Artificial Cells, Nanomedicine, and Biotechnology

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Nanoparticles as carriers for drug delivery in

cancer

Ankita Dadwal, Ashish Baldi & Raj Kumar Narang

To cite this article: Ankita Dadwal, Ashish Baldi & Raj Kumar Narang (2018) Nanoparticles as
carriers for drug delivery in cancer, Artificial Cells, Nanomedicine, and Biotechnology, 46:sup2,
295-305, DOI: 10.1080/21691401.2018.1457039

To link to this article: https://doi.org/10.1080/21691401.2018.1457039

Published online: 25 Jul 2018.

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ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY
2018, VOL. 46, NO. S2, S295–S305
https://doi.org/10.1080/21691401.2018.1457039

Nanoparticles as carriers for drug delivery in cancer

Ankita Dadwala,b, Ashish Baldib and Raj Kumar Naranga
a
Department of Pharmaceutics, I.S.F. College of Pharmacy, Moga, India; bDepartment of Pharmaceutical Science and Technology, Maharaja
Ranjit Singh Punjab Technical University, Bathinda, India

ABSTRACT ARTICLE HISTORY

Cancer nanotherapeutics are swiftly progressing and are being applied to solve several limitations of Received 15 December 2017
conventional drug delivery systems such as non-specific biodistribution and targeting, lack of water Revised 17 March 2018
solubility and poor oral bioavailability. Advances in protein engineering and materials science have con- Accepted 21 March 2018
tributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several
KEYWORDS
therapeutic nanocarriers have been approved for clinical use. Nanoparticles have been designed for Metallic nanocapsules;
optimal size and surface characteristics to improve their biodistribution and to increase their circulation thermoresponsive systems;
time in the bloodstream. By selectively using the unique pathophysiology of tumours, such as their viral nanoparticles
enhanced permeability and retention effect nanotherapeutics are able to carry loaded active drug to
cancer cells. In addition to this passive targeting mechanism, active targeting strategies using ligands or
antibodies directed against selected tumour targets magnify the specificity of these therapeutic nano-
particles. Drug resistance, another obstacle can also be overcome or reduced by using nanoparticles.
Multifunctional and multiplex nanoparticles are now being actively investigated and are on the horizon
as the next generation of nanoparticles, facilitating personalized and tailored cancer treatment.

Introduction nanoparticles offer many advantages as drug carrier systems,

Cancer remains one of the world’s most devastating diseases,
with more than 10 million new cases every year [1]. However,
mortality has decreased in the past 2 years [2] owing to bet-
ter understanding of tumour biology and improved diagnos-
tic devices and treatments. Current cancer treatments include
surgical intervention, radiation and chemotherapeutic drugs,
which often also kill healthy cells and cause toxicity to the
patient. Conventional chemotherapeutic agents also do not
show targeted action and are distributed non-specifically in
the body where they affect both cancerous and normal cells,
thereby limiting the dose achievable within the tumour cells
and also resulting in suboptimal treatment due to excessive
toxicities. Molecular targeting therapy has emerged as one
approach to overcome the lack of specificity of conventional
chemotherapeutic agents [3]. However, the resistance devel-
opment in cancer cells can dodge the cytotoxicity not only of
conventional chemotherapeutics but also of newer molecular
targeting therapeutics [4]. By using both passive and active
targeting strategies, intracellular concentration of drugs in
cancer cells can be improved by nanoparticles while avoiding
toxicity in normal cells (Figure 1) [5,6]. Passive targeting feats
the characteristic features of tumour biology that allows
nanocarriers to accumulate in a tumour by the enhanced per-
meability and retention (EPR) [2]. Active approaches achieve
this by conjugating nanocarriers containing chemotherapeu-
tics with molecules that bind to overexpressed antigens
or receptors on the target cells. However, although
there are still many limitations to be solved such as poor oral
bioavailability, instability in circulation, inadequate tissue dis-
tribution and toxicity. In this reviews provide perspective on
the use of nanotechnology as a fundamental tool in cancer
research and nanomedicine [7,8]. Here we focus on the types
and characteristics of nanoparticles, how nanoparticles are
being used as drug delivery systems to kill cancer cells more
effectively and also to reduce or overcome drug resistance
and how nanoparticles will be developed to improve their
therapeutic efficacy and functionality in future can-
cer treatments.
Targeted delivery of nanoparticles
Ideally, for the effectiveness of anticancer drugs in cancer
treatment, they should first, after administration, be able to
penetrate through the barriers in the body and reach the
desired tumour tissues with minimal loss of their volume or
activity in the blood circulation. Second, after reaching the
desired site, drugs should have the ability to selectively kill
tumour cells without affecting normal cells. These two basic
approaches are also associated with improvements in patient
survival and quality of life by increasing the intracellular con-
centration of drugs and reducing dose-limiting toxicities sim-
ultaneously. Increasingly, nanoparticles seem to have the
potential to satisfy both of these requirements for effective
drug carrier systems.

