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Nanotechnology, Biology and Medicine (Elsevier)
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Research Directions and Market
Trends in Nanomedicine
Lajos P. Balogh, Ph.D
Editor-in-Chief: Nanomedicine: Nanotechnology, Biology and Medicine (Elsevier)
Chief Scientific Advisor, AA Nanomedicine and Nanotechnology, Boston, MA
Adj. Professor, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA
External Member of the Hungarian Academy of Sciences
Executive Board Member and Founding Member of the American Society for Nanomedicine
US Technical Advisory Group to ISO on Nanotechnology TC229
baloghl@prodigy.net, baloghlp@gmail.com
I have no industrial relationships with any biomedical, pharmaceutical or medical device companies quoted in my talk and I am not receiving sponsorship or
any form of financial support from them.

Nano properties:
• are the result of cooperation between individual components and the
collective behavior of emergent system (transitional from molecular to bulk)
• Nanomaterials display chemical and materials properties simultaneously
Editorial, Nanomedicine NBM 6(4), 2010

Nanoscience, Nanotechnology, and
Nanomedicine
Nanoscience is the science of nanoscale materials and objects. As such, it is part of
all disciplines of natural science.
Nanoengineering is the process of designing and making predictive models, tools,
machines, apparatus, and systems to exploit basic and applied nanoscience for
practical human purposes. (Engineering is always quantitative.)
Nanotechnology is the engineering and technology to put the nanoscience to
practical use. (Technology always assumes commercialization and manufacturing.)
Nanomedicine is an interdisciplinary area, where nanoscience, nano-engineering,
and nanotechnology) interact with life sciences. It is not a separate discipline,
and eventually will merge with all areas of medicine (research, preclinical and
clinical).

Science, Engineering, Technology,
Business, Society relations
Basic &
Applied
Sciences
Business
Technology
Engineering
Technology
Business
Society
The way the hierarchy works
does not change by adding
nano.
Drivers:
1. Societal need (pull)
2. Scientific interest (push)
3. Business opportunity
Development of new nanoscience/technology based drugs/medications must be considered
as a system consisting of good science, creative engineering, and other
goal-oriented policies that provide a solid profit for businesses to improve public health

(NANO)MEDICINE
• Medicine is the study/cycle of diagnosis, treatment, monitoring, prediction, and
prevention of diseases supported by technology. Importantly, the term could also
mean a substance, which promotes healing.
• Medicine exploits and builds upon current research findings in science, technology,
biology, and life sciences in order to develop better approaches and solutions to
health-related issues.
• HYPOTHESIS:
– Better understanding of compounds, materials, and laws will lead to the
integration of theory and models and thereby enables the a priori prediction
and design of properties.
– Devices, drugs, and tools created from this knowledge will provide better tools
to protect human health and enhance quality of life.
Nanomedicine is an interdisciplinary field, where nanoscience, nano-engineering,
and nanotechnology) interact with life sciences. Nanomedicine is not a separate
discipline, and eventually will merge with all areas of medicine (research,
preclinical and clinical).

Medicine is moving from general
towards specific
Today
Restore health (focus on disease)
Experience based
Statistics-based
Pathway-based
Desired
Avoid loss of health (focus on prevention
Evidence based
Based on individual patient characteristics
System based
• Individual disease variables:
– Individual (genomic dimension)
– Age (anthropologic dimension)
– Disease stage (proteome,
metabolome)
– Body location (topologic, site)
– Physical and mental conditions
• Group disease variables:
– Sex (M-F)
– Race and geographic dimension
– Genomic dimension/differences
– Age (anthropologic dimension)
– Disease stage (proteome, metabolome)
– Body location (topologic, site), etc.

Issues that limit finding the right medicine
DESIRED: apply the right medicine in the right dose at the right
time to the right patient.
• SUBSTANCES: Most synthetic drugs are simple molecules that address the disease at the molecular level,
even though the problem may originate at a higher systemic level;
• TRANSLATION: First in vivo drug testing is typically done in mice (Balb/C and Black 6) that are
monozygotic twins of 200 generations, while the human genome is huge and it has enormous variability;
• TESTING: Experimental drugs are often tested in the most problematic cases (e.g., stage III-IV cancer
patients) when the preventive aspect cannot be developed
• TOXICITY: Generic toxicity vs. patient specific toxicity are the reason of 90% of drug withdrawals, and 50%
of clinical trials stopped in Phase 1-III
Toxic
Beneficial
Patient group I Y Y
Patient group II Y N
Patient group III N N
Patient group IV N Y
E.g.: Ipilimumab for Metastatic Melanoma, is effective for about 10% of the patients;
Xalkori against NSCLC is effective for 4% of the patients (ALK gene)

Properties of nanoscale objects are the
function of:
• Composition & chemical properties (what is connected)
• Architecture (how they are connected)
• Geometric form (size, shape) and the ability to change it
• Physical properties
• Surface state (activity, charge, etc.), AND
• THE DISTRIBUTION OF ALL THESE PROPERTIES
As a result, biologic responses (toxicity, bioavailability,
pharmacokinetics, pharmacodynamics, etc.) to different nanoobjects
do differ. These new properties and functions make
novel medical materials, methods, and strategies possible.

