Newsletter

From KING SKYFRONT to the world - NanoMedical Innovation

March
2017

Nanodiagnostic Technology
Changes Future Medicine
Contents
2

6
8

Talking about Theme 4

Early detection of cancer by miRNA   
and exosome analyses
Takanori ICHIKI, Hirofumi SHIONO, Ryo IIZUKAInterview with Researcher

Connecting Exosomes and miRNA research toan understanding of Biological phenomenon and Healthcare
Takahiro OCHIYA

Research Highlights

New light on cancer diagnosis! Success in capturing
nanoparticles released from cancer cells
Yusuke YOSHIOKA

Starry sky observations in microspaces?
Development of a revolutionary nanoparticle
analysis system
Takanori AKAGI

12 Listen to COINS’ Members
What we treasure

Kazuo HOSOKAWA, Ryo KOBAYASHI, Akira MATSUMOTO, Fumi TOSHIOKA

14 Activity Report

・3rd COINS International Symposium“ Towards Smart Health Society～ Challenge of Kawasaki based Medical Innovation ～”・Topics
・3rd Retreat Camp  
・7th General Meeting

3

Vol.

Talking about
Theme 4

Early detection ofcancer by miRNA andexosome analyses
The mission of Theme 4 of the “Center of Open Innovation Network for Smart
Health (COINS)”is“the development of a use-at-home cancer diagnostic method
not involving blood sampling,” which has the potential to change the current
approach used in medicine. We have Professor Takanori Ichiki (Department ofMaterials Engineering, Graduate School of Engineering, The University of Tokyo)
who is serving as the leader, Hirofumi Shiono (Section Manager, 1st Development
Section, 1st Development Department, Medical Business Development Division,
Nikon Corporation) who aims to manufacture and market diagnostic devices,and Assistant Professor Ryo Iizuka (Laboratory of Bioanalytical Chemistry,
Graduate School of Pharmaceutical Sciences, The University of Tokyo), who will
demonstrate the feasibility of miRNA＊1 detection using the method, come together
to discuss the purpose and progress of this innovation.

Ryo IIZUKA

Takanori ICHIKI

Hirofumi SHIONO

Assistant Professor, Laboratory of
Bioanalytical Chemistry, Graduate School of
Pharmaceutical Sciences, The University ofTokyo; Visiting Scientist, Innovation Centerof NanoMedicine (iCONM), Kawasaki
Institute of Industrial Promotion

Professor, Department of Materials
Engineering, Graduate School ofEngineering, The University of Tokyo;
Principal Research Scientist, Innovation
Center of NanoMedicine (iCONM), Kawasaki
Institute of Industrial Promotion

Section Manager,
1st Development Section,
1st Development Department,
Medical Business Development Division,
Nikon Corporation

In 20 04, he completed the doctoral programin E n gin e e rin g at th e G ra d u ate S c h o ol ofEngineering, Tokyo University of Agriculture
and Technology. After working as an IndustryAcademia-Government Collaboration Researcher
and a Project Assistant Professor at the Graduate
School of Engineering , Tokyo University ofAgriculture and Technology, a Research Fellow of
the Japan Society for the Promotion of Science(PD), and a Project Assistant Professor at theGraduate School of Pharmaceutical Sciences,
The University of Tokyo, he has held his current
position since 2012. He has also been serving
as a Visiting Scientist at the Innovation Centerof NanoMedicine since 2016. His expertise liesin protein science, biophysics, and bio-micro-/nanodevices. He aims to understand higher-order
biological functions through molecular research.

H e c o m plete d t h e d o cto ral p rog ra m at t h e
Department of Metallic Engineering, Graduate
School of Engineering, The University of Tokyo,
in 19 95. He started his career as a Special
Researcher under the Japan Society for the
Promotion of Science (JSPS). During 1995–2004,
he worked as Assistant Professor, Lecturer, andAssociate Professor at the Department of Electricand Electronics Engineering, Toyo University,where he taught LSI microfabrication technology
and bioelectronics. In 2004, he moved to theposition of Assistant Professor at the Department
of Institute of Engineering Innovation, and in
2006, he became the Associate Professor at the
Department of Bioengineering, Graduate Schoolof Engineering, The University of Tokyo. He thenmoved up to his current position. His specialization
includes biodevices, microfabrication technology,
and plasma engineering.