CONTACT Raj Kumar Narang drrknisf@gmail.com Department of Pharmaceutics, ISF College of Pharmacy, Moga 142001, Punjab, India
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
S296 A. DADWAL ET AL.
Figure 1. Improving cancer treatment.
Size and surface characteristics of nanoparticles
Nanoparticles must have the ability to remain in the blood-
stream for a considerable time without being eliminated for
effective delivery of drug to the targeted tumour tissue.
Conventional surface particles and non-modified nanopar-
ticles are usually caught in the circulation by the reticulo-
endothelial system, such as the liver and the spleen,
depending on their size and surface characteristics [9]. The
fate of injected nanoparticles can be controlled by adjusting
their size and surface characteristics.
Surface characteristics. Surface characteristics of nanopar-
ticles are an important factor for determining their lifespan
and destiny during circulation relating to their capture by
macrophages. Ideally, nanoparticles should have hydrophilic
surface so that they can escape macrophage capture [10].
This can be achieved by two methods, first coating the sur-
face of nanoparticles with a hydrophilic polymer, such as Peg,
second, protects them from opsonization by repelling plasma
proteins; alternatively, nanoparticles can be formed from
block copolymers with hydrophilic and hydrophobic
domains [11].
Size. In addition to their surface characteristics, there is
also one more advantage of nanoparticles is that their size
can be adjusted. The size of nanoparticles used in a drug
delivery system should be small enough to escape capture by
fixed macrophages that are lodged in the reticuloendothelial
system, such as the liver and spleen but should be large
enough to prevent their rapid leakage into blood capillaries.
The size of the sinusoid in the spleen and fenestra of the
Kuffer cells in the liver varies from 150 to 200 nm [12] and
the size of gap junction between endothelial cells of the
leaky tumour vasculature may vary from 100 to 600 nm [13].
Thus, the size of nanoparticles should be up to 100 nm to
reach tumour tissues by passing through these two particular
vascular structures.
Passive and active targeting
Nanocarriers come across numerous barriers in their route to
the target, such as mucosal barriers and non-specific uptake
[14,15]. To report the challenges in targeting tumours with
nanotechnology, it is essential to combine the rational design
of nanocarriers with the fundamental understanding of
tumour biology. General features of tumours include Poor
lymphatic drainage and leaky blood vessels. Whereas free
drugs may diffuse non-specifically, a nanocarrier can escape
into the tumour tissues via the leaky vessels by the enhanced
permeability and retention effect (EPR effect) [16] (Figure 2).
There is rapid and defective angiogenesis (formation of new
blood vessels from existing ones) because of which there is
increased permeability of blood vessels in tumour cells.
Furthermore, the dysfunctional lymphatic drainage in
tumours also helps in retaining the accumulated nanocarriers
and allows them to release drugs into the locality of the
tumour cells. Experiments using liposomes of different mean
size suggest that the threshold vesicle size for extravasation
into tumours is 400 nm [13], but other studies have shown
that particles having diameters <200 nm are more effective
[17,18]. Based on clinical therapy passive targeting
approaches suffer from several limitations. Some drugs can-
not diffuse efficiently so targeting cells within tumour is not
always possible and the random nature of the approach
makes it difficult to control the process because of this lack
of control multiple-drug resistance (MDR) may induce – a
situation where chemotherapy treatments fail patients shows
resistance of cancer cells towards one or more drugs.

