Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/236078621
CITATIONS READS
17 101
6 AUTHORS, INCLUDING:
1072 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
Today impressive achievements have been made at the cross
Gil Gonalves graduated in
section of nanotechnology and biotechnology by employing
2003 in Industrial Chemistry at
carbon nanomaterials, where GO has been one of the most
University of Aveiro (Portugal)
promising nanoparticles proposed for these applications in the
and obtained a Master degree
last few years. Its unique morphology, surface chemistry and
in Materials Science (EMMS,
structure can be the key point for the development of new mul-
Joint European Masters
tifunctional materials for cancer therapy.
Programme) in 2008, his
The surface chemistry of GO is highly versatile, because the
thesis was based on polymers
presence of the oxygen functional groups allows the use of sev-
nanocomposites from renew-
eral functionalization approaches.[20,21] Acylation is among the
able resources. In 2012 he
most common approaches to promote covalent attachment of
received his PhD in Mechanical
molecular precursors to the GO surface.[2226] Regarding non-
Engineering at the University of
covalent functionalization, the most usual is the stacking
Aveiro with a thesis dedicated
and/or hydrophobic interactions with the aromatic structure
to nanocomposite materials for biomedical application. Now,
of GO.[2730] Functionalized GO with unique and specific con-
his research interests are dedicated to the development of
trolled properties has been used to build up biological plat-
new carbon nanoplatforms for multimodal cancer therapy.
forms, biosensors and biodevices.[3134]
The GO aromatic structure allows strong light absorption
ability in the near-infrared (NIR) range (700900 nm), which Mercedes Vila graduated
is commonly called therapeutic window[35] as it is a non-inva- in Physics at Universidad
sive, harmless and skin penetrating irradiation. This property is Autnoma de Madrid (Spain),
particularly attractive for the induction of cellular hyperthermia and received her PhD in
in tumour treatments as a minimally invasive alternative to sur- Materials Physics (2003,
gery (Photothermal therapy)[36]. Materials Science Institute of
Curiously, graphene showed interesting photoluminescent Madrid, CSIC). She performed 5
properties without any type of surface modification. Since gra- years of post-doctoral research
phene has no band gap, photoluminescence is not expected at Aveiro University (Portugal),
from relaxed charge carriers. However, Lui et al.[37] observed and since 2008 she is a Ramon
significant light emission from graphene under excitation by y Cajal researcher at the
ultrashort (30-fs) laser pulses, that was found to occur across Universidad Complutense de
the visible spectral range. Photoluminescence is also observed Madrid. Her research interests include the design, synthesis
in GO that can shift from red to blue emission depending on and application of bioceramic materials for bone tissue engi-
the degree of oxidation, that means dependence from the pro- neering and carbon based nanosystems for cancer therapies.
portion between sp2 and sp3 carbon atoms.[3840] The authors
suggest that this behaviour can be attributed to electron-hole
recombination from two different types of excited states. This Paula Marques is Assistant
unusual property could make graphene and GO potential Researcher at the University
imaging agents on biological systems. of Aveiro (UA) Portugal, being
Recent research studies showed that functionalized graphene the Scientific Coordinator of
and GO have enormous potential as sensors for early cancer the Nanotechnology Research
detection.[41] The low limit detection for proteins such as Cyclin Division of the Centre for
A2[42,43] or telomerase,[44] which are usually overexpressed in Technology and Automation
many types of cancers, allows to prognostic aggressiveness, sur- (TEMA) at this University. She
vival and chemotherapy response for the different types of cancer. graduated in Chemistry (UA,
Regarding the biocompatibility of graphene derivatives, the 1994), completed a masters in
in vitro[4548] and in vivo[46,49] studies developed so far are still in Physics and Chemistry Teaching
a preliminary stage. In vitro studies demonstrated that the gra- (UA, 1997) and a doctorate in
phene can induce the generation of reactive oxygen species in Materials Science Engineering (UA, 2003). Paulas main field
neural pheochromocytoma derived PC12 cells by time/concen- of research is dedicated to the engineering and development
tration dependence and also cause apoptosis for concentrations of new nanostructured materials. In particular, she is working
up to 10 g/mL.[45] In the case of GO, the induction of apop- on the preparation and study of graphene based nanocompos-
tosis was also observed in human fibroblasts for concentrations ites with applications in the biomaterials and biosensors area.
of 50 g/mL.[46] In human lung epithelial cells, GO doses over
50 g/mL showed no toxicity in vitro,[48] but higher GO con-
centrations cause a dose-dependent oxidative stress in these
cells and a slight loss of cell viability. In fact, most studies agree A few in vitro studies were already performed in order to
that GO promotes cytotoxicity mainly through generating reac- compare the biocompatibility between single wall carbon nano-
tive oxygen species (ROS) in a dose-dependent manner which tubes (SWCNT) and graphene. Agarwal et al. reported that
induces oxidative stress.[5052] SWCNT cause inhibition on cell proliferation (neuroendocrine
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1073
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
PC12 cells, oligodendroglia cells and osteoblasts) in contrast to system (RES), as well as transport from the bloodstream to
reduced GO.[53] Zhang et al. found higher lactate dehydroge- target cells within tissues.[57] At cellular level, the nanoparticles
nase levels for neural phaeochromocytoma-derived PC12 cells must cross the cell membrane and, in some cases, the nuclear
for SWCNT as compared to the graphene.[45] The results sug- membrane.
gest high dependence of the nanotopography, aspect ratio and An improved knowledge of the cancer biology, including
shape of carbon nanostructures.[45,53] Other parameters such cancer microenvironment, signalling pathways and evolution
as hydrophilic character,[54] dosage levels[46] and lateral dimen- of metastasis, has resulted in clear advances in cancer therapy.
sions[55] of graphene derivatives make a decisive contribution to However, due to the complexity of tumour progression, tumour
the assessment of biocompatibility. composition, blood vessel structures, and drug resistance
In vivo tests in mice model showed that, after intravenous mechanisms, most of the current therapies have provided lim-
administration, GO doses of 0.1 and 0.25 mg did not exhibit ited extension of survival time across multiple cancer types. The
toxicity. However, GO doses of 0.4 mg exhibited chronic tox- development of blood vessels is an essential step in the growth
icity. Carefully analysis showed that administration of high of a tumour. Without vessels, tumours cannot grow to be larger
doses of GO leads to the lung granuloma formation.[46] How- than a small fraction of an inch. When the area around the cells
ever, other studies showed no toxicity after three months of in a tumour starts to get too far from a blood vessel, the oxygen
injection of GO (20 mg/Kg) in this animal model.[56] Those and nutrient levels begin to go down. A decrease in oxygen is
results suggest that graphene derivatives have a multitude of also called hypoxia. Hypoxia triggers changes in the behaviour
chemical structures and morphologies, which requires long of the tumour cells which start producing (or cause nearby
term toxicity/biocompatibility (dose and specificity on different cells to produce) growth factors that stimulate the formation
tissues) studies in order to further validate these materials in of blood vessels. The tumour is able to overcome the diffusion
biomedical applications. limitation by increasing the surrounding vasculature, this event
The main propose of this review is to discuss the intrinsic is called angiogenesis. It results in abnormal blood and lym-
properties of nano-GO that makes this nanomaterial so prom- phatic networks and vascular barriers. The increased internal
ising for the development of new therapeutic agents for cancer pressure causes an outward convective interstitial fluid flow,
therapy. In fact, nano-GO shows enormous potentialities which decreases drug diffusion to the centre of the tumour.
derived from its simple chemical structure and morphology. However, drugs and nanoparticles that gain interstitial access
However, it is necessary to bear in mind the challenges that to the tumour have higher retention times than in normal tis-
arise when trying to develop a material for therapeutic applica- sues. This is called enhanced permeability and retention effect
tions in humans. Herein, important biological details and syn- (EPR).
thesis approaches are reviewed in order to summarize the key From the biological point of view tumours can be structurally
concepts for developing new engineered nano-GO that could divided in three different regions: periphery, seminecrotic and
act efficiently and effectively in the detection and treatment of necrotic core, each one with metabolically compromised micro-
tumours. environment (Figure 1a).[58] The unstable state of tumours can
be attributed to accumulated solid stress,[59,60] abnormal blood
vessel networks,[6163] elevated fluid pressure,[64,65] and a dense
2. Fundamental Concepts on Nanoparticle interstitial structure.[66,67]
The transport barriers to drug delivery arise from those
Cancer Therapy
abnormal characteristics of the tumour microenvironment.
