Is nanomedicine really less harmful?
Evaluation of: Thakkar A, Chenreddy S, Thio A, Khamas W, Wang J, Prabhu S. Preclinical
systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin
and curcumin in combination with free sulforaphane in BALB/c mice. Int J Nanomedicine.
2016;11:3265–3276.
Nanomedicine1 has increasingly received a tremendous attention over the past two decades
as a potential multidimensional field, developing nano-applications that are transforming
a host of medical products and services,2,3 including drug delivery4 and health-monitoring
devices, and the possibility of gaining new insights about “undruggable targets” and
treatment through atomic-scale precision is increasing rapidly.5 Although it is uncertain
as to which of the new delivery platforms will become the most effective and useful,
it is certain that many new approaches will be investigated in the years to come.4,6
In one of the recent issues of the International Journal of Nanomedicine, Thakur et
al investigated the systemic toxicity of nanoengineered chitosan-solid lipid particles
encapsulated with aspirin and curcumin in combination with free sulforaphane (ACS
c-SLNs) in BALB/c mice, which is a very elaborative study using an animal model with
the capability to address how the benefits of new drug delivery approaches could be
achieved while minimizing potential risks. However, many toxicologists argue that
commercialization of nanomaterials is rapidly overtaking efforts to study their impact
on human and environmental health, and mostly, the toxicity of these particles remains
unclear.7 For a therapeutic molecule to be successful, it must behave properly in
physiological conditions, in addition to interacting with its molecular target, and
should undergo clinical trials where we can learn whether the mechanistic ideas are
having a therapeutic benefit and what the drawbacks are in terms of side effects.8
Noticeably, based on the findings of this study, the authors could not identify any
signs of toxicity in acute, subacute, and subchronic examinations following oral administration
of ACS c-SLNs, which clearly indicates that the oral dosing regimens were safe at
the levels tested for a long-term examination to prevent the onset of pancreatic cancer.
Importantly, the engineering of such carriers would further enable researchers to
improve their design to form advanced “delivery platforms” that accompany an escort
intelligent enough to evade destruction and minimize toxicity.9 It is likely that
we will be able to make those smart artificial machines or vehicles at the nanoscale,
which could be used, for example, to develop new types of computers, do finely targeted
drug delivery, or carry out computations inside the body for diagnostic evaluations
with fewer side effects.10
In summary, understanding and preventing risk often has a low priority in the competitive
world of research funding, and embracing a fixed idea is one of the main dangers in
the evolution of any scientific discipline. Ideally, errors or drawbacks must be uncovered
in the trial by fire of rigorous testing using cutting-edge molecular tools or animal
models, and the safety agencies around the world should continue efforts to work out
how best to regulate these novel materials. These are very important concerns.11 However,
it is going to be very hard to come up with a nanotherapeutic molecule that will be
more toxic than conventional drugs out in the market. If true, nanomedicine will at
least be less harmful than today’s cancer fighters, but if it works as intended, it
must also prove far more effective.
Combination nanotherapeutics: a real promise
Evaluation of: Jun X, Zou B, Luo L, et al. Codelivery of thioridazine and doxorubicin
using nanoparticles for effective breast cancer therapy. Int J Nanomedicine. 2016;11:
4545–4552.
Breast cancer is a devastating disease typically riddled with genetic mutations, a
leading cause of death afflicting millions of women worldwide.12 Although emerging
genome-analysis methods are now sufficiently powerful, fast, and reliable that they
are underpinning efforts to elucidate the molecular mechanics of human cancers, that
could prove to be helpful for target validation and molecular therapeutic interventions,
unfortunately, our basic approach to treat cancer has remained essentially unchanged
over decades and the medicines used have clear limitations.13,14 Nevertheless, in
the quest for better drug delivery, nanomedicine represents a new “powerful platform”,
which holds a great promise and is increasingly gaining momentum,15 to deliver multiple
drugs16 at a time, which is profoundly an “advancing approach” to treat cancer patients.
