (Mn)-doped NIR-
low efficiency of production of reactive oxygen intermediates/ QDs were recently used to image pancreatic tumors in mice
species (ROI/ROS), QD-PS conjugates can provide an efficient by fluorescence imaging and MRI.[280] Mn-doped CdTeSe/CdS
way to produce ROI. The poor efficiency of QDs stems from the nanoparticles with a fluorescence emission around 822 nm were
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REVIEW
prepared in a one-pot synthesis from manganese acetylacetonate at higher pH and ionic strength), the temperature, and whether
(Mn(acac)3) and were covered with lysine to enhance water solu- the reaction is carried out under an inert atmosphere. The main
bility. The QDs were further functionalized with the antibodies disadvantage of the coprecipitation method is the wide size dis-
anti-claudin 4, anti-mesothelin, or anti-PSCA, which are overex- tribution obtained.[294] Maghemite NPs can be obtained by oxida-
pressed in primary and metastatic pancreatic cancers and used tion of the Fe2+ centers in magnetite to Fe3+ with nitric acid.[295]
for Panc-1 and MiaPaCa pancreatic cancer cell staining and in In the microemulsion method, NPs are prepared within
vivo fluorescence imaging. In addition, QDs radiolabeled with micelles (1–10 nm diameter) or water–oil emulsion nanoreac-
125mTe (as Cd125mTe/ZnS) have been produced and used to asses
tors (10–100 nm), where encapsulation of the iron salt precur-
biodistribution of the QDs with specific targeting agents.[281,282] sors controls the nucleation and growth of the NPs.[292] This
Multicolor imaging with QDs is a significant recent develop- method produces NPs with narrow size distributions, however,
ment that could aid the diagnosis of cancer and other diseases, the removal of the surfactant is difficult and not amenable to
as it permits simultaneously tracking of multiple molecular tar- large scale synthesis.[295] In the hydrothermal synthesis, water
gets.[283,284] The utility of simultaneous detection of different is used as reaction media at high temperature and pressure and
tumor markers was demonstrated using QDs with different emis- is postulated to promote nucleation over particle growth of the
sion maxima (525, 565, 605, 655, and 705 nm) conjugated to a NPs.[292,296] Surfactants such as sodium bis(2-ethylhexyl)sulfo-
variety of primary antibodies. These were employed to detect the succinate (AOT), n-decanoic acid or n-decylamine are added to
markers in MCF-7 and BT-474 breast cancer cells. Multispectral improve the shape and size distribution of the NPs.[292,297]
confocal microscopy established the spatial distribution of the dif- The thermal decomposition of iron pentacarbonyl (Fe(CO)5)
ferent markers in the BT-474 and MCF-7 cells, cell membrane, and iron acetylacetonate (Fe(acac)3) in high temperature organic
cytoplasm, or cell nuclei. The markers were also quantified by solvents and surfactants is another widely used method for
single-cell spectroscopy and the expression of the markers in producing magnetite NPs. This yields NPs with a narrow size
human breast cancer specimens was evaluated and quantified.[285] distribution and the surfactant surrounds the NPs, acting as a
Quantum rods (QRs) are another type of fluorescent particle, stabilizing agent. Whilst high-quality NPs are obtained, their
which have been gaining increasing attention, as they exhibit large-scale production presents safety issues, mainly due to the
stronger fluorescence, larger Stokes shifts, and larger absorption toxic and flammable nature of the reactants. The NPs obtained
cross-sections compared to QDs. They produce linearly polarized by this method are not dispersible in water and phase transfer
emission, unlike the plane polarized emission from a single QD, into aqueous solution is necessary for biomedical applica-
and have large surface areas, which can be useful for conjugation tions.[292,296,298,299] Other synthetic methods include sol–gel, gas
to biomolecules. Furthermore, QR emission can be reversibly phase, polyol, and electrochemical syntheses.[292,300]
switched on and off by externally applied electric fields. Biotin, The protection, stabilization, and functionalization of iron
folic acid, and the cyclic RGD peptide have been conjugated to oxide NPs is important for medical applications. Stabilization
QRs for tumor targeting and in vitro and in vivo imaging.[286–289] in water has been achieved using carboxylates, phosphates,
sulphonates, silicon compounds, gold, and polymers sucha s
4.5. Iron Oxide Nanoparticles dextran, PEG and polyvinyl alcohol (PVA) (Figure 12).[292,295]
Citric acid is the most common carboxylate-stabilizing agent
used. Upon electrostatic binding to the surface via one carboxyl
group, the surface becomes negatively charged, increasing the
Iron oxide NPs are the most commonly explored members of a hydrophilicity of the NPs.[292,301] Silica and siloxane derivatives
broader class of NPs referred to as magnetic NPs, which have are also widely used for coating and derivatization of iron oxide
attracted great interest because of their potential use in a broad NPs. Silica can stabilize NPs by shielding magnetic dipole
range of applications, including catalysis, data storage, biosepa- interactions between NPs, and by introducing a negative sur-
rations, and MRI. Magnetite (Fe3O4, ferrimagnetic, superpara- face charge that increases inter-particle electrostatic repulsion,
magnetic when the size is smaller than 15 nm) and maghemite
(γ-Fe2O3, ferrimagnetic) have proven particularly popular for
biomedical applications because of their great biocompatibility.
