COMMENTARY

Seven challenges for nanomedicine

Wendy R. Sanhai1, Jason H. Sakamoto2, Richard Canady3 and Mauro Ferrari2,4,5*
are at 1the Office of the Commissioner, Food & Drug Administration, Rockville, Maryland 20857, USA; 2 Nanomedicine, Brown Foundation Institute of Molecular
Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA; 3Office of Science and Health Coordination, Food & Drug
Administration, Rockville, Maryland 20857, USA; 4Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas
77030, USA; 5Department of Bioengineering, Rice University, Houston, Texas 77005, USA.
*e-mail: mauro.ferrari@uth.tmc.edu

Nanomedicine offers new opportunities to fight diseases but a global effort is needed to
safely translate laboratory innovation to the clinic. Seven priority areas have been identified
for this endeavour.

T
he marriage of nanotechnology
and medicine has yielded an
offspring that is set to bring
momentous advances in the fight
against a range of diseases1,2.
Nanomedicine is actually a child well
past its infancy, with two families of
therapeutic nanocarriers — liposomes
and albumin nanoparticles — firmly in
clinical practice worldwide, a dozen or Nucleus
so therapeutic agents in clinical trials,
and still more in the preclinical phases
of development. The promises in store
may indeed drive the field forward,
yet, for the healthy growth of this child
into a mature contributor to society,
the fullest consideration must be given
to safety. If nanotechnology is to be Endothelial cell Enzyme Cancer cell Red blood cell Phagocytic cell
translated into meaningful benefits for
patients, innovation in the laboratory
must be supported by the pillars of Interstitial fluid Cell membrane Vessel fluid Ionic pump
evidence-based medicine and predictable pressure dynamics
regulatory pathways.
The know-how in nanotechnology
offers new ways to create better
Figure 1 Negotiating with the body’s defence systems. Several extremely effective obstacles, called biological
laboratory diagnostic tools for non-
barriers, largely prevent injected chemicals, biomolecules, nanoparticles and any other foreign agents of
invasive screening of different diseases3,4.
therapeutic action from reaching their intended destinations. The barriers include: the reticulo-endothelial
Accurate and early diagnosis, the
system, endothelial/epithelial membranes, complex networks of blood vessels, abnormal flow of blood, and
keystone of the practice of medicine,
interstitial pressure gradients. Inset: A magnified region of a tumour cell offers additional biological challenges:
will facilitate timely clinical intervention
cellular/nuclear membranes and ionic/molecular pumps that can expel drugs from the cancerous cells creating
and can mitigate patient risk and disease
drug resistance.
progression. Nanomedicine promises
a transfigured portrait of better health
care, health economics and personalized
medicine. Indeed, the hope of of language and the traditional practices sources with common goals, and making
administering safe and effective therapy of their respective areas of specialty, outcomes available to the stakeholder
that is lesion-specific, and with few side and work together to translate novel community — it will take a community
effects, necessitates the integration of laboratory innovation into commercially to serve the community5.
nanotechnology with molecular biology viable medical products. A practical Recognizing the importance of
and the medical sciences. The challenges solution to overcome these translational stimulating innovation in the field
are not minor. Experts from different barriers will come from leveraging of nanotechnology, the Food and
disciplines need to cross the boundaries resources and expertise from multiple Drug Administration (FDA) cited

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© 2008 Nature Publishing Group