In 19 8 9, he completed the first semester ofthe doctoral program (MA) in organic synthetic
chemistry at the Department of Science andEngineering, Graduate School of Engineering,
Aoyama Gakuin University. He then joined Nikon
Corporation , was affiliated to the Research
D e p a r t m e n t f r o m 19 9 0 to 2 0 0 0 , a n d g ot
re a s sig n e d to t h e L a b o rato r y of M ole c ula r
Biophotonics from 1994 to 2000. He was involved
with Materials R&D related to plastic lenses foruse in spectacles and development of opticalreagents used in biotechnology. From 2000 to
2003, he was involved in the development of new
business in the field of biotechnology. In 2004,
he was responsible for planning and developinga cell culture observation apparatus called the
BioStation CT, in the Biomicroscope Development
Department. He has been involved in medical R&D
since 2010, and rose to the position of the R&D
Manager with the establishment of the Medical
Business Development Division in 2014.

2 | NanoSky VOL.03 MARCH 2017

Studying miRNA- and exosomebased devices as well as otheranalytical instruments■ First, please introduce the kind of research you
are doing now.

available at home. This means that through new devices, we are trying to bring the methods used to monitor“illness” in hospitals closer to “health”, before the onsetof illness (Figure 1).
Early detection might just allow us to enable treatment
outside the hospital premises.
In Japan, medical functions are available only at hospitals and the health insurance system is well in place,and therefore, if you are sick, it is common to go to a
hospital to get treated.
However, Florence Nightingale, who laid the foundation of the medical treatment being provided in clinics
and hospitals today, said, in a letter addressed to her
cousin Henry Bonham Carter in 1867, “while dedicating
my life to hospital work, I have reached the conclusionthat it is not the best place for patients. .....The ultimate
destination of all nursing is the nursing of the sick intheir own homes. I look to the abolition of all hospitals
and workhouse infirmaries, however it is no use to talkabout the year 2000.” (Fig. 2). The COINS' concept ofan “in-body hospital” is to “bring diagnostics and therapy closer to us, from hospital.”
Iizuka: In fact, treatment is so heavily restricted to hospitals that medical treatment might end up becoming
unavailable in the event of natural and man-made disasters that can paralyze hospital functions.
Shiono: For example, elderly patients find it difficult toeven reach the hospital. This concept of “in-body hospital” will definitely hold great social significance.

In-body
hospitalIchiki: We are developing nanotechnology-based biodevices at the Department of Material Sciences, Graduate
School of Engineering, The University of Tokyo.
Cell-based methods have been our domain of interest
for more than 10 years, but we have recently shifted
our focus toward developing miRNA-based diagnostic
devices.
Exosome＊2 measurement becomes necessary whenstudying miRNA-based diagnostic devices; we are also
evaluating different methods to study cancer-related
exosomes (see pages 6, 8, and 10). Collaborative research with Professor Kazunori Kataoka is also underway because exosome evaluation techniques arethought to be useful in both diagnostics and therapeutics, especially because they can be used to characterize the nanomachines currently being studied at
COINS.
Shiono: I am involved in the development of microscopes at Nikon for use in cell-based studies. Also, currently, I am affiliated with the Medical Business Development Division set up in 2014. I am stationed at the
NanoMedicine Innovation Center (iCONM) and am responsible for working on new analytical deFigure 1. "In-Body Hospital" from Sick Care to Health Carevices and measurement devices for use in
medicine.
Iizuka: I am engaged in searching for and
HealthStart of sickness
Sick
Conventional treatment systemcreating functional biomolecules, and workHealth care
Diagnosis Sick careing on the functional analysis of proteins
Treatment
Between health and sickness?
and supramolecular complexes using singlemolecule measurement techniques. As avisiting scientist at iCONM, I am developProlongation ofWithdrawal fromhealthy life
ing an automated microarray system fortreatment/
Prognosis
Early
Rapid andexpectancy
nursing which is
ﬁrst lookcertainsimple and rapid miRNA profiling in collabexcessively
dependent
return to
Reduction
on hospitals
societyoration with Professor Ichiki, Mr. Shiono,
in medical cost
Carry out appropriate diagnosis
and others.
in vivo before onset
Productivity
improvement■ Please tell us about the positioning ofTheme 4 in COINS.
Ichiki: At present, treatment is administered to a patient. The objective of Theme
4 is to make the detection system smart
enough to discover a disease before its onset and allow therapy. This will lower
treatment costs.
We choose the methods used in large
hospital laboratories and bring them into
the clinical settings, while maintaining accuracy, and go ahead to making them