Figure 2. Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumours. (A) Passive tissue targeting and (B) active cellu-
lar targeting.
MDR occurs because of the overexpression of transporter pro-
teins that expel drugs from cells on the surface of cancer
cells [4,19,20]. Expelling drugs inevitably lowers the thera-
peutic effect and cancer cells soon develop resistance to a
variety of drugs. The passive strategy is further limited
because certain tumours do not exhibit the EPR effect, and
the permeability of vessels may not be the same throughout
a single tumour [21]. One way to overcome these limitations
is to modify the nanocarriers in such a way that they actively
bind to specific cells after extravasation. This can be achieved
by attaching targeting agents such as ligands – molecules
that can bind to specific receptors on the cell surface – to
the surface of the nanocarrier by a variety of conjugation
chemistries. Nanocarriers will recognize the receptor and bind
to target cells through ligand–receptor interactions, and drug
will be released inside the cell (Figure 2). In general, targeting
agent which is used to deliver nanocarriers to cancer cells, it
is imperative that the agent should binds with high selectivity
to molecules that are uniquely expressed on the cell surface.
Other important consideration is that to maximize specificity,
a surface marker which can be an antigen or receptor should
be overexpressed on target cells than in the normal cells. For
example, to efficiently deliver liposomes to B-cell receptors
using the anti-CD19 monoclonal antibody (mAb), the density
of receptors should be in the range of 104–105 copies per
cell. Those with lower density are less effectively targeted
[22]. In a breast cancer model, a receptor density of 105 cop-
ies of ErbB2 receptors per cell was necessary to improve
the therapeutic efficacy of an anti-ErbB2-targeted liposomal
doxorubicin relative to its non-targeted counterpart [23]. The
binding of certain ligands to their receptors may cause recep-
tor-mediated internalization, which is often necessary if nano-
carriers are to release drugs inside the cells [6,24,25]. For
example, when immunoliposomes targeted to human blood
ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY S297
cancer (B-cell lymphoma) were labelled with an internalizing
anti-CD19 ligand a more significant therapeutic outcome was
achieved rather than a non-internalizing anti-CD20 ligand
[26]. In contrast, owing to the bystander effect targeting
nanocarriers to non-internalizing receptors may sometimes be
advantageous in solid tumours, where cells lacking the target
receptor can be killed through drug release at the surface of
the neighbouring cells, where carriers can bind [27]. It is gen-
erally known that higher binding affinity increases targeting
efficacy. However, for solid tumours due to a “binding-site
barrier” high binding affinity can decrease penetration of
nanocarriers, where the nanocarrier binds to its target so
strongly that penetration into the tissue is prevented. In add-
ition to enhanced affinity, multivalent binding effects may
also be used to improve targeting. The collective binding in a
multivalent interaction is much stronger than monovalent
binding. For example, dendrimer nanocarriers conjugated to
3–15 folate molecules showed a 2500–170,000-fold enhance-
ment in dissociation constants (KD) over free folate when
attaching to folate-binding proteins immobilized on a surface.
This was attributed to the avidity of the multiple folic acid
groups on the periphery of the dendrimers [28].
Types of nanoparticles used as drug delivery systems
Nanoparticles useful as drug delivery systems these are sub-
micron sized particles (3–200 nm), devices or systems that
can be made by using a variety of materials including lipids
(liposomes), polymers (polymeric nanoparticles, micelles or
dendrimers), viruses (viral nanoparticles) and even organo-
metallic compound (nanotubes; Table 1).
 S298

Table 1. Representative examples of nanocarrier-based drugs on the market.

System Characteristics Structure Examples of compounds References
Polymeric nanoparticles (polymer- (a) Water-soluble, nontoxic, Drugs are conjugated to the side Albumin-Taxol (Abraxane) [29–32]
A. DADWAL ET AL.