The clinical application of nanoparticles has the potential to Actually, several nanoparticles were already designed to take
make paradigm-changing impacts on the detection, treatment, advantage of the EPR effect;[68,69] the concept is referred to as
and prevention of cancer. The design of nanoparticles repre- passive targeting, however this effect just starts to be observed
sents a new hope in the development of new therapeutic agents on tumours with volume higher than 2 mm3.[70] Three impor-
for cancer treatment. Here, we discuss the most relevant phys- tant pharmacokinetic steps govern the diffusion of nanoparti-
icochemical properties of nanoparticle platforms that make cles into tumours cells (Figure 1b and c).[71] Overall, the nan-
them effective in their interaction with biological structures. A oparticle internalization on the tumour is low and heteroge-
discussion of the basic biological structure of tumours, as well neous relatively to the different tumour regions, where a high
as the relevant properties of nanoparticles on cancer therapy retention rate is usually observed on the peritumor tissue.
will be discussed in this section. These fundamental concepts Besides the treatment of the primary tumour, one of the
are of extreme relevance to understand the factors which give most challenging facets in cancer therapy is the early detection
nano-GO huge potential as a nanoparticle for cancer therapy. and treatment of metastasis and secondary tumours. Cancer
metastasis consists on the spread of cancer cells from the pri-
mary tumour on affected organ to the blood stream leading to
2.1. Cancer Biology the formation of secondary tumours on other receptor organs
(Figure 2). Indeed, the rate of survival is high (> 90%) when
Engineering new nanoparticles for cancer therapy must take cancer is limited to one organ whereas there is only 20%
into account strategies to overcome the biological barriers, from 5-years survival rate when cancer cells metastasize.[72]
the mode of administration (inhalation, oral, intravenous etc) The therapy of metastatic cells remains a challenge. Nev-
to the organ and cellular level. Critical issues include rapid ertheless metastatic cells have the particularity of always
filtration in the kidney and clearance via reticulo-endothelial expressing a specific endogenous surface protein.[72] To take
1074 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
of nanoparticles varies from drug delivery
systems, imaging agents to theranostics
(combination of therapeutics and diagnosis).
The nanoparticle systems based on inor-
ganic structures that are approved for cancer
therapy are very few and composed of
superparamagnetic iron oxide nanoparticles
coated with dextran or carboxydextran for
bioimaging agents (ferumoxides and ferucar-
botran).[86] A few other nanoparticles based
on inorganic structures are under clinical
trials like gold nanoparticles (CYT-6091,
Aurimmune), quantum dots (Bioconjugated
nanoparticles) and iron oxide nanoparticles
(Combidex, Ferumoxtran-10).[87] In fact, inor-
ganic nanoparticles offer great potential for
future clinical applications in imaging, diag-
nosis and therapeutics of cancer, however,
their possible toxicity and accumulation on
cells and organs could be some important
limitations to their use.[88]
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1075
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
Figure 3. Time line of clinical stage nanomedicine. Liposomes, controlled release polymeric systems for macromolecules, dendrimers, targeted-
PEGylated liposomes, first FDA approved liposome (DOXIL), long circulating poly(lactic-co-glycolic acid)-polyethyleneglycol (PLGA-PEG) nanoparti-
cles, iron oxide MRI contrast agent nanoparticles (Ferumoxide), protein based drug delivery system (Abraxane; nab technologyt), polymeric micelle
nanoparticles (Genexol-PM),targeted cyclodextrin-polymer hybrid nanoparticles (CALAA-01), targeted polymeric nanoparticles (BIND-014; Accurint
Technology), fully integrated polymeric nanoparticle vaccines (SEL-068, tSVPt Technology) Reproduced with permission.[84] Copyright 2012, Royal
Society of Chemistry.
1076 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
Current methods to increase the circulation time of nanopar-
ticles have focused almost exclusively on reducing the opsonisa-
tion process, by rendering the particle surface more hydrophilic
or by reducing the surface charge. The surface of nanoparticles
can be tailored with polymers that increase the circulation half-
time. Polyethylene glycol (PEG) has been the most widely used
polymer so far for this application because it can enhance the
solubility and plasma stability of proteins and reduce immuno-
genicity.[100,114] Moreover, the PEG chemical structure effects on
cell uptake was also assessed by comparing internalization of a
branched PEG ligand to the PEG linear version, and it has been
found that the linear version is internalized in a greater propor-
tion than the branched one.[115]
Several multifunctional systems have been developed based
on the surface manipulation of nanoparticles providing new tools
for the diagnosis and treatment of cancer disease. The ability to
tailor the nanoparticle surface with conjugated fluorescent units
makes these materials excellent candidates for cell sensing.[116]
Figure 4. Physical and chemical properties of the nanoparticles that Using this sensor array, it was possible to obtain highly repro-
affect their performance, both in vitro and in vivo. The 3Ss factor (size, ducible characteristic patterns from different cell types enabling
shape and surface chemistry) governs the interaction of nanoparticles the identification of cell types and cancer states.[116,117] Cur-
with biological structures. rent trends in nanomedicine involve incorporation of targeting
moieties that are highly specific for receptors overexpressed in
highly dependent on nanoparticle geometry and on the biodis- tumoural cells (e.g., folic acid, proteins and antibodies).[104,118]
tribution in vivo on the diverse organs and tumours.[107,108] In
fact, the shape of nanoparticles also affects the circulation time
on bloodstream, for example, Geng et al.[81] observed that the 2.4. Design Nanoparticles for Cancer Therapy
filomicelles persisted in the circulation ten times longer than
the spherical micelles. The nanoparticles must be designed for the intended function:
Theoretical studies using mathematical modelling with in recognition, imaging, or treatment of cancer cells. To design
vitro and in vivo experimental data, allowed the optimization new nanoparticles for cancer therapy it is necessary to clearly
of mesoporous silica particles parameters for example specific identify what are the expected different levels of action and
geometries and sizes to maximize localization within tumour subsequently to define which chemical structures will be neces-
vasculate while minimizing RES uptake.[109] Design maps sary to achieve the predetermined objectives. This is part of a
have been generated to be used as a preliminary reference for multidisciplinary group of intervenients (Figure 5).[119] After the
choosing the properties of the nanoparticle as a function of
physiological parameters, such as the wall shear stress and the
receptors surface density, at the site of desired adhesion within
the target vasculature.
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1077
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
correct definition of the role to be played by the nanoparticles 3. Key Points of Nano-GO on Cancer Therapy
in the human body it is possible to consider the different syn-
Nano-GO is obtained after exfoliation of graphite in a strong
thesis mechanism and chemical structures. There are some
oxidant medium, followed by ultrasonication.[125] Nano-GO is
authors that call this area of knowledge of nanomedicine as
simply defined as a plane of carbon atoms in hexagonal struc-
Nano-oncology.[119]
ture with carboxylic and carbonyl groups on the edges and
Historically, the evolution of nanoparticle design can be
hydroxyl and epoxy groups in the basal planes. It holds a great
divided in three different generations.[89] The first genera-
potential for bio-engineering as nanoparticle vector, since its
tion of nanoparticles was based on basic surface chemistry
oxidized state provides negative surface charge and reactive
studies, only concerned with biocompatibility and toxicity.
sites for functionalization.[31]
The second generation of nanoparticles consisted on the opti-
One of the key parameters that makes nano-GO one of the
mization of the surface chemistry in order to increase the
most interesting materials for biological applications is its high
biological stability and targeting specific biological locations.
aspect ratio. The 2D structure of carbon atoms with dimensions
The third generation was described as nanoparticles that can
below 100 nm and atomic thickness, allows obtaining high
respond to biological (pH, oxidant medium, etc.) or external
values of specific surface area (Figure 7). This property is very
stimuli (temperature, light, etc.) in order to target and deliver
important because it allows a high rate of functionalization and
on the specific locations and improve the biological efficiency
maximizes the interaction with biological systems. In fact, the
(Figure 6).
planar and flexible structure of nano-GO, is also an additional
Conventional methods of preparing multifunctional nano-
factor that makes graphene a high-potential material for the
particles involve a series of chemical processes whereby the
interaction with biological structures.
nanoparticles core is initially formed, followed by the function-
As discussed in the previous sections, the 3Ss factor of the
alization of ligands (drugs, imaging agents, DNA, etc.) to the
therapeutic nanoparticles plays a crucial role in tumoural tissue
surface of the nanoparticles (Figure 6). These ligands can be,
extravasation and interstitial transport. Studies have shown
for example, small molecule drugs like Doxorubicin (DOX),
that macromolecules with linear, semi-flexible configurations
hydroxycamptothecin (HCPT), Paditaxel (PTX), Cisplatin, Car-
boplatin, Irinotecan, Gefitnib.