Despite this, there are recent reports that naked iron oxide NPs
could be toxic for neuronal cells and that they may potentially
induce oxidative stress processes in the body.[290,291]
Monodispersed magnetite and maghemite NPs can be syn-
thesized by methods that allow control of size, size distribution,
shape, and solubility. These techniques include co-precipitation
from aqueous solutions of iron salts and microemulsion as well
as hydrothermal and high temperature reactions. Coprecipita-
tion from ferric and ferrous salts in aqueous media is most com-
monly used to obtain large quantities of magnetite NPs (typical
size 2–17 nm).[292,293] Several factors affect the properties of the
NPs obtained, such as the Fe2+/Fe3+ ratio (ideally between 0.4 Figure 12. Iron oxide NPs offer a wide range of possibilities for their sta-
and 0.6), the iron concentration (typically 40–80 mM), the solu- bilization and functionalization with different molecules such as silanes,
tion pH and ionic strength (with smaller NPs being produced carboxylic acids, catechols, and phosphonates.
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avoiding aggregation.[292] Silica can be deposited on the NP sur-

REVIEW
on magnetic NPs by complexation to surface-bound organic lig-

face by deposition from silicic acid or the hydrolysis of tetra- ands (DOTA in the case of 64Cu(II)[314]). Iridium complexes have
ethylorthosilicate (TEOS) with ammonia.[292,302] Triethoxysilane been loaded into magnetic NPs for dual-modal luminescent and
derivatives can be attached by hydrolysis on the naked NP sur- magnetic resonance imaging, as well as photodynamic therapy.
face, or on the silanol-rich silica coating, and subsequently used Lai et al.[315] used silane chemistry to coat magnetite NPs with
to functionalize the NPs for biomedical applications. an iridium complex. The complex was reacted with IECTS
Different polymeric materials have been used to increase the (silane), mixed with TEOS, and the mixture hydrolyzed over the
stability of magnetic NPs in water and to avoid their clearance by surface of the NPs. The resulting water-dispersable, multimodal
the RES. These are typically biocompatible PEG and PEG deriva- system was used for phosphorescent labeling and to simultane-
tives, which can be easily functionalized with various biological ously induce apoptosis of cancer cells by production of 1O2.
molecules. Xie et al.[303] recently developed iron oxide NPs with
four PEG polymers (PEG600, PEG3000, PEG6000, and PEG20000 with
4.5.3. Iron Oxide Nanoparticles for Drug Delivery
sizes ranging from 40 to 90 nm) covalently bound to the surface
via the chelating o-catechol moiety of dopamine. The NPs coated Iron oxide NPs can also be used as drug-delivery systems due
with PEG600 exhibited the greatest macrophage uptake, while the vast opportunities that their surface provides for modifi-
uptake of the others was negligible. PEG has also been attached cation and subsequent incorporation of drugs and targeting
to magnetic NPs via a trichloro-s-triazine unit, yielding particles agents; doxorubicin being a classical example of this. Jain
with an average hydrodynamic diameter of 40 nm, which were et al.[316] have developed iron oxide NPs that can carry water-
stable in buffered saline solutions at pH 7.[304] Other polymeric insoluble drugs, releasing them in a controlled fashion via inter-
materials used for particle coating include dextran, starch, and action with pluronic acid bound to the NP surface. The NPs were
PVA. Dextran consists of R-D-glucopyranosyl units, making it coated with oleic acid and then with pluronic acid by mixing
highly compatible with the human body. Dextran-coated NPs are solutions of the acids and NPs and stirring overnight. Doxoru-
synthesized by coprecipitation of the iron oxide from ferrous and bicin was loaded onto the NPs by mixing a solution of the drug
ferric salts in the presence of dextran.[292,305,306] Starch, which with the pluronic-NP suspension, resulting in encapsulation
consists of a mixture of amylose and amylopectin, and PVA have of 82% of the drug, which was then available for slow release.