Nano-therapy strategies in cancer
(examples only)
Targeted delivery of chemotherapeutics
Pro-drug strategy
Photothermal
J. Baker, et al., Cancer Res. (2005)
65 : 5317
Hyperthermia
RF heated
Liposome
Magnetite nanoparticle
100
80
60
40
20
0
1st
Qtr
3rd
Qtr
Genetic therapy
East
West
North
Dhar, Langer et al. PNAS (2008) 105: 17356
N. Halas, J. West et al,
Ann Biomed Eng.
(2006) 34: 15
A. Ito et al., J. of Bioscience
and Bioeng. (2005 100: 1)
M. Davis et al. Nature (2010) 464: 1067
P. Grodzinski, NCI

Multifunctionality
of medication
is unavoidable
Only complex
nanoscale
devices will have
the necessary
multiple functionality

Challenges for Nanomedicine are
presented by
• Research (specifics and complexity)
• The overall state of Pharmaceutical Industry
• Communication between science, technology, and business
• Safety concerns
• Commercialization elements, such as:
– Standardization
– Regulations
– Financing
– IPO market
• Education of the next generation of MDs
• Public policies, prevention, etc.

MAJOR TRENDS
Research trends focus on the specifics and the more complex
• Exponentially growing publication activity
• New nanosystems and combinations of organic-inorganicnanobio
are being developed as we speak
• Targeting specific features (cell surface receptors, intermediates)
• Personalized medicine
• Theranostics
Industry trends focus on economic outcome/profitability (~18% ROI)
• Lowering cost
• Outsourcing to academia and to developing countries
• Mergers and acquisitions
• Running a lean business
Number of Big Pharma companies decreases, but
number of small companies keep increasing

General concept of targeted multifunctional
nanodevices integrating organic, inorganic, and
biomaterials
Salata O., Journal of Nanobiotechnology , 2004, 2:3
R. Kopelman, UM, 2002

Nanomedicine research is intensifying
Publication counts derived from the Thompson ISI database on 1/2/2009 using the indicated keywords.
The vertical axis is the natural logarithm of the number of publications. There is a clear change in slope
for the publications associated with biology and medicine around the year 2000.
JS. Murday, RW. Siegel, J Stein, JF Wright, Nanomedicine NBM, 2009

Targeted Diagnostic and Therapeutic Agents
Nothing can be specific and general simultaneously

Personalized Medicine
Personalized medicine explores individuality
in single patients or small groups of patients
Personalized medicine may be
(A) the application of existing drugs to personal genetic and biologic
characters of the patient and the illness, or
(B) a substance designed and synthesized to the characteristics of the
specific illness of a specific individual
Personalized medicines in group B are technically sound and can be
synthesized, but it is impossible to commercialize under present
regulatory procedures (no statistical proof is possible); they would not be
reimbursed by insurance companies, therefore it cannot enter the clinic
(not to mention MDs liability insurance).

Theranostics
Theranostics (therapeutics and diagnostics) is a proposed
process of using the same agent/process for patients first for
diagnosis and then for treatment based on the test results.
Theranostics are thought to be a key part of personalized
medicine and will require considerable advances in predictive
medicine.
The present system of medical practice, health system
monitoring, and insurance network is unsupportive of the
theranostic approach.

Challenges for nanomedicine
commercialization
are presented by social and business aspects:
• Nanomedicine is developing in a fast-paced and multilingual
global theater – effective communication is crucial
• Academic research and traditional drug development are
moving in opposite directions
• IP, Regulatory, and Standardization activities are lagging
behind exploding research data, of which only ~10% is
reproducible
• To accelerate commercialization, safety and regulatory systems
and the way they operate, will have to be reinvented

What are the dominant reasons for the delay in
commercialization of nanomedicines
1. Lack of accepted terminology and nomenclature. The reason for the 1-100
nm definition is that Y/N decision-maker agencies (NIH, EPA, FDA, etc.)
need exact terms.
Editorial, Nanomedicine NBM 6(3), 2010)
Editorial, Nanomedicine NBM 6(4), 2010)
2. The traditional Composition -> Efficacy relationship for Nanomedicine is
replaced by the (Composition + Structure + Architecture + Controlled
function) -> Efficacy relationship - but FDA regulates only new material
entities, not processes.
3. Medical research is much more supported than regulation science