Strategies for delivering nanoparticles to cancerous tissue
have been focused on passive and active targeting.[120] As
has been explained before, the passive targeting approach on
cancer therapy is based on the non-selective process of EPR,
which allows the higher accumulation of macromolecules
in tumoural tissues than in normal tissues. Active targeting
approaches are based on recent methods of targeting the
nanoparticles, which consist of the surface functionalization
of nanoparticles with specific ligands that are highly selective
in binding to specific receptors that are overexpressed on the
surface of cancer cells (Figure 6).[121123] A few examples of
molecular targeting used to recognise specific types of cells Figure 7. 2D structure of nano-GO with lateral dimensions below 100 nm
and increase the biodistribution are: small molecules (biotin and atomic thickness.
1078 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
like nano-GO, diffuse more efficiently in the interstitial matrix These approaches have already been explored with carbon
than do comparable sized, rigid spherical particles.[126] Yue et nanotubes: both single- (SWCNTs) and multi-walled
al. studied the role of the lateral dimension of GO in the regu- (MWCNTs) carbon nanotubes. However, some limitations on
lation of cellular responses showing that, in comparison with the control of the synthesis parameters, such as the presence
nanosized GO, micro-sized GO showed divergent intracellular of metallic impurities and homogeneous size and length dis-
locations and induced much stronger inflammation response tributions, demonstrated some ambiguity in studies of possible
in six cell types.[55] toxic effects.[142] In addition, their morphology, similar to that
Nano-GO acts as the next generation of carbon materials of asbestos, which is known to exhibit deleterious effects with
intended to be used as anticancer therapeutic agents. One the induction of mesothelioma,[143] has limited their potential
important aspect of nano-GO, which derives from its aromatic biological applications.
chemical structure, is the strong optical absorbance in NIR Non-targeted nano-GO can be of particular interest for
(therapeutic window, 700900 nm range) that makes it an excel- the treatment of primary tumours by taking advantage of the
lent candidate for tumour cells ablation by photothermal treat- enhanced permeability and retention effect.[68] However, one
ment (Hyperthermia).[36,127129] Acik et al. described a strong of the biggest challenges in the cancer therapy context is the
infrared-absorption of reduced GO at 800 cm1 due to the combat of metastatic cells, because they can spread in the
oxygen edge.[130] This new phenomenon opens the door to tai- bloodstream or be mixed with healthy cells developing sec-
loring giant infrared absorption at different spectral positions ondary tumours. Nevertheless, as has been already mentioned,
by modifying the nature of the edge termination. metastatic cells have the particularity of expressing always a
Moreover, the upconversion fluorescence property of nano- specific endogenous surface protein.[72] Taking advantage of this
GO allows them to be excited in the NIR region without inter- feature, the non-targeted nano-GO could be further improved
ference auto-fluorescence from tissues, making bio-detection by tailoring its surface with specific target ligands, like peptides
and bio-imaging efficient.[131136] or antibody conjugates. Those targeted nanomaterials can be
The photoluminescence of nano-GO is becoming a subject used to detect, visualize, and destroy cancer cells with minimal
of research for optical bioimaging.[137] It has been demonstrated side effects on normal cells and monitoring treatment effects
that strong photoluminescence from two-photon excitation can in real time (Figure 8).[144,145] Nano-GO has been also proposed
be induced in nano-GO by an ultrafast pulsed laser.[138] Peng as a drug delivery vehicle for anti-cancer drugs[145149] or bio-
et al. demonstrated that the photoluminescence of the nano-GO imaging agents with many molecular imaging techniques,
can be tailored through varying the size of the nano-sheets.[139] including magnetic resonance imaging (MRI), optical, photoa-
The application of this technique to cancer cell imaging has coustic and radionuclide-based imaging (Figure 8).[150153]
already been investigated with different types of cells, gastric All the referred characteristics of nano-GO highlight its
cancer cell line (AGS),[140] BT549 breast cancer cells line[141] and potential and point out the importance of further exploring
MG-63 human osteosarcoma cell line[135]. Photoluminescence this nanomaterial in the emerging area of nanomedicine. This
of nano-GO was also investigated along with the potential appli- review focuses on the engineering of multifunctional nano-
cation on photothermal cancer cell therapy. Li et al. observed GO platforms able to respond to particular demands in cancer
that intensive microbubbling can be induced by irradiation at therapy.
a laser power lower than 4 mW in the presence of nano-GO,
which causes instant cell damage.[140]
The nano-GO aromatic molecular structure and the richness 4. Developments on Nano-GO Platforms
of its surface functional groups allow functionalization with
for Cancer Therapy
small molecules or biostructures to build-up new hybrid systems
that can perform in all stages of the cancer therapy: recognition The nano-GO potentialities have been explored by several
imaging, and treatment of cancer cells (Figure 8). The chemical research groups worldwide with the hope of finding realistic
versatility of nano-GO is, surely, a key point for the combina- procedures to fight one of the most dramatic diseases. In this
tion of several diagnosis and therapy techniques on the same section the recent approaches developed on nano-GO based
system, usually defined as a multifunctional nano-platform. systems as therapeutic agents on cancer are reviewed.
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1079
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
1080 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
this strategy can be used with other types of
insoluble drug molecules including CPT ana-
logues and Iressa (geftinib) to increase the
effects of chemotherapy. Dong et al. inves-
tigated the potentialities of nano-GO-PEG
system on the delivery of Zinc phthalocyanine
(photosensitizer for photodynamic therapy)
towards MCF-7 carcinoma cell line.[164] The
results showed a drug loading efficiency
up to 14 wt% and high phototoxicity under
Xe light irradiation. Wen et al. developed a
new nano-GO disulfide-linked PEG system
for DOX delivery that is able to respond to
redox environments by detachment of PEG
chains.[165] In vitro studies with HeLa cells
showed after internalization that DOX is 1.55
times effectively released by nano-GO dis-
sulfide linked PEG then nano-GO-PEG sys-
tems. They believe that the incorporation of
stable PEG shell on nano-GO/DOX system
can create a diffusion barrier that decreases
the drug release. Dembereldorj et al. inves-
tigated both in vitro and in vivo glutathione-
triggered DOX realease in real time from
nano-GO-PEG platform.[166] In vitro studies
on A549 cells demonstrated a drug delivery
efficiency of 23.5 wt% from nano-GO-PEG
platforms after treatment with 2 mM glu-
tathione within 15 min. They also observed
Figure 10. Morphology evaluation by confocal microscopy of cultured human Saos-2 osteo- an increase of 2.5 times in vitro drug release
blasts after 1 day treatment with GOs. Cells were stained with DAPI (A) for the visualiza- on cells by externally triggering glutathione
tion of the cell nuclei in blue, Rhodamine phalloidin (B) for the visualization of cytoplasmic ethyl ester rather than endogeneous glu-
F-actin filaments in red and FITC-GOs for the visualization of GOs in green (C). Figure 10D
tathione. In vivo studies demonstrated the
shows the whole composition with the three stainings revealing that FITC-GOs colocalizes with
rhodamine phalloidin resulting in yellow/orange coloration. Reproduced with permission.[161] possibility to monitor the real-time release
Copyright 2013, Elsevier. of DOX by fluorescence images after an
external trigger with glutathione.
colon cancer cell line) killing when compared with irinotecan these different atoms were investigated with serial noninvasive
(CPT-11), a FDA approved water soluble SN38 prodrug used positron emission tomography imaging and biodistribution,
for the treatment of colon cancer. The authors postulate that showing very promising results during the in vitro or in vivo
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1081
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
1082 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
Figure 12. In vivo PET/CT imaging of 66 Ga-labeled GO conjugates in 4T1 tumour-bearing mice. (A) Serial coronal PET images of 4T1 tumour-bearing
mice at different time points post-injection of 66Ga-NOTA-GO-TRC105, 66Ga-NOTA-GO, or 66Ga-NOTA-GO-TRC105 at 2 h after a blocking dose of
TRC105 (denoted as blocking). (B) Representative PET/CT images of 66Ga-NOTA-GO-TRC105 in 4T1 tumour-bearing mice at 3 h post-injection.