typically been used to coat NPs by coprecipitation.[307–310] Chen et al.[317] covalently bound doxorubicin to iron oxide NPs
using silane chemistry. A thin shell of silica was formed around
the NPs, followed by a shell of aminopropyltriethoxysilane,
4.5.2. Iron Oxide Nanoparticles for MRI and Multi-Modal Imaging
which was then reacted with glutaric anhydride, leaving free
Iron oxide NPs have been extensively studied as contrast carboxyl groups on the surface that were used to link doxoru-
agents for imaging of tumors by MRI. They generally produce bicin molecules by amidation. The loaded doxorubicin could be
enhanced proton relaxation rates at significantly lower doses easily detached by the hydrolytic action of proteases at low pH,
than paramagnetic ions (Gd3+) because of their larger magnetic releasing the free drug inside the tumor cells only.
moment, and they provide negative (dark) contrast by enhancing Functionalized iron oxide NPs have been also used for
T2 relaxivity of water protons. Although passive targeting of iron simultaneous delivery of siRNA and imaging of tumors. Lee
oxide NPs to tumors can be achieved through the EPR effect, a et al.,[318] for example, prepared manganese-doped iron oxide
range of molecules have been attached to their surface to improve NPs coated with bovine serum albumin and PEG and func-
tumor targeting for MRI (and other) applications, including pro- tionalized with RGD peptide and siRNA labeled with Cy5. They
teins, antibodies, peptides, and oligosaccharides.[269] The simplest demonstrated that the expression of green fluorescence protein
method exploits electrostatic interactions between molecules and (GFP) was inhibited. Medarova et al.[319] used dextran-coated
the surface of the NPs. Hildebrandt et. al.[311] attached a small magnetic NPs, which were modified with Cy5.5 and siRNA for
peptide, IELLQAR, known to inhibit sialyl Lewis X binding the inhibition of GFP expression. Additionally, this probe was
to the E-selectin receptor, to the surface of negatively charged modified with myristoylated polyarginine peptides (MPAP),
dextran-coated magnetic NPs by appending a positively charged which serve as membrane translocation modules.
polylysine chain to the end of the peptide. Xie et al.[312] bound Recently, Agrawal et al.[320] designed dendriworms consisting of
the small peptide, c(RGDyK), specific for targeting integrin αvβ3- linear chains of iron oxide NPs (nanoworms) surface-coated with
rich tumor cells, to magnetite NPs via a Mannich reaction with generation 4 PAMAM dendrimer molecules for the delivery of
4-methylcatechol bound to the oxide surface. Very small NPs siRNA into cells. The dendriworms facilitated the in vitro and in
were obtained (diameter ≈ 8.4 nm) that were stable as a water dis- vivo delivery of the siRNA into cells, leading to reduced EGFR
persion, and could be used as contrast agents, as they localized in expression in glioblastoma (GBM) tumors. Functionalization of
tumors with limited uptake by macrophages. Herceptin, an anti- the dendrimers with NIR fluorophores enabled the uptake of
body specific for the HER2/neu receptor that is overexpressed in the dendriworms to be visualized by fluorescence.
breast cancer cells, has been attached to water-stable magnetite
NPs via conjugation to a dimercaptosuccinic acid coating.[313] In
4.5.4. Iron Oxide Nanoparticles for Hyperthermia Therapy
an in vivo experiment, these NPs accumulated in an induced
tumor within 5 min, reducing the T2 value by about 20%. Iron oxide NPs have considerable potential for use in
Iron oxide NPs have been popular materials for the prepa- hyperthermia treatment of cancer. In this therapy, the heat
ration of multimodal tumor imaging/therapeutic agents. For generated when NPs are exposed to an oscillating mag-
diagnosis, radionuclides such as 18F or 64Cu, have been loaded netic field is used to kill the tumor cells. Heating occurs by
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REVIEW
two particle-size-dependent mechanisms; for NPs less than Gold nanorods are typically prepared by seed-mediated
100 nm in dia-meter (single domain NPs), heat is produced synthesis and by the template method, in which gold is electro-
mainly through Brownian modes, which produces heat due to chemically deposited within the pores of nanoporous poly-
friction between oscillating particles, whilst for larger particles, carbonate or alumina template membranes.[333] Gold nanocages
Neél modes produce heat by rotation of the magnetic moment have been synthesized by galvanic replacement reactions against
with each field oscillation.[321,322] The use of biocompatible NPs silver nanocubes in the presence of HAuCl4; the Ag nanocubes
for hyperthermia treatment is increasing. Magnetic NPs coated are obtained by reducing Ag(I) salts in the presence of a polyol
with pullulan acetate, a polysaccharide used as a food additive and (e.g., ethylene glycol).[331,333]
shown to be safe for human use, were used for in vitro hyper-
thermia treatment of KB cells, producing therapeutic efficacies of
4.6.2. Gold Nanoparticles for Photothermal Therapy
56% and 78% at 45 °C and 47 °C, respectively.[323] Chitosan-coated
magnetite NPs with a high heating capacity useful for hyper- Gold NPs have been widely studied for photothermal cancer
thermia have also been produced.[324] Recently, Bruners et al.[325] therapy (PTT), also called photothermal ablation therapy (PAT).
