Nanotechnology, Biology and Medicine (Elsevier)
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nanomedicine:<br />
<strong>Nanotechnology</strong>, <strong>Biology</strong> <strong>and</strong> <strong>Medicine</strong> (<strong>Elsevier</strong>)<br />
Publishes the latest experimental <strong>and</strong> theore.cal advances in basic, <br />
transla.onal <strong>and</strong> clinical nanomedicine (web only) <br />
Average publica.on .me is 60 days, rejec.on rate: 75-‐80% <br />
FREE DOWNLOAD AREAS at www.nanomedjournal.com <br />
2010 Impact Factor = 4.88, h-index: 32<br />
• 7th of 106 in <strong>Medicine</strong>, Research & Experimental<br />
• 8th out of 64 in Nanoscience <strong>and</strong> <strong>Nanotechnology</strong> <br />
By immediacy index <br />
Most read articles include:<br />
• Multistability in platelets <strong>and</strong> their response to gold nanoparticles<br />
• Polymer nanoparticles containing tumor lysates as antigen delivery vehicles for dendritic<br />
cell–based antitumor immunotherapy<br />
• Mechanism of anti-angiogenic property of gold nanoparticles: role of nanoparticle size <strong>and</strong><br />
surface charge<br />
Access all results for your search in Scopus
Research Directions <strong>and</strong> Market<br />
Trends in Nanomedicine<br />
Lajos P. Balogh, Ph.D<br />
Editor-in-Chief: Nanomedicine: <strong>Nanotechnology</strong>, <strong>Biology</strong> <strong>and</strong> <strong>Medicine</strong> (<strong>Elsevier</strong>)<br />
Chief Scientific Advisor, AA Nanomedicine <strong>and</strong> <strong>Nanotechnology</strong>, Boston, MA<br />
Adj. Professor, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA<br />
External Member of the Hungarian Academy of Sciences<br />
Executive Board Member <strong>and</strong> Founding Member of the American Society for Nanomedicine<br />
US Technical Advisory Group to ISO on <strong>Nanotechnology</strong> TC229<br />
baloghl@prodigy.net, baloghlp@gmail.com<br />
I have no industrial relationships with any biomedical, pharmaceutical or medical device companies quoted in my talk <strong>and</strong> I am not receiving sponsorship or<br />
any form of financial support from them.
Nano properties: <br />
• are the result of cooperation between individual components <strong>and</strong> the<br />
collective behavior of emergent system (transitional from molecular to bulk) <br />
• Nanomaterials display chemical <strong>and</strong> materials properties simultaneously <br />
Editorial, Nanomedicine NBM 6(4), 2010
Nanoscience, <strong>Nanotechnology</strong>, <strong>and</strong><br />
Nanomedicine<br />
Nanoscience is the science of nanoscale materials <strong>and</strong> objects. As such, it is part of<br />
all disciplines of natural science.<br />
Nanoengineering is the process of designing <strong>and</strong> making predictive models, tools,<br />
machines, apparatus, <strong>and</strong> systems to exploit basic <strong>and</strong> applied nanoscience for<br />
practical human purposes. (Engineering is always quantitative.) <br />
<strong>Nanotechnology</strong> is the engineering <strong>and</strong> technology to put the nanoscience to<br />
practical use. (Technology always assumes commercialization <strong>and</strong> manufacturing.)<br />
Nanomedicine is an interdisciplinary area, where nanoscience, nano-engineering,<br />
<strong>and</strong> nanotechnology) interact with life sciences. It is not a separate discipline,<br />
<strong>and</strong> eventually will merge with all areas of medicine (research, preclinical <strong>and</strong><br />
clinical).