Tumours are indicated by arrowheads. In vivo PET/CT imaging of 64Cu-labeled GO conjugates in 4T1 murine breast tumour-bearing mice. (a) Serial
coronal PET images of 4T1 tumour-bearing mice at different time points postinjection of 64Cu-NOTA-GO-TRC105, 64Cu-NOTA-GO, or 64Cu-NOTA-
GO-TRC105 after a preinjected blocking dose of TRC105. (b) RepresentativePET/CT images of 64Cu-NOTA-GO-TRC105 in 4T1 tumour-bearing mice at
16 h postinjection. (A) and (B) reproduced with permission.[167] Copyright 2012, American Chemical Society. (a) and (b) reproduced with permission.
Copyright[168] 2012, Elsevier.
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1083
www.advhealthmat.de
www.MaterialsViews.com
1084 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
Photodynamic therapy (PDT) has emerged as an alternative combination with nano-GO, thereby developing materials for
and promising non-invasive treatment for different types of cancer therapy with high performance. Yang et al. described
cancer, which involves the uptake of photosensitizers (PSs) by one of the first attempts to build up a multifunctional nano-GO
cancer cells followed by irradiation. One of the photosensitizer platform with Fe3O4, further loaded with DOX.[186] These hybrid
molecules most used is Chlorin e6 (Ce6), due to its capacity materials showed interesting magnetic properties and pH-trig-
to generate cytotoxic singlet oxygen when exposed under light gered controlled magnetic behaviour that makes them a prom-
excitation. However the lower solubility on biological fluids ising candidate for controlled targeted drug delivery. Recently
remains a problem. The combination of the photosensitizer they further developed a nano-GO platform by including a tar-
Ce6 with GO nanocarriers previously modified with targeting geting molecule of FA.[187] In vitro studies showed an increase
molecule FA, can be achieved by simple non-covalent interac- of the specificity of nanoplatforms to SK3 cells and high toxicity
tions (hydrophobic and stacking).[181] The resultant system to Hela cells. Gollavelli et al.[188] developed a nano-GO platform
can efficiently deliver Ce6 to the tumour due to high affinity with in situ growth of iron oxide nanoparticles by microwave
of the targeting molecules to MGC803 cells and can increase functionalized with polyacrylic acid (PAA) bridge for linking
the photodynamic efficiency upon irradiation. Tian et al.[182] the fluorescein o-methacrylate (FMA), to increase the hydro-
observed that the combination of GO with Ce6 can result in a philic behaviour and add fluorescent property. In vitro studies
controlled drug delivery system. They used the photothermal with HeLa cells showed that nanoplatforms locate only in the
effect of GO to deliver Ce6 molecules in specific locations, in an cytoplasm and evidence low cytotoxic effects.
efficient way, enhancing the PDT against cancer cells. Another important application of nano-GO platforms with
iron oxide nanoparticles is for cellular magnetic resonance
4.4.2. Hybrid nano-GO platforms imaging (MRI). Chen et al.[189] performed the surface modifi-
cation of GO with iron oxide nanoparticles by using a spacer
Inorganic nanoparticles have received increased attention in agent 1-ethyl-3(3-dimethylaminopropyl) carbodiimide. The
the last few years due to their high potential for diagnostic and nanocomposite materials showed a good physiological stability,
therapeutic systems in the oncologic area. They have demon- low toxicity and good internalization on HeLa cells. In addition,
strated a clear potential in wideranging fields of cancer therapy imaging studies demonstrated significant enhance of cellular
such as tumour targeting, imaging, hyperthermia therapy and MRI when compared with iron oxide nanoparticles alone.
drug delivery.[87,183] Indeed, iron oxide[184] and gold[185] nanopar- A truely multifunctional nano-GO platform with iron oxide
ticles are the ones most highlighted in the various approaches nanoparticles was recently developed and was explored in all
for the treatment of cancer due to their intrinsic properties. its potential. Yang et al.[190] assembled a new nano-GO hybrid
Several organic/inorganic hybrid materials based on these material based on the surface modification of GO with iron
kinds of nanoparticles are already in preclinical stages or even oxide nanoparticles and posterior noncovalent functionaliza-
in marketing.[83] tion with PEG that resulted in a nanoplatform with excellent
In view of the success achieved by these nanoparticles, some physiological stability, strong NIR optical absorbance and
authors have tried to obtain synergistic effects through their superparamagnetic properties that has been used as a thera-
nostic agent for in vivo triple modal imaging
(flurescence, photoacoustic and magnetic
resonance) and effective photothermal abla-
tion.[190] The results showed high efficiency
tumour imaging in vivo of the nano-GO plat-
form using external radioactive or fluores-
cent labels and intrinsic optical and magnetic
properties and triple-modal fluorescence/
MR/PAT due to the high passive tumour
accumulation (Figure 15). The photothermal
in vivo treatment showed an efficient tumour
ablation at low laser power density. Both in
vivo and in vitro toxicity studies did not show
evidence of cross effects under the level of
experimental conditions.
Nano-GO modified with gold nanoparticles
can also be an interesting multifunctional
Figure 15. Blood circulation, biodistribution and multimodal imaging. a) The blood circula- nanoplatform for the cancer imaging and
tion of 125 I-RGOIONPPEG. The pharmacokinetics of RGOIONPPEG followed the two- therapy, however at the moment the potenti-
compartment model. b) Biodistribution of 125 I-RGOIONPPEG in 4T1 tumour-bearing ality of these materials is not fully explored.
mice. High tumour uptake of RGOIONPPEG was observed. ce) Multimodal imaging of Wang et al.[191] performed the surface modi-
4T1 tumour-bearing mice after intravenous injection of RGOIONPPEG: c) Fluorescence
imaging using Cy5 labeled RGOIONPPEG; d,e) T2-weigted MR imaging (d) and photoa-
fication of GO by electrostatic interactions
coustic imaging (e) using RGOIONPPEG. All the images showed that RGOIONPPEG with dodecanethiol-CTAB-capped gold nano-
could passively accumulate in the tumour after intravenous injection. Error bars in (a,b) were particles with RGO subsequently loaded with
based on four mice per group. Reproduced with permission.[190] DOX. In vitro results showed that these new
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1085
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
1086 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
of smart materials for the development of intelligent nano- [9] B. Dlubak, M.-B. Martin, C. Deranlot, B. Servet, S. Xavier,
systems that can improve the targeting efficiency and therapy R. Mattana, M. Sprinkle, C. Berger, W. A. De Heer, F. Petroff,
efficacy through biological or external stimuli-responses. A. Anane, P. Seneor, A. Fert, Nat. Phys. 2012, 8, 557.
The works described in this review effectively demonstrate [10] G. M. Rutter, J. N. Crain, N. P. Guisinger, T. Li, P. N. First,
J. A. Stroscio, Science 2007, 317, 219.
that multifunctional nano-GO platforms can combine high
[11] A. Ouerghi, M. G. Silly, M. Marangolo, C. Mathieu, M. Eddrief,
targeting efficiency, good imaging contrast and extraordinary M. Picher, F. Sirotti, S. El Moussaoui, R. Belkhou, ACS Nano 2012,
therapy efficacy for cancer cells and tumours. In fact, it has 6, 6075.
been shown that the use of nano-GO as a drug delivery carrier [12] S. Park, R. S. Ruoff, Nat. Nanotechnol. 2009, 4, 217.
may be useful to deliver very efficient drugs, which have pre- [13] S. Stankovich, D. A. Dikin, R. D. Piner, K. A. Kohlhaas,
viously failed due to solubility issues, in a targeted molecular A. Kleinhammes, Y. Jia, Y. Wu, S. T. Nguyen, R. S. Ruoff, Carbon
form. This fact would open the door to completely new treat- 2007, 45, 1558.
ment options. [14] C. Gomez-Navarro, J. C. Meyer, R. S. Sundaram, A. Chuvilin,
The future research work in nano-GO field requires a deep S. Kurasch, M. Burghard, K. Kern, U. Kaiser, Nano Lett. 2010, 10,
understanding of the interaction between cells and nano-GO 1144.