reported the use of magnetic NPs for thermal ablation of malig- PTT is based on the surface-plasmon resonance (SPR) property
nant kidney tumors (followed by computed tomo-graphy). Zhang of the particles. Gold NPs are much more efficient photon–
et al.[326] reported that core/shell iron/iron oxide NPs coated with thermal-energy converters than typical organic dyes due to
a biocompatible phospholipid layer provide an increase in mag- the much higher photon-capture crosssection of gold NPs
netization, and are more effective for hyperthermia treatment and nanoshells around the SPR absorption band (4–5 orders
due to improved local heating than for iron oxide NPs alone. of magnitude greater than for photothermal dyes). Gold NPs
Another potential treatment for cancer involves attaching absorb and convert the photon energy into thermal energy
magnetic NPs, via targeting ligands, to free-floating cancer when a laser beam is used to irradiate them at the SPR wave-
cells in the circulatory system, allowing them to be captured length. The NP temperature can suddenly increase, even above
and removed from the body with a permanent magnet. Such a their melting point, releasing the energy to the surroundings
strategy might help to improve the long-term survival rates of or destroying the NPs.[334–336] Photoinduced hyperthermia
cancer patients by dimininshing the probability of cancer-cell treatment with gold NPs works better for tissue close to the
migration (metastasis) throughout the body.[327] skin due to the limited penetration of visible and IR light into
the tissue; treatment deep inside tissues works better with
hyperthermia induced by magnetic NPs.[328] Dickerson et al.[337]
4.6. Gold Nanoparticles
used plasmonic photothermal therapy (PPTT) with PEGylated
plasmonic gold nanorods and a NIR laser. After accumulation
of the nanorods in subcutaneous squamous cell carcinoma
Among the metal NPs, gold NPs are receiving greatest atten- xenografts, grown in nude (nu/nu) mice, they were exposed to
tion, mainly because their properties lend themselves to NIR light, which elevated the rod temperature and suppressed
multiple applications, such as labeling, delivery, heating, and tumor growth. Other work has revealed the possibility of using
sensing. Gold NPs are made by simple reduction of metal salt gold NPs for PAT after aggregation is induced by mild acidic
precursors with reducing agents under controlled conditions, in in the intracellular environments similar to those found in
either water or organic solvents (Figure 13). Addition of a stabi- tumors. Aggregation of the particles inside the tumor allows
lizing agent (surfactant), which is typically charged to increase the application of an external light source.[338] A NP system
the repulsion between particles, is also required during the was designed that included citraconic amide molecules bearing
synthetic procedure.[328–330] Seed-mediated growth of gold NPs thiol groups for anchoring to the surface of NPs. The amide
is another widely used method that involves growing the NPs bonds remained stable under neutral or basic conditions, but
from small seed particles of gold. Initially, very small, uniformly were easily hydrolyzed at pH < 7, producing citraconic acid and
spherical seed particles are formed. The reaction conditions are changing their charge from negative to positive under acidic
then altered, adding more gold ions, a different reducing agent, conditions. B16 F10 mouse melanoma and HeLa cells were
and a shape-templating surfactant, to obtain specific particle incubated with the NPs, and pH-induced accumulation was
morphology.[329,331] The conventional methods for the synthesis confirmed, which shifted their absorption to the far- and near-
of gold NPs are the citrate reduction of HAuCl4 in water and IR spectral regions. This was used to establish the efficacy of
the Brust–Schiffrin method, in which thiol ligands that strongly photothermal treatment after aggregation.[338] Release of drugs
bind to the surface of the particles are used.[332] induced by the thermal effect produced by irradiating gold NPs
with NIR could become a major application. You et al. elec-
trostatically loaded doxorubicin onto hollow Au nanospheres
and used them for doxorubicin delivery and dual treatment
of cancer by PAT.[339] Drug release in MDA-MB-231 cells was
induced by heat produced after PAT with NIR light.