Science, Engineering, Technology,<br />
Business, Society relations <br />
Basic & <br />
Applied<br />
Sciences <br />
Business <br />
Technology <br />
Engineering <br />
Technology <br />
Business <br />
Society <br />
The way the hierarchy works<br />
does not change by adding<br />
nano. <br />
Drivers: <br />
1. Societal need (pull) <br />
2. Scientific interest (push) <br />
3. Business opportunity <br />
Development of new nanoscience/technology based drugs/medications must be considered<br />
as a system consisting of good science, creative engineering, <strong>and</strong> other<br />
goal-oriented policies that provide a solid profit for businesses to improve public health
(NANO)MEDICINE <br />
• <strong>Medicine</strong> is the study/cycle of diagnosis, treatment, monitoring, prediction, <strong>and</strong><br />
prevention of diseases supported by technology. Importantly, the term could also<br />
mean a substance, which promotes healing.<br />
• <strong>Medicine</strong> exploits <strong>and</strong> builds upon current research findings in science, technology,<br />
biology, <strong>and</strong> life sciences in order to develop better approaches <strong>and</strong> solutions to<br />
health-related issues.<br />
• HYPOTHESIS: <br />
– Better underst<strong>and</strong>ing of compounds, materials, <strong>and</strong> laws will lead to the<br />
integration of theory <strong>and</strong> models <strong>and</strong> thereby enables the a priori prediction<br />
<strong>and</strong> design of properties. <br />
– Devices, drugs, <strong>and</strong> tools created from this knowledge will provide better tools<br />
to protect human health <strong>and</strong> enhance quality of life. <br />
Nanomedicine is an interdisciplinary field, where nanoscience, nano-engineering,<br />
<strong>and</strong> nanotechnology) interact with life sciences. Nanomedicine is not a separate<br />
discipline, <strong>and</strong> eventually will merge with all areas of medicine (research,<br />
preclinical <strong>and</strong> clinical).
<strong>Medicine</strong> is moving from general<br />
towards specific <br />
Today <br />
Restore health (focus on disease)<br />
Experience based<br />
Statistics-based<br />
Pathway-based<br />
Desired <br />
Avoid loss of health (focus on prevention<br />
Evidence based<br />
Based on individual patient characteristics<br />
System based<br />
• Individual disease variables:<br />
– Individual (genomic dimension)<br />
– Age (anthropologic dimension)<br />
– Disease stage (proteome,<br />
metabolome)<br />
– Body location (topologic, site)<br />
– Physical <strong>and</strong> mental conditions<br />
• Group disease variables:<br />
– Sex (M-F)<br />
– Race <strong>and</strong> geographic dimension<br />
– Genomic dimension/differences<br />
– Age (anthropologic dimension)<br />
– Disease stage (proteome, metabolome)<br />
– Body location (topologic, site), etc.
Issues that limit finding the right medicine <br />
DESIRED: apply the right medicine in the right dose at the right<br />
time to the right patient.<br />
• SUBSTANCES: Most synthetic drugs are simple molecules that address the disease at the molecular level,<br />
even though the problem may originate at a higher systemic level;<br />
• TRANSLATION: First in vivo drug testing is typically done in mice (Balb/C <strong>and</strong> Black 6) that are<br />
monozygotic twins of 200 generations, while the human genome is huge <strong>and</strong> it has enormous variability;<br />
• TESTING: Experimental drugs are often tested in the most problematic cases (e.g., stage III-IV cancer<br />
patients) when the preventive aspect cannot be developed<br />
• TOXICITY: Generic toxicity vs. patient specific toxicity are the reason of 90% of drug withdrawals, <strong>and</strong> 50%<br />
of clinical trials stopped in Phase 1-III<br />
Toxic <br />
Beneficial <br />
Patient group I Y Y <br />
Patient group II Y N <br />
Patient group III N N <br />
Patient group IV N Y <br />
E.g.: Ipilimumab for Metastatic Melanoma, is effective for about 10% of the patients; <br />
Xalkori against NSCLC is effective for 4% of the patients (ALK gene)
Properties of nanoscale objects are the<br />
function of: <br />
• Composition & chemical properties (what is connected) <br />
• Architecture (how they are connected) <br />
• Geometric form (size, shape) <strong>and</strong> the ability to change it <br />
• Physical properties<br />
• Surface state (activity, charge, etc.), AND <br />
• THE DISTRIBUTION OF ALL THESE PROPERTIES <br />
As a result, biologic responses (toxicity, bioavailability,<br />
pharmacokinetics, pharmacodynamics, etc.) to different nanoobjects<br />
do differ. These new properties <strong>and</strong> functions make<br />
novel medical materials, methods, <strong>and</strong> strategies possible.