[15] X. Huang, Z. Y. Yin, S. X. Wu, X. Y. Qi, Q. Y. He, Q. C. Zhang,
as well as an integration of the immunological, metabolic and
Q. Y. Yan, F. Boey, H. Zhang, Small 2011, 7, 1876.
pharmacological processes to provide insight into how cells [16] S. Pan, I. A. Aksay, ACS Nano 2011, 5, 4073.
respond to nano-GO. Thus, it has become necessary to iden- [17] M. Mermoux, Y. Chabre, A. Rousseau, Carbon 1991, 29, 469.
tify a map of potential toxicities for each material, including [18] T. Szabo, O. Berkesi, P. Forgo, K. Josepovits, Y. Sanakis, D. Petridis,
relevant physiology, biodistribution, movement of materials I. Dekany, Chem. Mater. 2006, 18, 2740.
through tissues, phagocytosis, opsomization and endocytosis [19] T. Szabo, E. Tombacz, E. Illes, I. Dekany, Carbon 2006, 44, 537.
and establish a risk/benefit considerations for every system. [20] D. R. Dreyer, S. Park, C. W. Bielawski, R. S. Ruoff, Chem. Soc. Rev.
To sum up, there is currently no definitive conclusion that 2010, 39, 228.
can be made regarding the potentialities or risks of nano-GO [21] K. P. Loh, Q. Bao, P. K. Ang, J. Yang, J. Mater. Chem. 2010, 20,
systems. In fact, while there are still many opportunities pre- 2277.
[22] S. Stankovich, R. D. Piner, S. T. Nguyen, R. S. Ruoff, Carbon 2006,
sented by nano-GO in the development of multifunctional
44, 3342.
platforms for cancer therapy, it is also very highly important [23] S. Niyogi, E. Bekyarova, M. E. Itkis, J. L. McWilliams, M. A. Hamon,
to assimilate knowledge about nano-GO interaction with bio- R. C. Haddon, J. Am. Chem. Soc. 2006, 128, 7720.
logical tissues: normal or carcinogenic. Overall, an improved [24] N. Karousis, S. P. Economopoulos, E. Sarantopoulou,
specificity to tumours and cancer cells leading to an increase N. Tagmatarchis, Carbon 2010, 48, 854.
of success rate of treatments, and a decrease in the number of [25] X. Zhang, Y. Huang, Y. Wang, Y. Ma, Z. Liu, Y. Chen, Carbon 2009,
operations or the risk of postoperative intervention, is expected 47, 334.
from the design of nano-GO therapeutic agents. This would [26] G. Goncalves, P. A. A. P. Marques, A. Barros-Timmons, I. Bdkin,
allow shorter recovery times and a diminution of side effects M. K. Singh, N. Emami, J. Gracio, J. Mater. Chem. 2010, 20, 9927.
for patients. In general, the ultimate goal of nano-GO research [27] A. J. Patil, J. L. Vickery, T. B. Scott, S. Mann, Adv. Mater. 2009, 21, 3159.
[28] C.-H. Lu, H.-H. Yang, C.-L. Zhu, X. Chen, G.-N. Chen, Angew.
as a therapeutic agent in cancer therapy will be the improve-
Chem.-Int. Edit. 2009, 48, 4785.
ment of life quality, life expectancies and a reduction in the [29] P. Laaksonen, M. Kainlauri, T. Laaksonen, A. Shchepetov, H. Jiang,
global cost of treatments of oncologic patients. J. Ahopelto, M. B. Linder, Angew. Chem.-Int. Edit. 2010, 49, 4946.
[30] E. Morales-Narvaez, A. Merkoci, Adv. Mater. 2012, 24, 3298.
Received: January 18, 2013
[31] Y. Wang, Z. Li, J. Wang, J. Li, Y. Lin, Trends Biotechnol. 2011, 29,
Published online: March 22, 2013
205.
[32] H. Shen, L. Zhang, M. Liu, Z. Zhang, Theranostics 2012, 2, 283.
[33] Y. Zhang, T. R. Nayak, H. Hong, W. Cai, Nanoscale 2012, 4, 3833.
[34] K. Yang, L. Feng, X. Shi, Z. Liu, Chem. Soc. Rev. 2013, 42, 530.
[1] Y. Zhu, S. Murali, W. Cai, X. Li, J. W. Suk, J. R. Potts, R. S. Ruoff, [35] R. Weissleder, Nat. Biotechnol. 2001, 19, 316.
Adv. Mater. 2010, 22, 3906. [36] Z. M. Markovic, L. M. Harhaji-Trajkovic, B. M. Todorovic-Markovic,
[2] K. S. Kim, Y. Zhao, H. Jang, S. Y. Lee, J. M. Kim, K. S. Kim, D. P. Kepic, K. M. Arsikin, S. P. Jovanovic, A. C. Pantovic,
J.-H. Ahn, P. Kim, J.-Y. Choi, B. H. Hong, Nature 2009, 457, 706. M. D. Dramicanin, V. S. Trajkovic, Biomaterials 2011, 32, 1121.
[3] A. Reina, X. Jia, J. Ho, D. Nezich, H. Son, V. Bulovic, [37] C. H. Lui, K. F. Mak, J. Shan, T. F. Heinz, Phys. Rev. Lett. 2010, 105.
M. S. Dresselhaus, J. Kong, Nano Lett. 2009, 9, 30. [38] C. T. Chien, S. S. Li, W. J. Lai, Y. C. Yeh, H. A. Chen, I. S. Chen,
[4] X. Li, W. Cai, J. An, S. Kim, J. Nah, D. Yang, R. Piner, L. C. Chen, K. H. Chen, T. Nemoto, S. Isoda, M. W. Chen, T. Fujita,
A. Velamakanni, I. Jung, E. Tutuc, S. K. Banerjee, L. Colombo, G. Eda, H. Yamaguchi, M. Chhowalla, C. W. Chen, Angew. Chem.-
R. S. Ruoff, Science 2009, 324, 1312. Int. Edit. 2012, 51, 6662.
[5] S. J. Chae, F. Guenes, K. K. Kim, E. S. Kim, G. H. Han, S. M. Kim, [39] G. Xin, Y. Meng, Y. Ma, D. Ho, N. Kim, S. M. Cho, H. Chae, Mater.
H.-J. Shin, S.-M. Yoon, J.-Y. Choi, M. H. Park, C. W. Yang, D. Pribat, Lett. 2012, 74, 71.
Y. H. Lee, Adv. Mater. 2009, 21, 2328. [40] K. Krishnamoorthy, M. Veerapandian, R. Mohan, S.-J. Kim, Appl.
[6] K. S. Subrahmanyam, L. S. Panchakarla, A. Govindaraj, Phys. A-Mater. 2012, 106, 501.
C. N. R. Rao, J. Phys. Chem. C 2009, 113, 4257. [41] L. Feng, L. Wu, X. Qu, Adv. Mater. 2013, 25, 168.
[7] I. Levchenko, O. Volotskova, A. Shashurin, Y. Raitses, K. Ostrikov, [42] L. Feng, L. Wu, J. Wang, J. Ren, D. Miyoshi, N. Sugimoto, X. Qu,
M. Keidar, Carbon 2010, 48, 4570. Adv. Mater. 2012, 24, 125.
[8] O. Volotskova, I. Levchenko, A. Shashurin, Y. Raitses, K. Ostrikov, [43] X. Wang, C. Wang, K. Qu, Y. Song, J. Ren, D. Miyoshi,
M. Keidar, Nanoscale 2010, 2, 2281. N. Sugimoto, X. Qu, Adv. Funct. Mater. 2010, 20, 3967.
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1087
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
[44] L. Wu, J. Wang, L. Feng, J. Ren, W. Wei, X. Qu, Adv. Mater. 2012, 24, [77] M. A. Cheever, J. P. Allison, A. S. Ferris, O. J. Finn, B. M. Hastings,
2447. T. T. Hecht, I. Mellman, S. A. Prindiville, J. L. Viner, L. M. Weiner,
[45] Y. Zhang, S. F. Ali, E. Dervishi, Y. Xu, Z. Li, D. Casciano, A. S. Biris, L. M. Matrisian, Clin. Cancer Res. 2009, 15, 5323.