4.6.3. Gold Nanoparticles for Imaging

Gold NPs provide a convenient way to image tumors as they can
Figure 13. Representation of gold NPs. Different shaped NPs exhibit dif- be detected by simple methods (e.g., using an optical microscope
ferent properties that maybe useful for different applications. equipped with a dark-field condenser), due to the ability of noble
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REVIEW
metal NPs to scatter light very strongly at their localized SPR

frequency.[336,340] Other NPs usually require sophisticated instru-
mentation such as lasers, optical components, and detectors, or
complex image processing methods or dark-field imaging.[340]
SPR is based on the interaction of light and the conduction elec-
trons in gold NPs. When light interacts with the metal, the con-
duction electrons oscillate at a resonance frequency relative to
the lattice of positive anions. Some of the photons are released
at the same resonance frequency in all directions, a process
known as scattering.[341,342] Tuning of the optical properties of
the gold NPs is possible because the SPR effect is very sensitive
to changes in size, shape and the dielectric constant of the sur-
rounding medium.[343,344] Usually, 30–100 nm particles scatter
intensely and can be detected by a conventional microscope
under dark-field conditions.[336] The SPR peak can also be tuned
by using gold shell NPs (gold nanoshells) and changing the
shell thickness-to-particle dia-meter ratio.[341,343] Gold nanocubes
are useful for cancer imaging as they possess the highest photo-
luminescence quantum yield among gold NPs. This effect is due Figure 14. Schematic representation of energy upconversion by an UCNP.
to the SPR-involved local field enhancement and can be used for
phototherapy using visible light.[345] As with many other NPs, the majority of methods produce
Gold NPs have been also decorated with different targeting either uncoated or hydrophobic, oleic acid-coated UCNPs
agents for specific uptake by tumors and tumor cells. For that aggregate strongly or do not suspend in water. Several
example, NPs modified with human transferrin,[346,347] folic methods to render them water-dispersable have been described,
acid,[348] methotrexate (MTX),[348] and also loaded with drugs including coating with polymers such as polyacrylic acid,[362]
such as doxorubicin, placlitaxel, and kahalalide F (a cyclodep- ligand exchange with molecules such as PEG-phosphate
sipeptide with antitumoral activity isolated from a marine mol- and mercaptopropionic acid,[355] and silica coating (using
lusk, Elysia rubefescens) are being developed for specific delivery aminopropyl-trimethoxysilane),[363,364] followed by conjugation
and release.[349,350] to the biomolecule. The addition of PEI during hydrothermal
synthesis of UCNPs allows for direct surface functionaliza-
tion, circumventing the need for an additional coating or ligand
4.7. Upconverting Nanophosphors exchange step.[358] Active targeting of UCNPs has been achieved
by conjugating a range of bioactive molecules to their surface,
4.7.1. General Characteristics and Synthetic Aspects including antibodies,[364] folic acid,[364,365] and peptides.[363,366]
Upconverting nanophosphors (UCNPs) are an exciting new

4.7.2. UCNPs for Fluorescence Imaging
class of fluorescent probes for biomedical imaging that are
essentially lanthanide (rare earth)-doped ceramic materials. In The major appeal of UCNPs for tumor imaging is that relatively
contrast to organic fluorophores and semiconductor QDs (so- inexpensive low-power NIR diode lasers may be used as the
called “down-converters”), UCNPs convert longer wavelength excitation source, which allows for deeper tissue penetration