drug conjugates) (b) Biodegradable Surface modifica- chain of a linear polymer with a PGA-Taxol (Xyotax)
tion (pegylation) linker (cleavable bond) PGA-Camptothecin (CT-2106)
(c) Selective accumulation and reten- HPMA-DOX (PK1)
tion in tumour tissue (EPR effect) HPMA-DOX-galactosamine (PK2)
(d) Specific targeting of cancer cells
while sparing normal cells – recep-
tor-mediated targeting with
a ligand
Liposomes (a) Amphiphilic, biocompatible Self-assembling closed colloidal Pegylated liposomal DOX (Doxil) [33–35]
(b) Ease of modification structures composed of Non-pegylated liposomal
(c) Targeting potential lipid bilayers DOX (Myocet)
Liposomal daunorubicin (DaunoXome)
Polymeric micelles (a) Suitable carrier for water-insoluble Amphiphilic block copolymers assem- PEG-pluronic-DOX [36–38]
drug ble and form a micelle with a PEG-PAA-DOX (NK911)
(b) Biocompatible, self-assembling, hydrophobic core and hydro- PEG-PLA-Taxol (Genexol-PM)
biodegradable philic shell
(c) Ease of functional modification
(d) Targeting potential
Viral nanoparticles (a) Surface modification by mutagen- Protein cages, which are multivalent, HSP-DOX
esis or bioconjugation – multiva- self-assembled structures CPMV-DOX
lency
(b) Specific tumour targeting, multi-
functionality
(c) Defined geometry and remarkable
uniformity
(d) Biological compatibility and
inert nature
Carbon nanotubes (a) Water-soluble and biocompatible Carbon cylinders composed of CNT-MTX
through chemical modification benzene ring CNT-amphotericin B
(organic functionalization)
(b) Multifunctionality
Dendrimers (a) Biodistribution and PK can be Radially emerging hyperbranched PAMAM-MTX [39]
tuned synthetic polymer with regular pat- PAMAM-platinate
(b) High structural and chemical tern and repeated units
homogeneity
(c) Ease of functionalization, high
ligand density
(d) Controlled degradation
(e) Multifunctionality
 ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY S299

Figure 3. Types of nanocarriers for drug delivery. (A) polymeric nanoparticles: polymeric nanoparticles in which drugs are conjugated to or encapsulated in poly-
mers. (B) Polymeric micelles: amphiphilic block copolymers that form to nanosized core/shell structure in aqueous solution. The hydrophobic core region serves as a
reservoir for hydrophobic drugs, whereas hydrophilic shell region stabilizes the hydrophobic core and renders the polymer to be water-soluble. (C) Dendrimers: syn-
thetic polymeric macromolecule of nanometer dimensions, which is composed of multiple highly branched monomers that emerge radially from the central core.
(D) Liposomes: self-assembling structures composed of lipid bilayers in which an aqueous volume is entirely enclosed by a membranous lipid bilayer. (E) Viral-based
nanoparticles: in general structure are the protein cages, which are multivalent, self-assembles structures. (F) Carbon nanotubes: carbon cylinders composed of ben-
zene rings.

Polymer-based drug carriers
Depending on the method of preparation of polymeric-based
drug carriers, the drug is either covalently bound to or phys-
ically entrapped in polymer matrix [40]. The resulting com-
pounds may have the structure of capsules (polymeric
nanoparticles or polymer–drug conjugates), amphiphilic core/
shell (polymeric micelles), or may be hyperbranched macro-
molecules (dendrimers; Figure 3). Polymers used as drug con-
jugates can be divided into two groups one is natural
polymers and other is synthetic polymers.
circumvent the shortcomings of their free drug counterparts
[43]. Among them, Xyotax (PGA paclitaxel; [30]) and CT-2106
(PGA-camptothecin; [31]) are now in clinical trials. HPMA and
PEG are the most widely used non-biodegradable synthetic
polymers [44]. PK1, which is a conjugate of HPMA with doxo-
rubicin, was the synthetic polymer-drug conjugate to be eval-
uated in clinical trials as an anticancer agent. A phase I
clinical trial has been completed in patients with a variety of
tumours that were refractory or resistant to prior therapy
such as chemotherapy and/or radiation [32]. PK1 should be
further evaluated in the next level of clinical trials.

Polymeric nanoparticles (polymer–drug conjugates)