ACS Nano 2010, 4, 3181. [78] L. Brannon-Peppas, J. O. Blanchette, Adv. Drug Delivery Rev. 2004,
[46] K. Wang, J. Ruan, H. Song, J. Zhang, Y. Wo, S. Guo, D. Cui, 56, 1649.
Nanoscale Res. Lett. 2011, 6. [79] K. E. Scarberry, E. B. Dickerson, Z. J. Zhang, B. B. Benigno,
[47] S.-R. Ryoo, Y.-K. Kim, M.-H. Kim, D.-H. Min, ACS Nano 2010, 4, J. F. McDonald, Nanomed-Nanotechnol. 2010, 6, 399.
6587. [80] E. I. Galanzha, E. V. Shashkov, T. Kelly, J. W. Kim, L. L. Yang,
[48] Y. Chang, S.-T. Yang, J.-H. Liu, E. Dong, Y. Wang, A. Cao, Y. Liu, V. P. Zharov, Nat. Nanotechnol. 2009, 4, 855.
H. Wang, Toxicol. Lett. 2011, 200, 201. [81] Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko,
[49] X. Zhang, J. Yin, C. Peng, W. Hu, Z. Zhu, W. Li, C. Fan, Q. Huang, D. E. Discher, Nat. Nanotechnol. 2007, 2, 249.
Carbon 2011, 49, 986. [82] L. Zhang, F. X. Gu, J. M. Chan, A. Z. Wang, R. S. Langer,
[50] G. Gollavelli, Y.-C. Ling, Biomaterials 2012, 33, 2532. O. C. Farokhzad, Clin Pharmacol Ther 2008, 83, 761.
[51] X. Liu, S. Sen, J. Liu, I. Kulaots, D. Geohegan, A. Kane, [83] R. Duncan, R. Gaspar, Mol. Pharm. 2011, 8, 2101.
A. A. Puretzky, C. M. Rouleau, K. L. More, G. T. R. Palmore, [84] N. Kamaly, Z. Xiao, P. M. Valencia, A. F. Radovic-Moreno,
R. H. Hurt, Small 2011, 7, 2775. O. C. Farokhzad, Chem. Soc. Rev. 2012, 41, 2971.
[52] W. Hu, C. Peng, M. Lv, X. Li, Y. Zhang, N. Chen, C. Fan, Q. Huang, [85] K. J. Cho, X. Wang, S. M. Nie, Z. Chen, D. M. Shin, Clin. Cancer
ACS Nano 2011, 5, 3693. Res. 2008, 14, 1310.
[53] S. Agarwal, X. Zhou, F. Ye, Q. He, G. C. K. Chen, J. Soo, F. Boey, [86] Y.-X. Wang, Quant Imaging Med Surg 2011, 1, 35.
H. Zhang, P. Chen, Langmuir 2010, 26, 2244. [87] S. Bhattacharyya, R. A. Kudgus, R. Bhattacharya, P. Mukherjee,
[54] A. Sasidharan, L. S. Panchakarla, P. Chandran, D. Menon, S. Nair, Pharm. Res. 2011, 28, 237.
C. N. R. Rao, M. Koyakutty, Nanoscale 2011, 3, 2461. [88] S. J. Soenen, P. Rivera-Gil, J.-M. Montenegro, W. J. Parak,
[55] H. Yue, W. Wei, Z. Yue, B. Wang, N. Luo, Y. Gao, D. Ma, G. Ma, S. C. De Smedt, K. Braeckmans, Nano Today 2011, 6, 446.
Z. Su, Biomaterials 2012, 33, 4013. [89] A. Albanese, P. S. Tang, W. C. W. Chan, Annu. Rev. Biomed. Eng.
[56] K. Yang, J. Wan, S. Zhang, Y. Zhang, S.-T. Lee, Z. Liu, ACS Nano 2012, 14, 1.
2011, 5, 516. [90] A. P. R. Johnston, G. K. Such, S. L. Ng, F. Caruso, Curr. Opin. Col-
[57] J. A. Hubbell, A. Chilkoti, Science 2012, 337, 303. loid Interface Sci. 2011, 16, 171.
[58] R. K. Jain, N. S. Forbes, Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 14748. [91] R. A. Petros, J. M. DeSimone, Nat. Rev. Drug Discovery 2010, 9,
[59] G. Helmlinger, P. A. Netti, H. C. Lichtenbeld, R. J. Melder, 615.
R. K. Jain, Nat. Biotechnol. 1997, 15, 778. [92] S. D. Conner, S. L. Schmid, Nature 2003, 422, 37.
[60] T. P. Padera, B. R. Stoll, J. B. Tooredman, D. Capen, E. di Tomaso, [93] H. Hillaireau, P. Couvreur, Cell. Mol. Life Sci. 2009, 66, 2873.
R. K. Jain, Nature 2004, 427, 695. [94] S. S. Yu, C. M. Lau, S. N. Thomas, W. G. Jerome, D. J. Maron,
[61] Y. Gazit, D. A. Berk, M. Leunig, L. T. Baxter, R. K. Jain, Phys. Rev. J. H. Dickerson, J. A. Hubbell, T. D. Giorgio, Int. J. Nanomedicine
Lett. 1995, 75, 2428. 2012, 7, 799.
[62] W. S. Kamoun, S.-S. Chae, D. A. Lacorre, J. A. Tyrrell, M. Mitre, [95] C. He, Y. Hu, L. Yin, C. Tang, C. Yin, Biomaterials 2010, 31, 3657.
M. A. Gillissen, D. Fukumura, R. K. Jain, L. L. Munn, Nat. Methods [96] S. E. A. Gratton, M. E. Napier, P. A. Ropp, S. Tian, J. M. DeSimone,
2010, 7, 655. Pharm. Res. 2008, 25, 2845.
[63] E. M. Sevick, R. K. Jain, Cancer Res. 1989, 49, 3513. [97] D. X. Liu, A. Mori, L. Huang, Biochim. Biophys. Acta 1992, 1104, 95.
[64] Y. Boucher, R. K. Jain, Cancer Res. 1992, 52, 5110. [98] A. Schadlich, H. Caysa, T. Mueller, F. Tenambergen, C. Rose,
[65] P. A. Netti, L. T. Baxter, Y. Boucher, R. Skalak, R. K. Jain, Cancer Res. A. Gopferich, J. Kuntsche, K. Mader, ACS Nano 2011, 5, 8710.
1995, 55, 5451. [99] M. Ekkapongpisit, A. Giovia, C. Follo, G. Caputo, C. Isidoro, Int. J.
[66] V. P. Chauhan, R. M. Lanning, B. Diop-Frimpong, W. Mok, Nanomedicine 2012, 7, 4147.
E. B. Brown, T. P. Padera, Y. Boucher, R. K. Jain, Biophys. J. 2009, [100] S. D. Perrault, C. Walkey, T. Jennings, H. C. Fischer, W. C. W. Chan,
97, 330. Nano Lett. 2009, 9, 1909.
[67] P. A. Netti, D. A. Berk, M. A. Swartz, A. J. Grodzinsky, R. K. Jain, [101] T. Cedervall, I. Lynch, M. Foy, T. Berggard, S. C. Donnelly,
Cancer Res. 2000, 60, 2497. G. Cagney, S. Linse, K. A. Dawson, Angew. Chem.-Int. Edit. 2007,
[68] A. K. Iyer, G. Khaled, J. Fang, H. Maeda, Drug Discov. Today 2006, 46, 5754.
11, 812. [102] M. Lundqvist, J. Stigler, G. Elia, I. Lynch, T. Cedervall, K. A. Dawson,
[69] V. Torchilin, Adv. Drug Delivery Rev. 2011, 63, 131. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 14265.
[70] P. P. Adiseshaiah, J. B. Hall, S. E. McNeil, WIREs Nanomed. Nano- [103] H. S. Choi, W. Liu, P. Misra, E. Tanaka, J. P. Zimmer, B. I. Ipe,
biotechnol. 2010, 2, 99. M. G. Bawendi, J. V. Frangioni, Nat. Biotechnol. 2007, 25, 1165.
[71] V. P. Chauhan, T. Stylianopoulos, Y. Boucher, R. K. Jain, Annu. Rev. [104] W. Jiang, B. Y. S. Kim, J. T. Rutka, W. C. W. Chan, Nat. Nanotechnol.