Nano-therapy strategies in cancer <br />
(examples only) <br />
Targeted delivery of chemotherapeutics <br />
Pro-drug strategy <br />
Photothermal<br />
J. Baker, et al., Cancer Res. (2005)<br />
65 : 5317 <br />
Hyperthermia <br />
RF heated <br />
Liposome <br />
Magnetite nanoparticle <br />
100<br />
80<br />
60<br />
40<br />
20<br />
0<br />
1st<br />
Qtr<br />
3rd<br />
Qtr<br />
Genetic therapy <br />
East<br />
West<br />
North<br />
Dhar, Langer et al. PNAS (2008) 105: 17356 <br />
N. Halas, J. West et al,<br />
Ann Biomed Eng.<br />
(2006) 34: 15 <br />
A. Ito et al., J. of Bioscience<br />
<strong>and</strong> Bioeng. (2005 100: 1) <br />
M. Davis et al. Nature (2010) 464: 1067 <br />
P. Grodzinski, NCI
Multifunctionality<br />
of medication<br />
is unavoidable<br />
Only complex<br />
nanoscale<br />
devices will have<br />
the necessary<br />
multiple functionality
Challenges for Nanomedicine are<br />
presented by <br />
• Research (specifics <strong>and</strong> complexity) <br />
• The overall state of Pharmaceutical Industry <br />
• Communication between science, technology, <strong>and</strong> business <br />
• Safety concerns <br />
• Commercialization elements, such as:<br />
– St<strong>and</strong>ardization <br />
– Regulations<br />
– Financing <br />
– IPO market<br />
• Education of the next generation of MDs <br />
• Public policies, prevention, etc.
MAJOR TRENDS <br />
Research trends focus on the specifics <strong>and</strong> the more complex <br />
• Exponentially growing publication activity <br />
• New nanosystems <strong>and</strong> combinations of organic-inorganicnanobio<br />
are being developed as we speak <br />
• Targeting specific features (cell surface receptors, intermediates) <br />
• Personalized medicine <br />
• Theranostics<br />
Industry trends focus on economic outcome/profitability (~18% ROI)<br />
• Lowering cost <br />
• Outsourcing to academia <strong>and</strong> to developing countries <br />
• Mergers <strong>and</strong> acquisitions <br />
• Running a lean business <br />
Number of Big Pharma companies decreases, but<br />
number of small companies keep increasing
General concept of targeted multifunctional<br />
nanodevices integrating organic, inorganic, <strong>and</strong><br />
biomaterials<br />
Salata O., Journal of Nanobiotechnology , 2004, 2:3 <br />
R. Kopelman, UM, 2002
Nanomedicine research is intensifying <br />
Publication counts derived from the Thompson ISI database on 1/2/2009 using the indicated keywords.<br />
The vertical axis is the natural logarithm of the number of publications. There is a clear change in slope<br />
for the publications associated with biology <strong>and</strong> medicine around the year 2000. <br />
JS. Murday, RW. Siegel, J Stein, JF Wright, Nanomedicine NBM, 2009
Targeted Diagnostic <strong>and</strong> Therapeutic Agents <br />
Nothing can be specific <strong>and</strong> general simultaneously <br />
Personalized <strong>Medicine</strong> <br />
Personalized medicine explores individuality<br />
in single patients or small groups of patients<br />
Personalized medicine may be<br />
(A) the application of existing drugs to personal genetic <strong>and</strong> biologic<br />
characters of the patient <strong>and</strong> the illness, or<br />
(B) a substance designed <strong>and</strong> synthesized to the characteristics of the<br />
specific illness of a specific individual<br />
Personalized medicines in group B are technically sound <strong>and</strong> can be<br />
synthesized, but it is impossible to commercialize under present<br />
regulatory procedures (no statistical proof is possible); they would not be<br />
reimbursed by insurance companies, therefore it cannot enter the clinic<br />
(not to mention MDs liability insurance).
Theranostics <br />
Theranostics (therapeutics <strong>and</strong> diagnostics) is a proposed<br />
process of using the same agent/process for patients first for<br />
diagnosis <strong>and</strong> then for treatment based on the test results.<br />
Theranostics are thought to be a key part of personalized<br />
medicine <strong>and</strong> will require considerable advances in predictive<br />
medicine.<br />
The present system of medical practice, health system<br />
monitoring, <strong>and</strong> insurance network is unsupportive of the<br />
theranostic approach.