radiation (typically NIR) into shorter wavelength luminescence, compared to traditional fluorescence imaging as well as higher-
i.e., they exhibit anti-Stokes emission (Figure 14).[351] Pres- contrast optical imaging due to an absence of autofluorescence
ently, the two major types of inorganic host matrices used to and decreased light scattering.[367] Unlike many organic fluoro-
prepare UCNPs are rare earth fluorides (e.g., NaYF4 and LaF3) phores, UCNPs are extremely resistant to photobleaching and
and oxides (e.g., Y2O3 and Y2O2S).[352] These are co-doped with their rare earth components are approximately one-thousand-
Yb3+ and Ln3+ (Ln = Er and Tm) ions to tune their emission fold less toxic than the heavy metals within QDs.[368] Moreover,
spectra.[353–355] UCNPs featuring Er3+ as the emitter display the NIR wavelengths that UCNPs are excited at are less cytotoxic
two predominant emission lines, one in the green (ca. 540 nm) than the radiation used to excite most other fluorophores.[367]
and one in the red (ca. 650 nm),[342] whilst Tm3+-doped UCNPs UCNPs functionalized with the cyclic RGD peptide have
exhibit an intense NIR emission around 800 nm and two weak been successfully used for imaging of integrin αvβ3-positive
visible emission peaks (ca. 480 and 650 nm).[355] tumor cells.[363,365] Zako et al.[363] prepared silica-coated Er3+-
UCNPs are commonly prepared via surfactant-mediated doped Y2O3 NPs and modified their surface by treatment with
hydrothermal synthesis.[353,356,357] Additives such as polyeth- a heterobifunctional PEG derivative and then the RGD pep-
ylenimine (PEI)[358] and poly(vinyl pyrrolidone)[359] have been tide. Upconversion emission was observed from the NPs for
used to control the growth of UCNPs. Recently, a facile micro- U87MG cancer cells (high integrin αvβ3 expression), but not for
wave-based method for preparing high-quality UCNPs has MCF-7 cancer cells (low integrin αvβ3 expression), confirming
been described.[360] The spectral properties of UCNPs can be integrin αvβ3-specific binding/uptake. Xiong et al.[366] reported
tuned not only by varying the dopants and their relative pro- similar in vitro findings for RGD-labelled NaYF4 UCNPs that
portions,[352] but also by controlling the temperature during had been tri-doped with Yb3+, Tm3+, and Er3+ to produce multi-
thermolysis.[361] color upconversion luminescence (green, red, and NIR). These
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REVIEW
workers also reported the successful in vivo and ex vivo imaging 4.7.4. UCNPs for Drug Delivery
of U87MG tumors within nude mice. Luminescence imaging
Another area of recent application of UCNPs is the fluorescent
of tissue slices showed no autofluorescence, even at penetra-
imaging and targeted delivery of siRNA into cancer cells. To facili-
tion depths as high as 600 μm, and a high signal-to-noise ratio
tate uptake into SK-BR-3 cells with high Her2 receptor expression,
(ca. 24) between tumor and background tissue.
Jiang et al.[365] prepared silica-coated NaYF4:Yb/Er UCNPs conju-
Hu et al.[364] have produced folate-displaying, silica-coated
gated to anti-Her2 antibodies and electrostatically bound siRNA
NaYF4:Yb/Er UCNP composites incorporating fluorescein iso-
onto the protonated amine-bearing surface of the NPs. Successful
thiocyanate. These display good water solubility, photostability,
uptake of the UCNPs was established via confocal microscopy,
and biocompatibility and can be monitored by down- and up-
whilst delivery of the siRNA was confirmed by the down-regu-
converting luminescence simultaneously. Using confocal micro-
lation of expression of the target gene (luciferase) in the SK-BR-
scopy and localized spectroscopy, receptor-mediated delivery
3 cells, but not in MCF-7 cells with low Her2 receptor expression.