Chem. Biomol. Eng., 2011, 2, 281. 2008, 3, 145.
[72] A. Schroeder, D. A. Heller, M. M. Winslow, J. E. Dahlman, [105] J. A. Champion, S. Mitragotri, Proc. Natl. Acad. Sci. U. S. A. 2006,
G. W. Pratt, R. Langer, T. Jacks, D. G. Anderson, Nat. Rev. Cancer 103, 4930.
2012, 12, 39. [106] C. Bussy, H. Ali-Boucetta, K. Kostarelos, Acc. Chem. Res. 2012.
[73] G. Sarfati, T. Dvir, M. Elkabets, R. N. Apte, S. Cohen, Biomaterials [107] P. Decuzzi, B. Godin, T. Tanaka, S. Y. Lee, C. Chiappini, X. Liu,
2011, 32, 152. M. Ferrari, J. Controlled Release 2010, 141, 320.
[74] W. Yang, D. Luo, S. Wang, R. Wang, R. Chen, Y. Liu, T. Zhu, X. Ma, [108] B. R. Smith, P. Kempen, D. Bouley, A. Xu, Z. Liu, N. Melosh,
R. Liu, G. Xu, L. Meng, Y. Lu, J. Zhou, D. Ma, Clin. Cancer Res. H. Dai, R. Sinclair, S. S. Gambhir, Nano Lett. 2012, 12, 3369.
2008, 14, 5494. [109] P. Decuzzi, M. Ferrari, Biomaterials 2008, 29, 377.
[75] J. S. Desgrosellier, D. A. Cheresh, Nat. Rev. Cancer 2010, 10, 9. [110] Z. G. Yue, W. Wei, P. P. Lv, H. Yue, L. Y. Wang, Z. G. Su, G. H. Ma,
[76] D. B. Kirpotin, D. C. Drummond, Y. Shao, M. R. Shalaby, K. Hong, Biomacromolecules 2011, 12, 2440.
U. B. Nielsen, J. D. Marks, C. C. Benz, J. W. Park, Cancer Res. 2006, [111] A. Asati, S. Santra, C. Kaittanis, J. M. Perez, ACS Nano 2010, 4,
66, 6732. 5321.
1088 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
[112] T. Nomura, N. Koreeda, F. Yamashita, Y. Takakura, M. Hashida, [144] X. Sun, Z. Liu, K. Welsher, J. T. Robinson, A. Goodwin, S. Zaric,
Pharm. Res. 1998, 15, 128. H. Dai, Nano Research 2008, 1, 203.
[113] A. S. Abu Lila, T. Ishida, H. Kiwada, Pharm. Res. 2010, 27, 1171. [145] L. M. Zhang, J. G. Xia, Q. H. Zhao, L. W. Liu, Z. J. Zhang, Small
[114] R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, 2010, 6, 537.
R. Langer, Science 1994, 263, 1600. [146] Z. Liu, J. T. Robinson, X. Sun, H. Dai, J. Am. Chem. Soc. 2008, 130,
[115] M. Vila, M. T. Portoles, P. A. A. P. Marques, M. J. Feito, 10876.
M. C. Matesanz, C. Ramirez-Santillan, G. Goncalves, S. M. A. Cruz, [147] H. Q. Bao, Y. Z. Pan, Y. Ping, N. G. Sahoo, T. F. Wu, L. Li, J. Li,
A. Nieto, M. Vallet-Regi, Nanotechnology 2012, 23, 465103. L. H. Gan, Small 2011, 7, 1569.
[116] A. Bajaj, O. R. Miranda, R. Phillips, I. B. Kim, D. J. Jerry, [148] H. Q. Hu, J. H. Yu, Y. Y. Li, J. Zhao, H. Q. Dong, J. Biomed. Mater.
U. H. F. Bunz, V. M. Rotello, J. Am. Chem. Soc. 2010, 132, 1018. Res. A 2012, 100A, 141.
[117] A. Bajaj, S. Rana, O. R. Miranda, J. C. Yawe, D. J. Jerry, [149] Y. Z. Pan, H. Q. Bao, N. G. Sahoo, T. F. Wu, L. Li, Adv. Funct. Mater.
U. H. F. Bunz, V. M. Rotello, Chemical Science 2010, 1, 134. 2011, 21, 2754.
[118] E. Tasciotti, X. Liu, R. Bhavane, K. Plant, A. D. Leonard, B. K. Price, [150] C. Peng, W. Hu, Y. Zhou, C. Fan, Q. Huang, Small 2010, 6, 1686.
M. M.-C. Cheng, P. Decuzzi, J. M. Tour, F. Robertson, M. Ferrari, [151] M.-L. Chen, J.-W. Liu, B. Hu, M.-L. Chen, J.-H. Wang, Analyst 2011,
Nat. Nanotechnol. 2008, 3, 151. 136, 4277.
[119] K. K. Jain, BMC Med. 2010, 8, 83. [152] C. L. Guo, B. Book-Newell, J. Irudayaraj, Chem. Commun. 2011, 47,
[120] F. X. Gu, R. Karnik, A. Z. Wang, F. Alexis, E. Levy-Nissenbaum, 12658.
S. Hong, R. S. Langer, O. C. Farokhzad, Nano Today 2007, 2, 14. [153] S.-H. Hu, Y.-W. Chen, W.-T. Hung, I. W. Chen, S.-Y. Chen, Adv.
[121] F. Fay, C. J. Scott, Immunotherapy 2011, 3, 381. Mater. 2012, 24, 1748.
[122] Z. Xiao, E. Levy-Nissenbaum, F. Alexis, A. Luptak, B. A. Teply, [154] B. S. Zolnik, A. Gonzalez-Fernandez, N. Sadrieh, M. A. Dobrovolskaia,
J. M. Chan, J. Shi, E. Digga, J. Cheng, R. Langer, O. C. Farokhzad, Endocrinology 2010, 151, 458.
ACS Nano 2012, 6, 696. [155] J. V. Jokerst, T. Lobovkina, R. N. Zare, S. S. Gambhir, Nanomedicine
[123] C. Li, L. Li, A. C. Keates, Oncotarget 2012, 3, 365. 2011, 6, 715.
[124] M. E. Davis, Z. Chen, D. M. Shin, Nat. Rev. Drug Discovery 2008, 7, [156] J. Suh, K.-L. Choy, S. K. Lai, J. S. Suk, B. C. Tang, S. Prabhu,
771. J. Hanes, Int. J. Nanomedicine 2007, 2, 735.
[125] W. Gao, L. B. Alemany, L. Ci, P. M. Ajayan, Nature Chem. 2009, 1, [157] L. E. van Vlerken, T. K. Vyas, M. M. Amiji, Pharm. Res. 2007, 24,
403. 1405.
[126] R. K. Jain, T. Stylianopoulos, Nat. Rev. Clin. Oncol. 2010, 7, 653. [158] D. F. Moyano, M. Goldsmith, D. J. Solfiell, D. Landesman-Milo,
[127] J. T. Robinson, S. M. Tabakman, Y. Liang, H. Wang, O. R. Miranda, D. Peer, V. M. Rotello, J. Am. Chem. Soc. 2012, 134,
H. S. Casalongue, V. Daniel, H. Dai, J. Am. Chem. Soc. 2011, 133, 3965.
6825. [159] H. Otsuka, Y. Nagasaki, K. Kataoka, Adv. Drug Delivery Rev. 2003,
[128] W. Zhang, Z. Guo, D. Huang, Z. Liu, X. Guo, H. Zhong, Biomate- 55, 403.
rials 2011, 32, 8555. [160] X. Zhang, R. Yang, C. Wang, C.-L. Heng, Acta Phys-Chim Sin. 2012,
[129] K. Yang, J. Wan, S. Zhang, B. Tian, Y. Zhang, Z. Liu, Biomaterials 28, 1520.
2012, 33, 2206. [161] M.-C. Matesanz, M. Vila, M.-J. Feito, J. Linares, G. Gonalves,
[130] M. Acik, G. Lee, C. Mattevi, M. Chhowalla, K. Cho, Y. J. Chabal, M. Vallet-Regi, P.-A. A. P. Marques, M.-T. Portols, Biomaterials
Nat. Mater. 2010, 9, 840. 2013, 34, 1562.