Physical treatment/diagnosis
can be enjoyed anywhere

and conducts preventive
treatment oneself

Noninvasive
diagnosis

Nanomachine

Regenerative
medicine/vaccinePreemptive therapy by early
diagnosis prevents diseases
beforehand anda high QOL is achievedby prognostic
judgment of therapeutic eﬀects

Figure 2

My view is, as you know, that the ultimate destinationof all nursing is the nursing of the sick in their own
homes. I look to the abolition of all hospitals andworkhouse inﬁrmaries. But it is no use to talk about
the year 2,000.
From a letter to her cousin Henry Bonham Carter (1867)

Florence Nightingale

NanoSky VOL.03 MARCH 2017

|3

TALK
■ How a bou t t h e p rog ress a n d ou t look of
research?

understood if it is not investigated before
administration of treatment, when the patient is not unwell.
＊3
miRNA may be used as a biomarker toIchiki: The future prospects of fully automated, packjudge the effectiveness of such therapy.
aged cancer diagnostic devices for steps leading up to
Ichiki: It is not possible to quantify thethe separation/purification/detection of exosomal miReffects and side effects of current medical
NA in blood that are currently being developed withtreatment. Even if medicines are prethe participation of iCONM, Nikon, The National Canscribed, patients do not consume them as
cer Research Center, The University of Tokyo, Riken,
instructed, and neither doctors nor paand the Tokyo Medical and Dental University looktients are able to verify their effects.
good. Small prototype devices are also being evaluatedMany patients stop taking medicines because they(Figs. 3 and 4).
think that they have been cured or give up treatment
Iizuka: Although microarrays are effective tools forbecause they think they will not be cured.
comprehensive detection of miRNAs, it takes one whole
Iizuka: Until now, the time-course of varying biomarker
day to gather results. In combination with our originallevels has been not examined in detail. Our diagnostic
microarray method, the system besystem would allow frequent monitoring of physicaling developed allows miRNA detecconditions by measuring the exosomal miRNA levels.
tion in 20 min.
We may be in a position to discuss general diseases, inShiono: It is a fairly compact decluding cancer, if 50 of the 2,500 miRNAs are detected.
vice, but I think that some kind of
Ichiki: Specific cancers might be detected using several
breakthrough is necessary to makemiRNAs. Nevertheless, it is noted by researchers in
it small enough for doctors to carryother fields that, because the human body is made up
around. We believe that in vitro diof various molecules, whether it can be judged using noagnosis using body fluids such as
more than several kinds of molecules.
urine and saliva is favorable, but
Iizuka: I agree. For example, when the stomach andhurdles such as those regarding achead hurt at the same time, one can anticipate excuracy and safety arise when thetremely complex events in the body. In such a situation,
general public uses it for themselves rather than
it is better to compare the profile of exosomal miRNAs
healthcare workers.
with that observed during normal conditions, because
Iizuka: I hope the diagnostic system is also available inthis is likely to yield information about the body. The
places such as convenience stores. Then, people whodrive toward personalized medicine was initiated inbuy self-test kits will get results on the site.
2003 when the human genome was completely seShiono: Pharmacies are also a good option. People
quenced, but it is yet to be practiced in reality. I thinkwould be happy to get quick results.
that our approach would certainly advance personalIchiki: We believe that preventive diagnosis using thisized medicine in the near future.
device will not be popular unless health checkups canIchiki: Researchers in the US, who led the human gebe conducted at a low cost.
nome project, are working on another project to gather
Shiono: Although importance is attached to diagnosis
samples from healthy individuals over a period of time,at the site of treatment, it is difficult to judge the effecto further explore biomarkers that indicate the actual
tiveness of the treatment provided. Individual differencstate of health.
es in the state of health or effects of treatment are obThis is an indispensable approach in preventive medivious, and the effect of these differences will not becine. It is difficult to obtain samples from healthy individuals; such research requires time
Figure 3. Development of an miRNA Diagnostic Device
and money.
Procedure so far
Rapid + fully automated system
In Theme 4, we are developing inexpensive, large-scale, information-gathLiquid sample

1 Plasma separation
2 Exosome purification

Exosome separation
and recovery

Blood
Reagent

3 miRNA purification

Reagent
Waste
liquidOptimaL-90K

4 Detection

Waste
liquidWaste liquid

miRNA purification
miRNA

Sequence analysis
using a microarrayetc.