Trends in the pharmaceutical industry
• Increasing R&D costs: Number of New Drug Approvals
decreasing, R&D costs are increasing (~2.4 B USD per NDA)
• Globalization: Mergers & Acquisitions of large companies – 28
in 1980, 7 in 2011. Global companies shift resources and
manufacturing to other sites freely
.
• Basic research is more and more directed towards specific
solutions, resulting in fractured and increasingly smaller
markets with low ROIs, for which no good business models
exist yet
Companies are forced to outsource much of formerly in-house
research either to academy or to developing countries

The problem of outsourcing pharmaceutical
development of nano-drugs
Pharma companies have sequestered considerable knowledge on
what can be developed and what is problematical. However, many
nanomedicine researchers do not have access to the knowledge
how to do Safety, Technical, Competitive, Regulatory,
Reimbursement, and Commercial Evaluation
• Expertise is needed and should be transferred in:
» 1. Regulatory Affairs
» 2. Analytical methods and instruments
» 3. Manufacturing, process and scale-up
» 4. Pharmaceutics
» 5. Market analysis
» 6. Soft information, competitor intelligence, patents
Eaton, Nanomedicine: NBM Vol. 7, Issue 4, Pages 371-375

Financing challenges
Government funding
Private funding (VCs, IPO market)

VC in life sciences
• Andy Parker: ...”the problem with venture backed IPOs is not in
tech but in life sciences. And the issue is more related to the
venture capital model of financing now being inconsistent with
the clinical and regulatory process/timeline/cost of drug
development.
• Timeframes and trial costs due to tough trial endpoints are do
not fit into the VC model that requires only a certain amount of
capital to be invested and milestones to be hit within a shorter
time period. Therefore, the IPO is no longer a monetization for a
VC in life sciences. It is just an interim financing that requires
existing VCs to participate in the IPO.
• The only true way to create investment returns is M&A (...of
small successful companies…). This phenomenon has caused
VC dollars targeting life sciences to shrink.

MARKET ANALYSIS BY
KEY TECHNOLOGIES
• The Total Addressable Market in 2010, for nanotechnology in drug delivery
(NDD), all key technologies studied shows the following values in 2010:
• 1.
• 2.
• 3.
• 4.
Drug Nanocrystals (596 US$ Million Dollars), (45%);
Total Nanocarriers (434 US$ Million Dollars), (32%);
Targeted Delivery (178 US$ Million Dollars), (13%);
Solubility + Bioavailability (139 US$ Million Dollars), (10%).
• The top 5 nanocarriers TAM values in 2010 as follows (by descending order):
• 1.
• 2.
• 3.
• 4.
• 5.
Liposomes (118 US$ Million Dollars), (28%);
Dendrimers (84 US$ Million Dollars), (19%);
Micelles (63 US$ Million Dollars), (15%);
Gold Nanocarriers (56 US$ Million Dollars), (13%);
CNTs (56 US$ Million Dollars), (13%).
Cientifica Ltd., 2011

J. Paradise, UMinn

Focus areas:
• Diagnostics
– Imaging agents
– Imaging technology and instruments
• Therapeutics
– Western (synthetic)
– Traditional (China, India) - natural extracts etc. based
drugs and procedures
• Medical devices

Some (new and old) key players
(only as examples, in no particular order)
Companies New in 2011 Instrument companies
Abraxis BioSciences, Ironwood IZON
AstraZeneca, Tengion Astos Technology,
Capsulation NanoscienceAG, Codexis Cytometrics
Elan Corporation, GenMark Diagnostics NanoSight
J.R. Nanotech, Alimera Epitomics
Liquidia Technologies, Trius Caliper Life Sciences
Merck KGaA, NuParhe LUCAS (pocket microscope)
Novartis, Pacific Bio BioFlect (3D fl. microscope)
Pioneer Surgical, Complete Genomics FilmArray (PCR in a Pouch)
Star Pharma,
Wyeth Pharmaceutical
CyTOF (Single-Cell Mass
Cytometry)
N-SIM Super Resolution
Microscope

US NanoMetro Map
Total in 2010: 2600
This map shows the locations (by zip code) of companies, universities, government
laboratories, and organizations working in nanotechnology around the United States.
www.nanotechproject.com

