Clinically, cancer is defined as a large number (up to a hundred)
of complex diseases that behave differently depending on
the cell types from which they originate. Cancers vary in
age of onset, growth rate, invasiveness, prognosis, and
responsiveness to treatment 1
. The most common cancer
treatments are limited to chemotherapy, radiation, and surgery.
Frequent challenges encountered by current cancer therapies
include the nonspecific systemic distribution of antitumor
agents, inadequate drug concentrations reaching the tumor,
and the limited ability to monitor therapeutic responses.
Poor drug delivery to the target site leads to significant
complications, such as multidrug resistance 2
to overcome all these limitations in the treatment of cancer,
researchers have started working on nanotechnological
applications in the field of clinical oncology.
Nanotechnology can be defined simply as the technology
at the scale of one-billionth of a metre. It is the design,
characterization, synthesis and application of materials,
structures, devices and systems by controlling shape and size
at the nanometre scale 3. Nanomedicine is defined as the
application of nanobiotechnology to medicine and is based
on the use of nanoscale materials and devices for diagnosis
and drug delivery as well as for the development of advanced
pharmaceuticals referred to as nanopharmaceuticals 4.
In this review, some nanodrugs, which can both increase
the effectiveness and reduce side effects of cancer treatment,
increasing the effectiveness of radiation therapy with gold
nanoparticles and the application of hyperthermia through
the nanomaterials are discussed.
Chemotherapy based on nanotechnology
Most current anticancer agents do not differentiate
between cancerous and normal cells, leading to systemic
toxicity and adverse effects. This greatly limits the maximum
allowable dose of the drug. In addition, rapid elimination
and widespread distribution into targeted organs and tissues
requires the administration of a drug in large quantities, which
is not economical and often results in undesirable toxicity 5.
Techniques for controlled drug delivery represents one of the
frontier areas of science, which involves multidisciplinary scientific approaches that can contribute to human health
care. These delivery systems offer numerous advantages
compared to conventional dosage forms, including improved
efficacy, reduced toxicity, and improved patient compliance
and convenience 6.
The new generation of nanotechnology-based drug
formulations is challenging the accepted ways of cancer
treatment. Multi-functional nanomaterial constructs have
the capability to be delivered directly to the tumor site and
eradicate cancer cells selectively, while sparing healthy cells.
Tailoring of the nano-construct design can result in enhanced
drug efficacy at lower doses that can free drug treatment, can
produce a wider therapeutic window, and lower side effects.
Nanoparticle carriers can also address several drug delivery
problems that could not be effectively solved in the past,
including reduction of multi-drug resistance effects, delivery
of small interfering RNA (siRNA), and penetration of the
blood-brain-barrier. Although challenges in understanding
toxicity, biodistribution, and in paving an effective path for
regulating the actions of the nanoscale devices carry a vast
promise to change ways cancer is diagnosed and treated 7.
The design of a universal nanotechnology formulation with
chemotherapeutic agents is crucial. A successful formulation,
one that acts as a good therapeutic carrier for cancer therapies,
would exhibit the following features: (i) it would be stable in
the physiological environment, (ii) have a longer circulation
life time than currently available treatments, (iii) avoid
opsonization and processing by the reticuloendothelial system
(RES), (iv) promote endocytosis, and (v) enhance tumor uptake.
The specificity of these formulations can be further enhanced
by the conjugation of antibodies to the nanoformulations
and these immunoconjugated formulations will have a better
therapeutic efficacy than other drug formulations 8.
Albumin Bound Paclitaxel
Taxanes are a class of chemotherapy agents that
promote the polymerization of tubulin into highly stable,
intracellular microtubules. These microtubules cause cell
death by interfering with normal cell division. The first
taxane developed and tested in the field of oncology was
paclitaxel 9. Paclitaxel is a naturally occurring complex
product extracted from the bark of the Western yew (Taxus
brevifolia) and is widely used for the treatment of breast,
lung, and advanced ovarian cancer 10-12. Advances in the
use of taxanes clinically have been limited by their chemical
formulation: they are highly hydrophobic molecules. To
overcome this poor water solubility, lipid-based solvents
are used as a vehicle. Solubility of paclitaxel is enhanced
with a mixture of 50:50 Cremophor EL® (CrEL, a non-ionic
surfactant polyoxyethylated castor oil; BASF, Florham Park,
NJ, USA) and ethanol (Taxol® and generic equivalents) 13.