Challenges for nanomedicine<br />
commercialization<br />
are presented by social <strong>and</strong> business aspects: <br />
• Nanomedicine is developing in a fast-paced <strong>and</strong> multilingual<br />
global theater – effective communication is crucial <br />
• Academic research <strong>and</strong> traditional drug development are<br />
moving in opposite directions<br />
• IP, Regulatory, <strong>and</strong> St<strong>and</strong>ardization activities are lagging<br />
behind exploding research data, of which only ~10% is<br />
reproducible <br />
• To accelerate commercialization, safety <strong>and</strong> regulatory systems<br />
<strong>and</strong> the way they operate, will have to be reinvented
What are the dominant reasons for the delay in<br />
commercialization of nanomedicines <br />
1. Lack of accepted terminology <strong>and</strong> nomenclature. The reason for the 1-100<br />
nm definition is that Y/N decision-maker agencies (NIH, EPA, FDA, etc.)<br />
need exact terms. <br />
Editorial, Nanomedicine NBM 6(3), 2010) <br />
Editorial, Nanomedicine NBM 6(4), 2010) <br />
2. The traditional Composition -> Efficacy relationship for Nanomedicine is<br />
replaced by the (Composition + Structure + Architecture + Controlled<br />
function) -> Efficacy relationship - but FDA regulates only new material<br />
entities, not processes. <br />
3. Medical research is much more supported than regulation science
Trends in the pharmaceutical industry <br />
• Increasing R&D costs: Number of New Drug Approvals<br />
decreasing, R&D costs are increasing (~2.4 B USD per NDA) <br />
• Globalization: Mergers & Acquisitions of large companies – 28<br />
in 1980, 7 in 2011. Global companies shift resources <strong>and</strong><br />
manufacturing to other sites freely<br />
. <br />
• Basic research is more <strong>and</strong> more directed towards specific<br />
solutions, resulting in fractured <strong>and</strong> increasingly smaller<br />
markets with low ROIs, for which no good business models<br />
exist yet <br />
Companies are forced to outsource much of formerly in-house<br />
research either to academy or to developing countries
The problem of outsourcing pharmaceutical<br />
development of nano-drugs <br />
Pharma companies have sequestered considerable knowledge on <br />
what can be developed <strong>and</strong> what is problematical. However, many<br />
nanomedicine researchers do not have access to the knowledge<br />
how to do Safety, Technical, Competitive, Regulatory,<br />
Reimbursement, <strong>and</strong> Commercial Evaluation <br />
• Expertise is needed <strong>and</strong> should be transferred in:<br />
» 1. Regulatory Affairs <br />
» 2. Analytical methods <strong>and</strong> instruments <br />
» 3. Manufacturing, process <strong>and</strong> scale-up <br />
» 4. Pharmaceutics <br />
» 5. Market analysis <br />
» 6. Soft information, competitor intelligence, patents <br />
Eaton, Nanomedicine: NBM Vol. 7, Issue 4, Pages 371-375
Financing challenges <br />
Government funding <br />
Private funding (VCs, IPO market)
VC in life sciences <br />
• Andy Parker: ...”the problem with venture backed IPOs is not in<br />
tech but in life sciences. And the issue is more related to the<br />
venture capital model of financing now being inconsistent with<br />
the clinical <strong>and</strong> regulatory process/timeline/cost of drug<br />
development.<br />
• Timeframes <strong>and</strong> trial costs due to tough trial endpoints are do<br />
not fit into the VC model that requires only a certain amount of<br />
capital to be invested <strong>and</strong> milestones to be hit within a shorter<br />
time period. Therefore, the IPO is no longer a monetization for a<br />
VC in life sciences. It is just an interim financing that requires<br />
existing VCs to participate in the IPO.<br />
• The only true way to create investment returns is M&A (...of<br />
small successful companies…). This phenomenon has caused<br />
VC dollars targeting life sciences to shrink.