Albumin, chitosan and heparin are naturally occurring poly-
mers and have been used as a material of choice for the
delivery of DNA, oligonucleotides and protein, as well as
drugs. Recently, serum albumin is included as a carrier for the
formulation of paclitaxel nanoparticle [nanometer-sized albu-
min-bound paclitaxel (Abraxane); Figure 3(A)], has been used
in the clinic for the treatment of metastatic breast cancer
[29]. Besides metastatic breast cancer, Abraxane has also
been evaluated in clinical trials for many other cancers
including non-small-cell lung cancer (phase II trial) and
advanced non-haematologic malignancies (phase I and
pharmacokinetics trials; [41,42]). PGA was the first biodegrad-
able polymer to be used for conjugate synthesis among other
synthetic polymers such as N-(2-hydroxypropyl)-methacryla-
mide copolymer (HPMA), polystyrene-maleic anhydride
copolymer, polyethylene glycol (PEG) and poly-L-glutamic
acid (PGA). Several representative chemotherapeutics that are
used widely in the clinic have been tested as conjugates with
PGA in vitro and in vivo and showed encouraging abilities to
Polymeric micelles (amphiphilic block copolymers)
Amphiphilic block copolymers are responsible for the func-
tional properties of micelles, which accumulate to form a
nanosized core/shell structure in aqueous media (Figure 3(B)).
For hydrophobic drugs hydrophobic core region serves as a
reservoir, while the hydrophilic shell region helps in stabiliz-
ing the hydrophobic core and renders the polymers water-
soluble, making the particle a suitable candidate for i.v.
administration [45]. There are two methods of drug loading
into a polymeric micelle: first is physical encapsulation [36]
and second is chemical covalent attachment [37]. The first
polymeric micelle formulation of paclitaxel, Genexol-PM (PEG-
poly(D,L-lactide)-paclitaxel), is a cremophor-free polymeric
micelle-formulated paclitaxel. A phase I trial and pharmacoki-
netic study has been conducted in patients with advanced
refractory malignancies [38]. Multifunctional polymeric
micelles containing targeting ligands, imaging and thera-
peutic agents are being actively developed [46] and will
S300 A. DADWAL ET AL.
become conventional among several models of the micellar
formulation in the near future.
Dendrimers
Dendrimers are synthetic polymeric macromolecules of nano-
meter dimensions, composed of multiple highly branched
monomers that emerge outward from the central core
(Figure 3(C)). Properties allied with these dendrimers such as
their monodisperse size, multivalency, modifiable surface
functionality, water solubility and available internal cavity
make them attractive for drug delivery [4]. Dendrimer which
is most widely used as a scaffold is polyamidoamine dendri-
mer, which was conjugated with cisplatin [39]. The easily
modifiable surface characteristic of dendrimers permits them
to be simultaneously conjugated with several molecules such
as imaging contrast agents, targeting ligands or therapeutic
drugs, yielding a dendrimer-based multifunctional drug deliv-
ery system [4].
Lipid-based drug carriers
Liposomes
First described in 1965, liposomes are one of the first nano-
particle platforms to be applied in medicine [47]. Today, there
are more than 11 formulations which are approved for clinical
use, with many more in clinical and preclinical development.
Liposomes are self-assembling closed colloidal structures
composed of lipid bilayers having a spherical shape in which
an outer lipid bilayer surrounds a central aqueous space
(Figure 3(D)) [17]. Their biocompatible and biodegradable
compositions, as well as their unique ability to encapsulate
hydrophilic agents in their aqueous core and hydrophobic
agents within their lamellae, make liposomes excellent thera-
peutic carriers. To improve their stability and circulation half-
life, liposomes can also be coated with polymers such as
polyethylene glycol (PEG) [17]. Liposomal drug formulations
typically improve the pharmacokinetics and biodistribution of
a drug. For example, pegylated liposomal doxorubicin
reduces the volume of distribution of doxorubicin from
1000 l/m2 in the free drug form to 2.8 l/m2 by restricting
the distribution within the plasma. Furthermore, it can
achieve higher drug concentrations within tumour while
reducing drug concentration in normal tissues, such as heart
[48]. Currently, several kinds of cancer drugs have been
applied to this lipid-based system using a variety of prepar-
ation methods. Among them, liposomal formulations of the
anthracyclines doxorubicin (Doxil, Myocet) and daunorubicin
(DaunoXome) are approved for the treatment of metastatic
breast cancer and AIDS-related Kaposi’s sarcoma [33,39].
Besides these approved agents, many liposomal chemothera-
peutics are currently being evaluated in clinical trials [34].
The next generation of liposomal drugs may be immunolipo-
somes, which selectively deliver the drug to the desired sites
of action [35].
Viral nanoparticles
A variety of viruses including cowpea mosaic virus, canine
parvovirus, cowpea chlorotic mottle virus and bacteriophages
have been developed for biomedical and nanotechnology
applications that include drug delivery and tissue targeting
(Figure 3(E)). By using chemical or genetic means on the cap-
sid surface a number of targeting molecules and peptides
can be displayed in a biologically functional. Therefore, for
specific tumour targeting in vivo several ligands or antibodies,
including transferrin, folic acid and single-chain antibodies,
have been conjugated to viruses [48]. Besides this artificial
targeting, a subset of viruses, such as canine parvovirus, have
natural affinity for receptors such as transferrin receptors that
are up-regulated on a variety of tumour cells [49]. By target-
ing heat shock protein, a dual-function protein cage with spe-
cific targeting and doxorubicin encapsulation has been
developed [50,51] the permeability of vessels and the EPR
effect may not be the same throughout a single tumour [10].
To overcome these limitations is to programme the nanocar-
riers in such a way so they actively bind to specific cells after
extravasation. This binding may be achieved by attaching tar-
geting agents such as ligands molecules that bind to specific
receptors on the cell surface to the surface of the nanocarrier
by a variety of conjugation chemistries. Nanocarriers will rec-
ognize and bind to target cells through ligand–receptor inter-
actions, and bound carriers are internalized before the drug
is released inside the cell. In general, when using a targeting
agent to deliver nanocarriers to cancer cells, it is imperative
that the agent binds with high selectivity to molecules that
are uniquely expressed on the cell surface. Other important
considerations are outlined below. To maximize specificity, a
surface marker (antigen or receptor) should be overexpressed
on target cells relative to normal cells. For example, to effi-
ciently deliver liposomes to B-cell receptors using the anti-
CD19 monoclonal antibody (mAb), the density of receptors
should be in the range of 104–105 copies per cell. Those
with lower density are less effectively targeted [11]. In a
breast cancer model, a receptor density of 105 copies of
ErbB2 receptors per cell was necessary to improve the thera-
peutic efficacy of an anti-ErbB2-targeted liposomal doxorubi-
cin relative to its non-targeted counterpart [14]. The binding
of certain ligands to their receptors may cause receptor-medi-
ated internalization, which is often necessary if nanocarriers
are to release drugs inside the cell [13,15,16]. For example, a
more significant therapeutic outcome was achieved when
immunoliposomes targeted to human blood cancer (B-cell
lymphoma) were labelled with an internalizing anti-CD19 lig-
and rather than a non-internalizing anti-CD20 ligand [17]. In
contrast, targeting nanocarriers to non-internalizing receptors
may sometimes be advantageous in solid tumours owing to
the bystander effect, where cells lacking the target receptor
can be killed through drug release at the surface of the
neighbouring cells, where carriers can bind [18]. It is generally
known that higher binding affinity increases targeting effi-
cacy. However, for solid tumours, there is evidence that high
binding affinity can decrease penetration of nanocarriers due
to a “binding-site barrier”, where the nanocarrier binds to its
target so strongly that penetration into the tissue is