A new study by Jun et al describes the development of an emerging multidrug-based
combination nanotherapeutic approach using methoxypoly (ethylene glycol)-poly(L-lactic
acid) nanoparticles, an innovative design with the potential to address one of the
current radical understanding about the future cancer therapy, how to get enough of
the right combination of multiple drugs to the right target. The fundamental aim has
got to be to hit multiple targets simultaneously6 so that the tumors cannot develop
resistance. These newly emerging approaches ideally seek to completely eliminate highly
complex tumor tissues, that have, thus far, been resistant to available therapies,
not only by the elimination of every malignant cell type but essentially by confronting
cancer at different molecular levels or pathways involving tumor cell growth, migration,
and invasion, at all possible targets in the most effective manner.17
In the 2020s,1,18 nanomedicine will most likely see continued growth in the discovery
and development of new combination therapeutic approaches with regard to the existing
drugs, targeting multiple genetic pathways and attacking specific attributes of each
disease using multidrug delivery devices. However, the future of oncology – and the
opportunity to eliminate the suffering and death due to cancer – will absolutely depend
on our ability to confront cancer at its molecular level.19
Taken together, presently both oncologists and academic researchers are trying very
hard to figure out how to make smart combination therapies that really work. This
push toward most effective treatment has been underway for many years, but there should
also be an effort to combine all of these advances, engineering clinically relevant
delivery platforms with a capability of carrying potent multiple drugs designed to
kill “only” cancer cell types. The promise of these advances in human cancer remains
quite real, and with ever promising results from the clinic, humankind will be on
the verge of gaining immense, new power to heal.
Next-generation nanodevices
Evaluation of: Zheng H, Li X, Chen C, et al. Quantum dot-based immunofluorescent imaging
and quantitative detection of TOP2A and prognostic value in triple-negative breast
cancer. Int J Nanomedicine. 2016;11:5519–5529.
Emergence of new effective imaging devices for early diagnosis and treatment continues
to become an inevitable need and indispensable scope for both oncologists and academic
researchers wishing to study molecular complexities of cancer with an astonishing
level of detail.20,21 Quantum dots (QDs), the luminescent size- and shape-tunable
nanocrystals, are also still a research frontier,22 with the potential of single-cell
molecular profiling23 in systems biology, gene expression studies, signaling pathway
analysis, and molecular diagnosis;24 however, QDs are next-generation nanodevices
that would open up application, in which nanoparticles can be injected into a tumor,
for example, to make it glow and help surgeons to remove all traces of it.25
Recently, Zheng et al for the first time investigated the relationship between TOP2A
protein expression and major clinical pathological parameters using QD-based immunofluorescent
imaging and quantitative analytical system in triple-negative breast cancer. In recent
years, biotechnology and biomedical research have immensely benefited from the introduction
of a variety of sophisticated imaging tools whose well-defined, optically distinguishable
signatures enable simultaneous tracking of numerous clinically important indicators.
Notably, outstanding QD photostability proves essential for robust image acquisition
and quantitative analysis of staining intensity, which is otherwise a fundamental
limitation of other organic molecular probes.2,25 Such advances in QD synthesis and
surface nanofabrications achieved during the last decade have produced multicolor
QD–antibody conjugates aiming to expand multiplexing capabilities of immunofluorescence
staining, offering exciting opportunities in gene expression studies.
In addition to sophisticated cell-based and in vivo tests, promising candidate drugs
have to be eventually tested in various animal models because even a smaller subset
of target interactions could affect tumor development and progression in vivo.26 It
is therefore pathophysiologically challenging to identify functionally relevant target
genes and pathways on the basis of dysregulated gene expression profiles in tumor
cell types. Common approaches to study target genes and function in cancer involve
experimental complexities of clinically important gene expression evaluation in cell
lines and mouse models.27,28 Although such models have yielded significant mechanistic
molecular insights into cancer biology, they are not fully capable of capturing those
molecular complexities of tumorigenesis in patients. However, nanoprobes, such as
QDs, are an advancing imaging system that could fluoresce in a wide variety of colors
and work as cell spies, showing the movements of their molecular quarries and comprehensively
enabling the investigator to follow the molecular events on a camera with an astonishing
level of detail.
These advancing molecular tools not only have the potential to significantly help
academic researchers to “better visualize” and understand how a therapeutic molecule
reacts, at a molecular level, in vivo, but also would embrace a translational approach
to epigenetics, to determine the abnormal epigenetic patterns found in tumors and
the use of epigenetic markers to predict which cancer patients will respond to an
anticancer drug that blocks DNA methylation or carry out computations inside the body
for diagnostic purposes.