The solvent Cremophor-EL used in formulations of paclitaxel
causes acute hypersensitive reactions. To reduce the risk of
allergic reactions when receiving paclitaxel, patients must undergo pre-medication using steroids and anti-histamines
and be given the drug using slow infusions lasting a few
hours 14. In order to overcome insolubility problems,
albumin bound paclitaxel was developed. This drug is the only
example of a regulatory approved (FDA, USA) nanoparticle
formulation for intravenous drug delivery in cancer patients.
It is paclitaxel bound to albumin nanoparticles, with a mean
diameter of 130 nm, for use in individuals with metastatic
breast cancer who have failed a combination chemotherapy or
relapsed within 6 months of adjuvant chemotherapy 15,16.
This formulation overcomes poor solubility of paclitaxel in
the blood and allows patients to receive 50% more paclitaxel
per dose over a 30-min period 17. Because it is solvent-free
solvent related toxicities are also eliminated 14.
Anthracyclines are an important class of antitumor agents
with significant biological activities. Anthracyclines are
DNA intercalating agents, which can bind to DNA. These
agents bind to specific DNA sequences, form topoisomerase-
DNA complexes, and cause double strand DNA breaks.
Anthracycline is a Doxorubicin that is an essential component
of treatment of breast cancer, childhood solid tumors, and soft
tissue sarcomas 18,19 . Although anthracyclines are used
in many types of cancer, they have cardiotoxic effects. Acute
cardiotoxicity may manifest as nonspecific ST-segment
and T-wave abnormalities. In contrast to early effects, late
anthracycline cardiotoxicity is cumulative, dose related, and,
at sufficiently high dosages, can result in congestive heart
failure (CHF) and left ventricular (LV) dysfunction 20.
Doxorubicin is recognized as one of the most active drugs
for breast cancer, but its clinical utility is limited because of
a cumulative dose-dependent cardiac myopathy that can lead
to potentially fatal congestive heart failure 21-24.
The mechanism of doxorubicin-induced cardiotoxicity
involves the formation of a stable complex of drug with
ferric iron, and this reacts with oxygen, forming superoxide
anions, hydrogen peroxide, and hydroxyl radicals. These
free radicals cause lipid peroxidation. The injury is initially
subclinical, but continued treatment results in progressive
myocyt damage leading to cumulative dose-dependent
cardiac dysfunction that can manifest during therapy, months
after the last anthracycline dose or even years later 25. In
an effort to minimize anthracycline-induced cardiotoxicity,
a liposome-encapsulated doxorubicin (Myocet™, St. Mary’s
Pharmaceutical Unit, Quadrant Centre, Cardiff Business
Park, Llaninishan, Cardiff Wales; Trade Company, Cephalon
Europe, Maison Alfort, France) has been developed 26.
Liposomal doxorubicin is approximately 190 nm in size and
was approved by the European Agency for the Evaluation
of Medicinal Products (EMEA) in 2000 for the treatment
of metastatic breast cancer 17. The formulation consists
of encapsulation of the water-soluble doxorubicin within
a phospholipid membrane to prevent doxorubicin from exiting the circulation through capillary junctions in healthy
tissues. However, liposome-encapsulated drug appears to
pass easily through the damaged capillaries of tumor tissues
26. Therefore, liposomal encapsulation of doxorubicin is
designed to increase safety and tolerability by decreasing
cardiac and gastrointestinal toxicity through decreased
exposure of these tissues to doxorubicin, while effectively
delivering the drug to the tumor 27.