of this nanocomposite to targeted FR(+) cell lines was demon-
strated, whereas there was almost no uptake in FR(_) cell lines,
after short incubation times (<1 h). The use of NaYF4:Yb/Tm
UCNPs for imaging of tumor cells has been reported.[355,369] A 4.8. Other Classes of Nanomaterials
major advantage offered by Tm3+-doped particles is that both
the excitation wavelength (980 nm) and upconverted emis- In addition to the various types of NMs described above, sev-
sion (ca. 800 nm) fall within the region of the electromagnetic eral other types of nanoscalic agents are gaining relevance in
spectrum, where human tissue is relatively transparent (the so- the field of oncology research. These include carbon nanotubes
called biological window), which is ideal for deeper tissue pen- (CNTs) (single- and multi-walled), which have been investigated
etration. Boyer et al.[369] prepared PEG phosphate-coated NPs as drug-delivery systems due to their low cytotoxicity, high sur-
of this type, and successfully employed them for upconversion face area, and easy surface modification.[373] Multi-walled carbon
imaging of an ovarian cancer cell line (CaOV3). Nyk et al.[355] nanotubes (MWCNTs) can be used for photothermal cancer
demonstrated in vitro cellular uptake of mercaptopropionic ablation, as they release substantial vibrational energy on expo-
acid-coated NaYF4:Yb/Tm NPs into Panc 1 human pancreatic sure to NIR radiation.[374] Also, the possibility of using CNTs
cancer cells. Animal imaging studies were also performed using as nanocontainers makes them very attractive for drug delivery;
Balb-c mice injected intravenously with the UCNPs. The lumi- they can be filled with metals, semiconductors, salts, organic
nescence signal at 800 nm was readily detectable through the materials, fullerenes, etc.[375,376] MWCNTs functionalized with
skin (without hair removal) and provided a high contrast image. polyethylenimine have been modified with QDs of different
sizes to produce a multicolor fluorescent nanoprobe for tumor
imaging.[377] CNTs have also been coated with PAMAM den-
4.7.3. UCNPs for Photodynamic Therapy
drimers functionalized with imaging and targeting agents.[378]
The ability of UCNPs to convert low-energy radiation to Small silicon NPs (1–10 nm) hold great potential in emerging
higher-energy emissions provides an elegant tool by which applications of diagnostic imaging due to their unique properties,
to extend the tissue penetration range of therapies based on such as, for example, tunable light emission, high brightness, sta-
the use of high-energy light. Zhang et al.[370] and Chaterjee bility against photo-bleaching, and low toxicity.[379,380] Surface func-
and Yong[371] have proposed that UCNPs with surface-bound tionalization with, for instance, amino groups opens the way for
photosensitizers could be potentially used as nanotransducers grafting specific biomolecules and, consequently, to achieve active
for photodynamic therapy of cancer in deep tissues, a possi- targeting. Initial bioimaging results have shown that these NPs are
bility otherwise precluded by the poor tissue penetration of the readily taken up by murine cells, allowing for efficient staining.[381]
high-energy light required to form cytotoxic oxygen species. Nanocontainers based on zeolite L represent a novel class
Zhang et al.[370] produced silica-coated NaYF4:Yb/Er UCNPs of NMs that could be of potential use in cancer diagnosis and
with a photosensitizing molecule (Merocyanine 540, M-540) therapy because they can be heavily loaded with luminescent mol-
doped into the silica layer, and a mouse monoclonal antibody ecules, photosensitizer and/or radiometals without leakage after
(anti-MUC1/episialin) highly specific toward MCF-7/AZ breast locking with stopper moieties (Figure 15). Efficient functionaliza-
cancer cells covalently attached to the surface. In vitro tests tion of the zeolite surface can be achieved by direct coupling of
confirmed the photodynamic cytotoxicity of the M-540-coated appropriate molecules via silanol groups or, for example, using
UCNPs toward MCF-7/AZ cells. Chaterjee and Yong[371] pro- click chemistry, allowing for selective targeting of desired systems.
duced NaYF4:Yb/Er UCNPs modified with a zinc phthalo- The potential use of zeolite L nanomaterials for scintigraphic
cyanine photosensitizer, which targeted folate receptors on imaging (loaded with 111In) and PDT (grafted with phthalocy-
human colon cancer cells. As well as enabling tumors in rats anines) has been demonstrated.[382,383] Preliminary results suggest
to be imaged with high signal-to-background ratio, NIR excita- the possibility of developing zeolite L nanocontainers suitable for
tion of the particles after deep intramuscular injection led to detecting and curing neoplastic tissue. Lo and co-workers very
the release of singlet oxygen and significant cell destruction. recently described mesoporous silica nanoparticles (MSNPs) for
Austin and co-workers[372] have produced three-layer composite the controlled release of anticancer chemotherapeutics, which
NPs with an UCNP interior, a coating of porphyrin photosen- feature doxorubicin (Dox) conjugated to the MSNPs channels via
sitizer, and a biocompatible PEG outer layer to prevent clear- acid-labile hydrazone linkages. Upon exposure to the acidic envi-
ance by the RES. These generate millimolar amounts of singlet ronment of endosomes/lysosomes, Dox is released intracellularly,
oxygen under NIR radiation. resulting in efficient apoptotic cell death.[384]
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REVIEW
for the highly spatially and temporally controlled, photo-

triggered release of caged cancer therapeutics. The development
of such systems would enable higher drug doses to be used,
whilst reducing side-effects and systemic toxicity.