MARKET ANALYSIS BY<br />
KEY TECHNOLOGIES <br />
• The Total Addressable Market in 2010, for nanotechnology in drug delivery<br />
(NDD), all key technologies studied shows the following values in 2010: <br />
• 1.<br />
• 2.<br />
• 3.<br />
• 4.<br />
Drug Nanocrystals (596 US$ Million Dollars), (45%); <br />
Total Nanocarriers (434 US$ Million Dollars), (32%); <br />
Targeted Delivery (178 US$ Million Dollars), (13%); <br />
Solubility + Bioavailability (139 US$ Million Dollars), (10%). <br />
• The top 5 nanocarriers TAM values in 2010 as follows (by descending order): <br />
• 1.<br />
• 2.<br />
• 3.<br />
• 4.<br />
• 5.<br />
Liposomes (118 US$ Million Dollars), (28%); <br />
Dendrimers (84 US$ Million Dollars), (19%); <br />
Micelles (63 US$ Million Dollars), (15%); <br />
Gold Nanocarriers (56 US$ Million Dollars), (13%); <br />
CNTs (56 US$ Million Dollars), (13%). <br />
Cientifica Ltd., 2011
J. Paradise, UMinn
Focus areas: <br />
• Diagnostics <br />
– Imaging agents <br />
– Imaging technology <strong>and</strong> instruments <br />
• Therapeutics <br />
– Western (synthetic) <br />
– Traditional (China, India) - natural extracts etc. based<br />
drugs <strong>and</strong> procedures <br />
• Medical devices
Some (new <strong>and</strong> old) key players<br />
(only as examples, in no particular order) <br />
Companies New in 2011 Instrument companies <br />
Abraxis BioSciences, Ironwood IZON<br />
AstraZeneca, Tengion Astos Technology,<br />
Capsulation NanoscienceAG, Codexis Cytometrics <br />
Elan Corporation, GenMark Diagnostics NanoSight <br />
J.R. Nanotech, Alimera Epitomics <br />
Liquidia Technologies, Trius Caliper Life Sciences <br />
Merck KGaA, NuParhe LUCAS (pocket microscope) <br />
Novartis, Pacific Bio BioFlect (3D fl. microscope) <br />
Pioneer Surgical, Complete Genomics FilmArray (PCR in a Pouch) <br />
Star Pharma,<br />
Wyeth Pharmaceutical <br />
CyTOF (Single-Cell Mass<br />
Cytometry) <br />
N-SIM Super Resolution<br />
Microscope
US NanoMetro Map<br />
Total in 2010: 2600 <br />
This map shows the locations (by zip code) of companies, universities, government<br />
laboratories, <strong>and</strong> organizations working in nanotechnology around the United States.<br />
www.nanotechproject.com
US NanoMetro Map <br />
Once you zoom in, the circles on the map will be replaced by pins, indicating individual<br />
companies, universities, government laboratories, or organizations in each area. Click on a<br />
pin to see more information about that entry <br />
http://www.nanotechproject.org
http://www.nanotechproject.org
FDA<br />
balancing risk with innovation <br />
• The US Food <strong>and</strong> Drug Administration (FDA) has raised the bar<br />
very high for those who seek to make a business out of<br />
biosimilars. (Another nail in the biosimilar coffin Nature<br />
Biotechnology 30, 198, 2012)<br />
• 2011: VCs turn up the heat on FDA for acting slow <br />
• 2012: The FDA <strong>and</strong> its EU <strong>and</strong> Australian<br />
counterparts have developed a blueprint for<br />
operating joint GMP inspections of active<br />
pharmaceutical ingredient manufacturing <br />
• EU: New Pharmacovigilance Regulations -<br />
biggest changes in past 10 years are coming
Latest developments in nano regulations <br />
• EPA announced plans to gather information on nanomaterials in pesticide<br />
products. EPA also will propose a new case-by-case approach for determining<br />
"whether a nanoscale ingredient is a 'new' active or inert ingredient … under the<br />
pesticide laws, when an identical, non-nanoscale form of the nanoscale<br />
ingredient is already registered under the pesticide law."<br />
http://www.epa.gov/pesticides/regulating/prepub-nanopest.pdf<br />
• FDA issued draft guidance for industry that describes the agency's "current<br />
thinking on whether FDA-regulated projects contain nanomaterials or otherwise<br />
involve the application of nanotechnology.<br />
• http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm<br />
• The White House also issued a joint memor<strong>and</strong>um on the regulation of<br />
nanotechnology from the Office of Science <strong>and</strong> Technology Policy, the Office of<br />
Management <strong>and</strong> Budget's Office of Information <strong>and</strong> Regulatory Affairs, <strong>and</strong> the<br />
office of the U.S. Trade Representative. The memo provides guidance to agency<br />
heads, stating that "regulators should use flexible, adaptive, <strong>and</strong> evidence-based<br />
approaches that avoid, wherever possible, hindering innovation <strong>and</strong> trade while<br />
fulfilling the federal government's responsibility to protect public health <strong>and</strong> the<br />
environment." The memo lists principles that agencies should follow.<br />
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/<br />
nanotechnology-regulation-<strong>and</strong>-oversight-principles.pdf.