US NanoMetro Map
Once you zoom in, the circles on the map will be replaced by pins, indicating individual
companies, universities, government laboratories, or organizations in each area. Click on a
pin to see more information about that entry
http://www.nanotechproject.org

http://www.nanotechproject.org

FDA
balancing risk with innovation
• The US Food and Drug Administration (FDA) has raised the bar
very high for those who seek to make a business out of
biosimilars. (Another nail in the biosimilar coffin Nature
Biotechnology 30, 198, 2012)
• 2011: VCs turn up the heat on FDA for acting slow
• 2012: The FDA and its EU and Australian
counterparts have developed a blueprint for
operating joint GMP inspections of active
pharmaceutical ingredient manufacturing
• EU: New Pharmacovigilance Regulations -
biggest changes in past 10 years are coming

Latest developments in nano regulations
• EPA announced plans to gather information on nanomaterials in pesticide
products. EPA also will propose a new case-by-case approach for determining
"whether a nanoscale ingredient is a 'new' active or inert ingredient … under the
pesticide laws, when an identical, non-nanoscale form of the nanoscale
ingredient is already registered under the pesticide law."
http://www.epa.gov/pesticides/regulating/prepub-nanopest.pdf
• FDA issued draft guidance for industry that describes the agency's "current
thinking on whether FDA-regulated projects contain nanomaterials or otherwise
involve the application of nanotechnology.
• http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm
• The White House also issued a joint memorandum on the regulation of
nanotechnology from the Office of Science and Technology Policy, the Office of
Management and Budget's Office of Information and Regulatory Affairs, and the
office of the U.S. Trade Representative. The memo provides guidance to agency
heads, stating that "regulators should use flexible, adaptive, and evidence-based
approaches that avoid, wherever possible, hindering innovation and trade while
fulfilling the federal government's responsibility to protect public health and the
environment." The memo lists principles that agencies should follow.
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/
nanotechnology-regulation-and-oversight-principles.pdf.

ISO definition of nanotechnology
• Application of scientific knowledge to manipulate and control matter in
the nanoscale in order to make use of size- and structure-dependent
properties and phenomena, as distinct from those associated with
individual atoms or molecules or with bulk materials.
• Note: Manipulation and control includes material synthesis.
• ISO/TS 80004-1 -- Nanotechnologies -- Vocabulary -- Part 1: Core terms
has now been published and is available on the ISO Website:
http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm
csnumber=51240&commid=381983
• Definitions in this Core Terms document are also available for review on
the ISO Concept Database: http://cdb.iso.org
ISO Concept Database TC229

“COMMISSION RECOMMENDATION
of XXX
on the definition of nanomaterial”
• (4) The definition in this Recommendation should be used as a reference for determining
whether a material should be considered as a "nanomaterial" for legislative and policy
purposes in the Union. The definition of the term "nanomaterial" in Union legislation
should be based solely on the size of the constituent particles of a material, without regard
to hazard or risk. This definition, based only on the size of a material, covers natural,
incidental or manufactured materials.
• (8) …The lower limit was proposed at 1 nm. An upper limit of 100 nm is commonly used
by general consensus, but there is no scientific evidence to support the appropriateness of
this value. The use of a single upper limit value might be too limiting for the classification
of nanomaterials and a differentiated approach might be more appropriate. For regulatory
purposes, the number size distribution should also be considered using the mean size and
the standard deviation of the size to refine the definition.
• (11) …A nanomaterial as defined in this recommendation should consist for 50 % or
more of particles having a size between 1nm – 100 nm. In accordance with the
SCENIHR's advice, even a small number of particles in the range between 1 nm – 100 nm
may in certain cases justify a targeted assessment. However, it would be misleading to
categorise such materials as nanomaterials. Nevertheless there may be specific legislative
cases where concerns for the environment, health, safety or competitiveness warrant the
application of a threshold below 50 %.

Recent US Government Actions to
jumpstart/fix markets
• H. R. 1249 This Act may be cited as the ‘Leahy-
Smith America Invents Act01.05.2011
• S.1933 - Reopening American Capital Markets to
Emerging Growth Companies Act of 2011
(Introduced in Senate 12.1.2011)
• Exploring new ways of funding: Crowdfunding,
revitalization of IPO markets, etc.

What is next
• Big Pharma is maxed out, but small teams of closely integrated
interdisciplinary groups can and will be highly successful (both
in academic research and in business)
• Treatment options of patients will keep improving in time using
more complex medications fine-tuned for small groups of people
• Nanomedicine uses small amounts of highly effective materials,
which will open up more opportunities for small and medium
size businesses in the pharmaceutical industry
THE FUTURE: Personalized medicine, even though today we still
to figure out how to validate, regulate, and monetize it…