The application of different types of NPs in combination to
achieve improved therapeutic outcomes presents some further
exciting opportunities. Park et al. recently demonstrated that
gold nanorods could be used to improve the delivery of mag-
netic nanoworms or doxorubicin-loaded liposomes exhibiting
the peptide LyP1, which binds specifically to the p32 protein or
gC1qR receptor, overexpressed in tumor-associated cells under-
going stress.[387] Heating of the gold nanorods with NIR light
not only induced local tumor heating, but also accelerated the
accumulation of the targeted NPs, leading to faster rates of
drug delivery. Other combinations of NPs might similarly dis-
play synergistic effects that prove useful for cancer therapy.
Notwithstanding the significant advances made in the field
of NP-based cancer diagnostics and therapeutics, our overall
understanding of NP pharmacokinetics (adsorption, uptake, dis-
tribution, metabolism, and excretion) is quite limited at present.
Further in-depth exploration of the physicochemical and physi-
Figure 15. Representation of zeolite L loaded with fluorescent molecules ological processes that NPs are subjected to within biological
or radiometals. environments is required before the biodistribution of NPs can
be predicted from their physicochemical properties. Moreover,
careful studies need to be done on investigating and improving
5. Conclusion and Outlook
the safety profile of these systems before they will find exten-
The past decade has witnessed an explosion of interest in the sive application in the clinic. In this context, the role of protein-
use of NMs in oncology research because of their potential to nanoparticle interactions has recently been recognized as the key
revolutionize the way cancer is diagnosed and treated. Signifi- to nanomedicine and nanotoxicity.[388,389] A deep understanding
cant advances have been made in synthetic methodology, such of the biological effects of NPs thus requires knowledge of the
that it is now possible to prepare a variety of NPs with highly equilibrium and kinetic binding properties of proteins (and
controlled size, shape, surface charge and physicochemical other biomolecules such as lipids and polysaccharides) that
characteristics, and to decorate their surface with polymers and associate with the particles, and especially under competi-
bioactive molecules in order to improve biocompatibility and tive binding conditions, such as occur in vivo. Consequently,
achieve active targeting. As this review demonstrates, this has reliable methods have to be developed and introduced for the
facilitated the development of a diverse range of nanometer- characterization of the true risks of new NMs.[390]
sized objects that are able to recognize cancer tissue and enable Currently, there is an emerging rush to commercialize NMs for
visualization of tumors, delivery of anti-cancer drugs, and/or therapeutic purposes.[42,391,392] So far, Doxil,[393] a liposomal system
the destruction of tumors by different therapeutic techniques. for doxorubicin delivery and treatment of ovarian carcinoma, and
Future research will undoubtedly see the discovery and Abraxane,[393,394] an albumin-taxol NP for the treatment of meta-
exploration of new types of NM. Increasing attention will be static breast cancer, are the only two NPs that have achieved FDA
paid to the development of hybrid systems, incorporating approval for use in cancer therapy. That said, promising pre-clin-
multiple types of NMs (nanocomposites), since this will enable ical results have seen many NP systems moving rapidly to clinical
greater multifunctionality to be achieved. Recent research has, trials recently, including: i) CALAA-01, a cyclodextrin containing
for example, seen the emergence of silica nanostructures con- NP for siRNA delivery (phase I),[395,396] ii) INGN-401, a liposomal
taining both embedded QDs and magnetic NPs, enabling both formulation for metastatic, non-small cell lung cancer (phase
magnetic guidance and optical tracking.[385] Even more sophisti- I),[396] iii) SGT-53, a liposome for treatment of cancer tumors
cated designs will no doubt emerge over time. (phase I),[396] iv) Auroshell, gold NPs for solid tumors (phase I),[396]
There is considerable scope for further development of v) XMT-1001, a campothencin based prodrug (phase I),[396] and
stimulus-responsive nanoagents (smart nanoparticles) designed to vi) Aurimmune CYT-6091, a colloidal gold formulation for solid
enhance the localization and efficacy of therapeutic payloads, and tumors (phase II).[396] It is expected that there will be significant
new strategies for controlled drug release are continually being progress in improving our understanding of the structure–activity
proposed. For example, Carling et al.[386] very recently presented relationships for NPs in the coming years.
evidence that UCNPs can be employed for NIR-triggered release
of surface bound molecules. Previously, the release of caged mole-
cules, or photoconversion of inactive compounds to active forms,
has required direct excitation with high-energy light, limiting in Acknowledgements
vivo application. Although not yet demonstrated, it is foreseeable We gratefully acknowledge financial support in the form of a Go8/
that UCNPs might find future application as nanotransducers DAAD (German Academic Exchange Service (DAAD) grant. J.A.S. is the
www.advmat.de
REVIEW
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