nanomedicine as a priority in its 2006
report: “The Critical Path Opportunities
List and Report”. This resonates with
the need for investment in evaluative
‘critical path’ sciences that aim to
improve the ability of regulatory agencies
to promote and protect public health.
Specifically, new quantitative methods
must be developed and refined through
the continued advancement of our
scientific knowledge and understanding
of safety and efficacy when applied to
medical devices and therapies. The FDA
acknowledges the need for predictive
and evaluative tools and their potential
to provide healthcare professionals
with the information they need to
appropriately assess the risks and benefits
of nanoengineered medical products.
The seven priorities
With the vision of creating a more
efficient and transparent ‘critical path’
to nano-product development, the FDA
and the Alliance for NanoHealth (ANH)
co-convened a workshop on nanomedical
regulatory science in Houston in March
to identify the top scientific hurdles in
bringing nanoengineered products to
patients, specifically in the pre-clinical,
clinical and manufacturing phases of
product development (see Supplementary
Information). Workshop participants
were briefed by FDA senior staff on
the current position and activities of
the agency on nanotechnology, and
commercially successful case studies of
nanoengineered products were shared
by representatives of companies that
have products in the clinic, or have
received FDA approval. Following two
days of presentations, discussions and
breakout sessions, seven priority areas
were identified and presented on the
third day. These areas of concern are
presented below in no particular order
of importance.
One of the top priorities is the
determination of the distribution of
nanoparticulate carriers in the body
following systemic administration
through any route. This is tied to a
second concern, which involves the
development of imaging modalities
for visualizing the biodistribution over
time. Although pictorial evidence of
nanoparticle accumulation in vivo can
be obtained by all radiological imaging
methods6,7, the only technique that
can give quantitative mass-balance
information at this time is through
radionuclide labelling8. The ability to
account for the full administered dose
and its fate is of paramount importance
nature nanotechnology | VOL 3 | MAY 2008 | www.nature.com/naturenanotechnology
COMMENTARY
Key stakeholders Public–private partnership
Industry Neutral ground
Academia Infrastructure
Patient advocacy Executive/steering committee
groups
Oversight: scientific/
and working groups
administrative/financial
Professional
organisations Identify mutual priorities
Non-profit Pool resources/expertise
Other Define roles/responsibilities
Co-develop proposals
Implement projects
Data in public domain
Figure 2 A representation of the proposed public–private partnership among the Food and Drug Administration
(FDA) and members of the Alliance for NanoHealth (ANH). It is anticipated that activities conducted under the
public–private partnership umbrella (green boxes) will be managed and guided by an executive committee
together with several steering committees and working groups that may be project-specific and that will be
responsible for project implementation and management. All outcomes are expected to be made available
in the public domain. The FDA and the members of ANH are shown in blue boxes. Double arrows depict flow
of information.
to ensure safety9. Radio-labelling involves intestines. Further on, boundaries exist
chemical conjugation of emitters to on the cell membrane and the different
nanoparticles — a process that may organelles inside the cell such as those
be unstable in the body environment enveloping the nucleus and ‘trapping’
and could therefore lead to unreliable vesicles known as endosomes.
results. Furthermore, the distribution of The problem is further compounded
radio-labelled nanovectors may differ by barriers of different nature: enzymatic
from the same nanovectors without the degradation, uptake by scavenging
radio-label. Finally, one most promising phagocytic cells, abnormal flow of blood
advantage of nanovector technology is and hydrostatic pressure at target sites,
the ability to carry and deliver multiple and molecular and ionic efflux pumps
therapeutic and imaging payloads10, that expel drugs from target cells. A
which may require individual tracking. full understanding of the basic science
Research into biodistribution is expected of nanoparticle transport in view of
to work hand in hand with fundamental these barriers will lead to an improved
endeavours such as the development of understanding of their basic biology,
targeted imaging probes. improved control over potential adverse
A third issue is the understanding effects, and ultimately the development
of mass transport across compartmental of improved classes of therapeutic agents.
boundaries in the body. The Success in these three priority areas
biodistribution of administered agents is will provide insight into developing
a function of their biological affinity, and nanotechnology-based therapies that can
enormous efforts have been expended by predict the distribution of the therapeutic
the scientific community on achieving as a function of its size, shape, physical
targeted delivery through the use of properties and surface chemistry.
monoclonal antibodies, aptamers, In line with this, the fourth and fifth
ligands, peptides, and other strategies11. priorities identify the need to develop
However, the biodistribution of new mathematical and computer models
nanoparticles — and any other agent — is that will contribute to a ‘periodic
primarily governed by their ability to table’ of nanoparticles12 for predicting
negotiate biological barriers1 (Fig. 1). risk and benefit parameters. Equally
Among these compartmental boundaries important is a sixth priority, which
are the endothelial and epithelial barriers is the establishment of standards or
found in vessel walls, the placenta and reference materials and consensus testing
243
© 2008 Nature Publishing Group
Commentary
protocols that can provide benchmarks
for the development of novel classes of
materials — an effort that is pioneered
by the National Cancer Institute’s
Nanotechnology Characterization
Laboratory. The final objective to
be presented is the realization of an
analytical toolkit for nanopharmaceutical
manufacturing, accompanied by
specification sheet of toxicological, safety,
and biodistribution properties obtained
through standardized, validated methods.
Leveraging resources
Success in these endeavours requires
a broadly collaborative effort from
many partners. The resulting medical
breakthroughs will benefit the global
village. Now it is necessary for the
villagers who can make a difference to
join forces and conquer the challenges —
pharma and bio, academia and industry,
technologist and toxicologist, patient
advocate, clinician and ethicist, federal,
state and private, joined in a true
partnership modality — to solve the
problems that cannot be solved by any
244
individual partner, and that can benefit
everyone. Public–private partnerships
involving the FDA have been highly
successful in several domains of medicine
(Fig. 2; see Supplementary Information,
Public–Private Partnership).
An example to follow might be
the SEMATECH consortium: in 1987
fourteen US-based semiconductor
manufacturers and the US government
came together to solve common
manufacturing problems in the
microelectronics industry by leveraging
resources and sharing risks13, thus
allowing the companies to focus
resources on solving specific problems
for the development of new products.
In nanomedicine we are at a similar
critical juncture — will we partner on
medical advances, or retreat to our
individual camps and unnecessarily delay
progress? The FDA, the ANH, and ANH’s
members are evaluating the merits of
developing a collaborative framework to
facilitate joint scientific programmes in
nanomedicine. If developed, this unique
public–private partnership will involve
many stakeholders, will be inclusive, and
nature nanotechnology | VOL 3 | MAY 2008 | www.nature.com/naturenanotechnology
© 2008 Nature Publishing Group
by sharing results and reducing costs
in this pre-competitive domain, should
lead to benefits for all — striving to be of
service, with all, to all.
Disclaimer
The views expressed herein may not necessarily represent the
policies of the FDA.
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Supplementary Information accompanies this paper at
www.nature.com/naturenanotechnology