Figure 4. Temperature-based mechanisms of drug delivery.
prevented [19]. In addition to enhanced affinity, multivalent
binding effects (or avidity) may also be used to improve tar-
geting. The collective binding in a multivalent interaction is
much stronger than monovalent binding. For example, den-
drimer nanocarriers conjugated to 3–15 folate molecules
showed a 2500–170,000-fold enhancement in dissociation
constants (KD) over free folate when attaching to folate-bind-
ing proteins immobilized on a surface. This was attributed to
the avidity of the multiple folic acid groups on the periphery
of the dendrimers [20].
Carbon nanotubes
Carbon nanotubes are carbon cylinders composed of ben-
zene rings (Figure 3(G)) that have been applied in biology as
sensors for detecting DNA and protein, diagnostic devices for
the discrimination of different proteins from serum samples,
and carriers to deliver vaccine or protein [47]. Carbon nano-
tubes are completely insoluble in all solvents, generating
some health concerns and toxicity problems. However, the
introduction of chemical modification to carbon nanotubes
can render them water-soluble and functionalized so that
they can be linked to a wide variety of active molecules such
as peptides, proteins, nucleic acids and therapeutic agents
[17]. Antifungal agents (amphotericin B) or anticancer drugs
(methotrexate) have been covalently linked to carbon nano-
tubes with a fluorescent agent (FITC). In an in vitro study,
drugs bound to carbon nanotubes were shown to be more
effectively internalized into cells compared with free drug
alone and to have potent antifungal activity [48,52]. Single-
walled carbon nanotube (SWNT)-based drug delivery system
was developed by conjugation of human serum albumin
(HSA) nanoparticles for loading of antitumour agent PTX. The
SWNT-based drug carrier displayed high intracellular delivery
efficiency (cell uptake rate of 80%) in breast cancer MCF-7
cells, as examined by fluorescence-labelled drug carriers, sug-
gesting the needle-shaped SWNT-HSA drug carrier was able
to transport drugs across cell membrane despite its macro-
molecular structure. The drug loading on SWNT-based drug
carrier was through high binding affinity of PTX to HSA pro-
teins. The PTX formulated with SWNT-HSA showed greater
growth inhibition activity in MCF-7 breast cancer cells than
PTX formulated with HSA nanoparticle only (cell viability of
ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY S301
63 versus 70% in 48 h and 53 versus 62% in 72 h). The
increased drug efficacy could be driven by SWNT-mediated
cell internalization [53]. The multiple covalent functionaliza-
tions on the sidewall or tips of carbon nanotubes allow them
to carry several molecules at once, and this strategy provides
a fundamental advantage in the treatment of cancer.
Thermoresponsive systems
Thermoresponsive drug delivery is among the most explored
stimuli-responsive strategies and has been widely explored in
oncology. Thermoresponsiveness is usually governed by a
nonlinear sharp change with temperature in the properties of
at least one component of the nanocarrier material. Such a
sharp response triggers the release of the drug following a
variation in the surrounding temperature. Ideally, thermosen-
sitive nanocarriers should retain their load at body tempera-
ture (37  C), and rapidly deliver the drug within a locally
heated tumour (40–42  C) Figure 4 to nanochemotherapeu-
tics counteract rapid blood-passage time and washout from
the tumour.
Metallic nanocapsules
The advantage of using a magnetic field relies on the differ-
ent nature that the magnetic response can take, which can
be a magnetic guidance under a permanent magnetic field, a
temperature increase when an alternating magnetic field is
applied, or both when alternately used. Therefore, magnetic-
ally responsive systems allow for diversity in the drug delivery
pathway. Furthermore, there is the possibility of performing
magnetic resonance imaging, and hence to associate diag-
nostics and therapy within a single system (the so-called
theranostic approach) [54]. Magnetic guidance is typically
obtained by focusing an extracorporeal magnetic field on the
biological target during the injection of a magnetically
responsive nanocarrier. This concept has demonstrated great
potential in experimental cancer therapy because of