ISO definition of nanotechnology<br />
• Application of scientific knowledge to manipulate <strong>and</strong> control matter in<br />
the nanoscale in order to make use of size- <strong>and</strong> structure-dependent<br />
properties <strong>and</strong> phenomena, as distinct from those associated with<br />
individual atoms or molecules or with bulk materials.<br />
• Note: Manipulation <strong>and</strong> control includes material synthesis.<br />
• ISO/TS 80004-1 -- Nanotechnologies -- Vocabulary -- Part 1: Core terms<br />
has now been published <strong>and</strong> is available on the ISO Website:<br />
http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm<br />
csnumber=51240&commid=381983 <br />
• Definitions in this Core Terms document are also available for review on<br />
the ISO Concept Database: http://cdb.iso.org <br />
ISO Concept Database TC229
“COMMISSION RECOMMENDATION<br />
of XXX<br />
on the definition of nanomaterial”<br />
• (4) The definition in this Recommendation should be used as a reference for determining<br />
whether a material should be considered as a "nanomaterial" for legislative <strong>and</strong> policy<br />
purposes in the Union. The definition of the term "nanomaterial" in Union legislation<br />
should be based solely on the size of the constituent particles of a material, without regard<br />
to hazard or risk. This definition, based only on the size of a material, covers natural,<br />
incidental or manufactured materials. <br />
• (8) …The lower limit was proposed at 1 nm. An upper limit of 100 nm is commonly used<br />
by general consensus, but there is no scientific evidence to support the appropriateness of<br />
this value. The use of a single upper limit value might be too limiting for the classification<br />
of nanomaterials <strong>and</strong> a differentiated approach might be more appropriate. For regulatory<br />
purposes, the number size distribution should also be considered using the mean size <strong>and</strong><br />
the st<strong>and</strong>ard deviation of the size to refine the definition. <br />
• (11) …A nanomaterial as defined in this recommendation should consist for 50 % or<br />
more of particles having a size between 1nm – 100 nm. In accordance with the<br />
SCENIHR's advice, even a small number of particles in the range between 1 nm – 100 nm<br />
may in certain cases justify a targeted assessment. However, it would be misleading to<br />
categorise such materials as nanomaterials. Nevertheless there may be specific legislative<br />
cases where concerns for the environment, health, safety or competitiveness warrant the<br />
application of a threshold below 50 %.
Recent US Government Actions to<br />
jumpstart/fix markets <br />
• H. R. 1249 This Act may be cited as the ‘Leahy-<br />
Smith America Invents Act01.05.2011<br />
• S.1933 - Reopening American Capital Markets to<br />
Emerging Growth Companies Act of 2011<br />
(Introduced in Senate 12.1.2011)<br />
• Exploring new ways of funding: Crowdfunding,<br />
revitalization of IPO markets, etc.
What is next <br />
• Big Pharma is maxed out, but small teams of closely integrated<br />
interdisciplinary groups can <strong>and</strong> will be highly successful (both<br />
in academic research <strong>and</strong> in business) <br />
• Treatment options of patients will keep improving in time using<br />
more complex medications fine-tuned for small groups of people <br />
• Nanomedicine uses small amounts of highly effective materials,<br />
which will open up more opportunities for small <strong>and</strong> medium<br />
size businesses in the pharmaceutical industry<br />
THE FUTURE: Personalized medicine, even though today we still<br />
to figure out how to validate, regulate, <strong>and</strong> monetize it…