Radiotherapy involves the use of high-energy rays to kill
cancer cells 28. Treatment depends upon the sensitivity
of dividing cells being destroyed by X-rays or gamma rays
emitted from a radioactive source 29. Here, the ionizing
radiation presents the advantage of penetrating tissues, which
allows the treatment of deeply sited tumors 30. However,
radiotherapy has the disadvantage of causing some damage to
normal tissues and cells covering and surrounding the cancer
in the irradiated treatment area 29. One major difficulty
is the lack of selectivity between the tumor and the healthy
surrounding tissue. The implementation of such techniques
is therefore limited by the tolerance of normal tissues. The
challenge of future radiation therapies is to develop methods
for targeting the dose deposition to tumors and to enhance the
biological effects 30.
Chemical radiosensitizers have been developed to
increase the sensitivity of tumor cells’ to radiation by targeting
numerous different biochemical pathways, including
targeting of hypoxic cells, suppression of radioprotective
thiols, and inhibition of DNA repair 31-34. Although these
applications have shown promise in one or more areas,
they are generally toxic to normal tissues, have uncertain
radiosensitizing mechanisms, and sometimes rely on a subcellular
target that is subject to change. It has been concluded
that the synergistic gain from these chemical radiosensitizers
has been marginal 35.
Enhancement of the radiation dose by high atomic
number (Z) materials has long been of interest 36. It has
been reported that loading high Z materials into the tumor
could result in greater photoelectric absorption within the
tumor than in surrounding tissues, and thereby enhance the
dose delivered to a tumor during radiation therapy 36,37.
Among other nanoparticle systems, gold nanoparticles have
been explored as radiosensitizers 38. While most of the
research in this area has focused on either gold nanoparticles
with diameters of less than 2 nm or particles with micrometer
dimensions, it has been shown that nanoparticles 50 nm
in diameter have the highest cellular uptake 39. Gold
nanoparticles have properties that make them attractive for use
in cancer therapy including their small size, biocompatibility,
and passive accumulation in tumors because of the enhanced
permeability and retention effect 40. In addition to these
properties gold nanoparticles are capable of forming reactive
oxygen species when irradiated 41.
The results suggest that the enhancement of radio
sensitivity is due to the production of additional low-energy
secondary electrons caused by the increased absorption of
ionizing radiation energy by the metal of gold nanoparticles
or of a thick gold substrate. Since short-range low-energy
secondary electrons are produced in large amounts by any
type of ionizing radiation, and since on average only one
gold nanoparticle per DNA molecule is needed to increase
damage considerably, targeting the DNA of cancer cells
with gold nanoparticles may offer a novel approach that is
generally applicable to radiotherapy treatments 42.
Nanotechnology-based thermal ablation therapy
Thermal ablation therapy (hyperthermia) is defined as a
therapy in which tumor temperature is raised to values between
41ºC and 45ºC by external means. It can be applied locally/
regionally or to the whole body depending from the stage of the
cancer in patients For decades hyperthermia has been an area
of laboratory investigation 43. Hyperthermia therapy is the
most promising of these methods but is limited by incomplete
tumor destruction and damage to adjacent normal tissues.
The radiofrequency ablation technique currently used, is a
type of interstitial hypothermia that requires invasive needle
placement and is limited by the accuracy of the targeting.
Use of nanoparticles has refined noninvasive thermal ablation
of tumors, and several nanomaterials have been used for this
purpose. These include gold nanomaterials, iron nanoparticles,
magnetic nanoparticles, carbon nanotubes and affisomes.
Heating of the particles can be induced by magnets, lasers,
ultrasound, photodynamic therapy or low-power X-rays 4.
Perhaps the most researched property of carbon nanotubes
for cancer therapy in recent years has been their strong
absorbance in the near-infrared light range (700–1400 nm).
This property makes carbon nanotubes an enticing vehicle
for selective cell killing because many biological tissues are
transparent in the near-infrared range. It is well documented
that carbon nanotubes themselves are not toxic to cells but,
when combined with near-infrared light therapy, they have
been shown to cause cell death by hyperthermia 44.