improved drug accumulation inside solid-tumour models
Figure 5. Candidate nanosystems for such a therapeutic
approach are core–shell nanoparticles (a magnetic core made
of magnetite (Fe3O4) coated with silica or polymer) [55,56]
magnetoliposomes (Fe3O4 or maghemite (Fe2O3) nanocrystals
S302 A. DADWAL ET AL.
Figure 5. Magnetically responsive systems.
encapsulated in liposomes) [57] and porous metallic nanocap-
sules [58]. Most core–shell nanoparticles have shown promis-
ing results in vitro, yet only some of them have demonstrated
improved tumour accumulation and anticancer pharmaco-
logical efficacy in various in vivo models. To avoid limitations
related to physical drug entrapment (for instance, uncon-
trolled burst release or poor drug loading), the drugs and the
nanocarriers can be covalently linked [56,59]. For example,
Fe3O4 nanocrystals loaded into squalene–gemcitabine conju-
gate nanoassemblies exhibiting high drug payloads have
demonstrated the absence of burst release, enhancement of
the magnetic resonance imaging contrast in the targeted
L1210 solid-tumour nodule and significant thera-
peutic efficacy [59].
Nanoshells
Owing to their non-invasiveness and the possibility of remote
spatial and temporal control, in the past few years a large
variety of photoresponsive systems has been engineered to
achieve on-demand drug release in response to illumination
of a specific wavelength (in the ultraviolet, visible or near-
infrared (NIR) regions) Figure 6. The different strategies
available rely on either repeatable on–off drug-release or
one-time event triggered by photosensitiveness-induced
structural modifications of the nanocarriers. For instance,
doxorubicin-loaded hollow gold nanospheres showed acceler-
ated drug release when irradiated at 808 nm, allowing
enhanced anticancer activity and reduced systemic toxicity
compared with the free-drug treatment [60]
Important concepts in nanoparticle drug delivery
for cancer
There are several general concepts that are important in
nanoparticle drug delivery. These include the enhanced per-
meability and retention (EPR) effect, nanoparticle clearance
by the mononuclear phagocyte system (MPS) and desirable
nanoparticle characteristics for cancer applications.
Enhanced permeability and retention effect
Tumour vasculatures are generally abnormal, with aberrant
branching and leaky walls [21]. This leakiness is due to the
decreased number of pericytes and rapid proliferation of
endothelial cells. These characteristics result in large pores in
the tumour vasculatures, ranging from 100 nm to several hun-
dred nanometers in diameter, as compared to normal vessel
junctions of 5–10 nm [22]. These large pores allow higher vas-
cular permeability and hydraulic conductivity in tumours, ena-
bling macromolecules such as nanoparticles to pass into
tumours [21,23]. In normal tissue, lymphatic system clears the
macromolecules. However, solid tumours are generally char-
acterized by impaired lymphatics [6]. Proliferating tumour
cells compress lymphatic vessels and collapse most of the
vessels, especially at the centre of tumours. The impaired
lymphatic system coupled with increased permeability of
tumour vasculature results in the EPR effect. Nanoparticles,
like other macromolecules, have extended retention times in
tumour, which results in higher concentrations than in
plasma or in other tissues. Thus, nanoparticles can achieve
passive targeting to tumours through the EPR effect.
Nanoparticle clearance by the mononuclear
phagocyte system
To fully take advantage of the EPR effect, nanoparticles must
remain in circulation long enough for tumour accumulation.
However, nanoparticles are prone to clearance by the mono-
nuclear phagocyte system, previously called the reticuloendo-
thelial system. The MPS is part of the immune system that is
mainly responsible for clearing macromolecules from circula-
tion. Immunotoxin therapy of cancer [24]. The MPS comprises
bone marrow progenitors, blood monocytes and tissue mac-
rophages. It also includes the Kupffer cells of the liver and
macrophages of the spleen, which are responsible for clear-
ance of macromolecules from circulation. Nanoparticles can
interact with MPS cells and lead to their opsonization. Since
premature elimination from circulation will prevent nanopar-
ticles from accumulating in tumours, much effort has been