[131] D. Pan, J. Zhang, Z. Li, M. Wu, Adv. Mater. 2010, 22, 734. [162] K. Yang, S. Zhang, G. Zhang, X. Sun, S.-T. Lee, Z. Liu, Nano Lett.
[132] G. Eda, Y.-Y. Lin, C. Mattevi, H. Yamaguchi, H.-A. Chen, I. S. Chen, 2010, 10, 3318.
C.-W. Chen, M. Chhowalla, Adv. Mater. 2010, 22, 505. [163] K. Yang, J. M. Wan, S. Zhang, B. Tian, Y. J. Zhang, Z. Liu, Biomate-
[133] Q. Mei, K. Zhang, G. Guan, B. Liu, S. Wang, Z. Zhang, Chem. rials 2012, 33, 2206.
Commun. 2010, 46, 7319. [164] H. Q. Dong, Z. L. Zhao, H. Y. Wen, Y. Y. Li, F. F. Guo, A. J. Shen,
[134] X. Yan, X. Cui, L.-s. Li, J. Am. Chem. Soc. 2010, 132, 5944. F. Pilger, C. Lin, D. L. Shi, Science China Chemistry 2010, 53, 2265.
[135] S. Zhu, J. Zhang, C. Qiao, S. Tang, Y. Li, W. Yuan, B. Li, L. Tian, [165] H. Wen, C. Dong, H. Dong, A. Shen, W. Xia, X. Cai, Y. Song, X. Li,
F. Liu, R. Hu, H. Gao, H. Wei, H. Zhang, H. Sun, B. Yang, Chem. Y. Li, D. Shi, Small 2012, 8, 760.
Commun. 2011, 47, 6858. [166] U. Dembereldorj, M. Kim, S. Kim, E.-O. Ganbold, S. Y. Lee,
[136] L. Zhang, Y. Xing, N. He, Y. Zhang, Z. Lu, J. Zhang, Z. Zhang, J. S.-W. Joo, J. Mater. Chem. 2012, 22, 23845.
Nanosci. Nanotechnol. 2012, 12, 2924. [167] H. Hong, K. Yang, Y. Zhang, J. W. Engle, L. Feng, Y. Yang,
[137] J. H. Shen, Y. H. Zhu, C. Chen, X. L. Yang, C. Z. Li, Chem. Commun. T. R. Nayak, S. Goel, J. Bean, C. P. Theuer, T. E. Barnhart, Z. Liu,
2011, 47, 2580. W. Cai, ACS Nano 2012, 6, 2361.
[138] R. Liu, D. Wu, X. Feng, K. Muellen, J. Am. Chem. Soc. 2011, 133, [168] H. Hong, Y. Zhang, J. W. Engle, T. R. Nayak, C. P. Theuer,
15221. R. J. Nickles, T. E. Barnhart, W. Cai, Biomaterials 2012, 33, 4147.
[139] J. Peng, W. Gao, B. K. Gupta, Z. Liu, R. Romero-Aburto, L. H. Ge, [169] M. Neu, D. Fischer, T. Kissel, J. Gene Med. 2005, 7, 992.
L. Song, L. B. Alemany, X. B. Zhan, G. H. Gao, S. A. Vithayathil, [170] A. Akinc, M. Thomas, A. M. Klibanov, R. Langer, J. Gene Med.
B. A. Kaipparettu, A. A. Marti, T. Hayashi, J. J. Zhu, P. M. Ajayan, 2005, 7, 657.
Nano Lett. 2012, 12, 844. [171] B. Chen, M. Liu, L. Zhang, J. Huang, J. Yao, Z. Zhang, J. Mater.
[140] J.-L. Li, H.-C. Bao, X.-L. Hou, L. Sun, X.-G. Wang, M. Gu, Angew. Chem. 2011, 21, 7736.
Chem.-Int. Edit. 2012, 51, 1830. [172] T. Ren, L. Li, X. Cai, H. Dong, S. Liu, Y. Li, Polym. Chem. 2012, 3,
[141] B. Li, Y. Cheng, J. Liu, C. Yi, A. S. Brown, H. Yuan, T. Vo-Dinh, 2561.
M. C. Fischer, W. S. Warren, Nano Lett. 2012. [173] X. Zhou, F. Laroche, G. E. M. Lamers, V. Torraca, P. Voskamp,
[142] A. Kunzmann, B. Andersson, T. Thurnherr, H. Krug, A. Scheynius, T. Lu, F. Chu, H. P. Spaink, J. P. Abrahams, Z. Liu, Nano Research
B. Fadeel, Biochim. Biophys. Acta-Gen. Subj. 2011, 1810, 361. 2012, 5, 703.
[143] C. A. Poland, R. Duffin, I. Kinloch, A. Maynard, W. A. H. Wallace, [174] L. Feng, S. Zhang, Z. Liu, Nanoscale 2011, 3, 1252.
A. Seaton, V. Stone, S. Brown, W. MacNee, K. Donaldson, Nat. [175] H. Dong, L. Ding, F. Yan, H. Ji, H. Ju, Biomaterials 2011, 32,
Nanotechnol. 2008, 3, 423. 3875.
Adv. Healthcare Mater. 2013, 2, 10721090 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1089
www.advhealthmat.de
www.MaterialsViews.com
REVIEW
[176] L. M. Zhang, Z. X. Lu, Q. H. Zhao, J. Huang, H. Shen, Z. J. Zhang, [184] M. V. Yigit, A. Moore, Z. Medarova, Pharm. Res. 2012, 29,
Small 2011, 7, 460. 1180.
[177] H. Kim, R. Namgung, K. Singha, I.-K. Oh, W. J. Kim, Bioconjugate [185] S. Akhter, M. Z. Ahmad, F. J. Ahmad, G. Storm, R. J. Kok, Expert
Chem. 2011, 22, 2558. Opin. Drug Deliv. 2012, 9, 1225.
[178] N. G. Sahoo, H. Bao, Y. Pan, M. Pal, M. Kakran, H. K. F. Cheng, [186] X. Y. Yang, X. Y. Zhang, Y. F. Ma, Y. Huang, Y. S. Wang, Y. S. Chen,
L. Li, L. P. Tan, Chem. Commun. 2011, 47, 5235. J. Mater. Chem. 2009, 19, 2710.
[179] K. P. Liu, J. J. Zhang, F. F. Cheng, T. T. Zheng, C. M. Wang, [187] X. Y. Yang, Y. S. Wang, X. Huang, Y. F. Ma, Y. Huang, R. C. Yang,
J. J. Zhu, J. Mater. Chem. 2011, 21, 12034. H. Q. Duan, Y. S. Chen, J. Mater. Chem. 2011, 21, 3448.
[180] A. J. Shen, D. L. Li, X. J. Cai, C. Y. Dong, H. Q. Dong, H. Y. Wen, [188] G. Gollavelli, Y. C. Ling, Biomaterials 2012, 33, 2532.
G. H. Dai, P. J. Wang, Y. Y. Li, J. Biomed. Mater. Res. A 2012, 100A, [189] W. H. Chen, P. W. Yi, Y. Zhang, L. M. Zhang, Z. W. Deng,
2499. Z. J. Zhang, ACS Appl. Mater. Interfaces 2011, 3, 4085.
[181] P. Huang, C. Xu, J. Lin, C. Wang, X. Wang, C. Zhang, X. Zhou, [190] K. Yang, L. L. Hu, X. X. Ma, S. Q. Ye, L. Cheng, X. Z. Shi, C. H. Li,
S. Guo, D. Cui, Theranostics 2011, 1, 240. Y. G. Li, Z. Liu, Adv. Mater. 2012, 24, 1868.
[182] B. Tian, C. Wang, S. Zhang, L. Feng, Z. Liu, ACS Nano 2011, 5, [191] C. S. Wang, J. Y. Li, C. Amatore, Y. Chen, H. Jiang, X. M. Wang,
7000. Angew. Chem.-Int. Edit. 2011, 50, 11644.
[183] H.-C. Huang, S. Barua, G. Sharma, S. K. Dey, K. Rege, J. Controlled [192] S. H. Hu, Y. W. Chen, W. T. Hung, I. W. Chen, S. Y. Chen, Adv.
Release 2011, 155, 344. Mater. 2012, 24, 1748.
1090 wileyonlinelibrary.com 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Healthcare Mater. 2013, 2, 10721090