Figure 6. Light-triggered drug delivery systems.
devoted to creating “stealth” nanoparticles. The most com-
mon strategy has been grafting PEG or other macromolecules
such as polysaccharides onto the nanoparticle surface [25].
The presence of PEG or other molecules enables steric stabil-
ization, preventing protein adsorption, interactions among
particles and interactions with immune cells.
Future directions
Although nanomedicine is a relatively new branch of science,
its translation into clinical care has been rapid. The unique
properties of nanoparticle drug carriers make them well
suited for oncology applications. Nanoparticle chemothera-
peutics are composed to influence the treatment of most
cancers. However, there are still limited clinical data and a
limited number of nanotherapeutics approved for clinical use.
To fully understand the advantages and disadvantages of
nanoparticle therapeutics, more clinical data are needed it
can also help in identifying the best applications for nanoche-
motherapeutics. Thus, it is crucial to develop and carry out
ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY S303
well-designed clinical trials to further the development of
these drugs. Clinical investigators should fully understand
the particular nanoparticles they are investigating and design
trials that take advantage of nanoparticle properties. More
complex targeted systems, which can release nanochemo-
therapeutics at a target site when exposed to external stimuli
such as light and temperature, are also under development.
Another potential is to develop more nanoparticles capable
of delivering combination chemotherapeutics. CPX-351, a lip-
osomal formulation of cytarabine and daunorubicin, showed
promising results in its first human study [18]. Together with
the progression of nanoscale drug delivery systems, advances
in nanoscale imaging suggest the potential for the develop-
ment of multifunctional “smart” nanoparticles that may facili-
tate the realization of individualized cancer therapy. Almost
all types of nanoparticles including polymeric nanoparticles
[61], nanocrystals [62], polymeric micelles [17], dendrimers
[63] and carbon nanotubes [64] have been evaluated for their
suitability as multifunctional nanoparticles that can be
applied for simultaneous in vivo imaging and treatment of
S304 A. DADWAL ET AL.
cancers. Eventually, multiplex nanoparticles may be capable
of detecting malignant cells (active targeting moiety), visualiz-
ing their location in the body (real-time in vivo imaging), kill-
ing the cancer cells with minimal side effects by sparing
normal cells (active targeting and controlled drug release or
photothermal ablation) and monitoring treatment effects in
real time.
Disclosure statement
The authors have declared no conflict of interest. The authors alone are
responsible for the content and writing of the paper.
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