4 | NanoSky VOL.03 MARCH 2017

Waste liquid

Minimally invasive diagnosis
that automatically reads multi-biomarker
information from miRNAin blood/urine/saliva

Figure 4.
Nano-Diagnostic Device NDX-2

ering devices, and would like to collaborate with biomarker researchers by sharing a common purpose.
Because miRNA has not yet been clinically measured,
the evaluation indices of new medical devices are being
investigated, with institutes such as the National Institute of Health Sciences being on board.
Iizuka: The current diagnosis and treatment are basedon the knowledge and experience accumulated overmany years, and therefore, our concept of preventively
measuring exosomal miRNAs and using it for use-athome diagnostics and treatment seems challenging.
Whether we can create something that can convince
healthcare workers and thus overcome the historicalbarriers in medicine is, I believe, what we are now
challenging.

Research speed and network
attracts the attention of COINS■ What do you feel about the COINS researchsystem and iCONM?
Iizuka: The aim of COINS is clear, and it is good to beable to listen to the opinions of various individuals involved in research. For example, various kinds of microdevices have so far been developed. However, if
these are created without understanding the actual
need and use, they will remain unused. I feel the quality will differ depending on whether there is a clear
way out.
Ichiki: That’s right. The most important point about
this project is to share the vision of the futuristic technologies. When researchers participate in one major
project, they tend to focus primarily on what theywant to do, but, in this case, the direction of research
is unified while taking advantage of every original idea
presented by every scientist.
Shiono: The process of determining vision and mission
at retreat camps and the like is rather uncommon in
the business sector. This brings about an awarenessabout the extent of participation in this project, doesn’t
it?
Iizuka: It is characteristic that research and development are rapid enough to adopt new changes. For example, if I want to try to use the device with a different channel structure, my co-researcher can prepare it
quickly. If it succeeds, and this may not be the best example, it feels like assembling a radio-controlled modeland exclaiming “It’s good! It worked!”–simply because I
could not fly radio-controlled models well as a child.
Ichiki: Even if we develop an elementary technology,
for example, an miRNA detection method, we need engineers who can work together to take the technology
to a point where it is turned into a device, refine it at
the site of utilization, and integrate it into a medical
system. Here, we have invested research funds and resources over a period of time; universities and businesses have participated, and we are literally bouncing

ideas off each other. This would not have been possible
based on basic research funds alone.
Iizuka: I think that repeated attempts to create andevaluate cutting-edge innovations are difficult for a single university, research institution, or company.
Shiono: I think it is characterized that we could workwhole-heartedly toward it as a national project. The
iCONM has assembled related areas such as biochemistry, organic chemistry, and nanofabrication, and has thenecessary infrastructure and laboratory to safely undertake biological experiments. Thus, an environment
consistent with its objectives is in place. It is also goodto have so many exchange meetings and study meetings. You end up meeting new people within the company.
Ichiki: We usually never get to meet
people from the medical industry.
However, here, we are always able tocommunicate with each other and understand the varying thought processes prevalent in the industry.
Iizuka: In general, young academic
researchers, including undergraduate
and graduate students, have little
chance to interact with people fromdifferent research communities. However, it will be possible here. I thinkiCONM is a great place to nurture
people.

■ With COINS and iCONM systemizing and linking
elemental technologies, this collaboration canachieve things, which neither a university nor an
enterprise can, by incorporating cutting-edge
research into innovative products and give rise to a
new networking place. The yet-to-be-generated
results of this research are already garnering a lotof interest, and we are all waiting in anticipation.
Thank you very much.
(Interviewer: Science Writer Ayumi KOJIMA)
Terminology＊1 miRNA (microRNA)
miRNAs are approximately 22 nucleotides in length, which posttranscriptionally regulate gene expression. The existence of miRNAs was
first discovered in nematodes in 1993, and they are found in variousorganisms, including plants, and animals and viruses. miRNAs are involvedin various biological events and diseases, and expected to be used as
nucleic acid drugs and diagnostic markers. Most of extracellular miRNAs
are encapsulated in exosomes.
＊2 Exosome
A lipid bilayer vesicle, ～100 nm in diameter that is secreted by many cells
and encapsulates various molecules. Exosomes have recently been foundto function as a communication tool between cells. They are actively being
studied in detail.
＊3 Biomarker
An entity characterized by objective measurement to be an indicatorof conventional biological processes, pathological processes, or
pharmacological responses to therapeutic intervention. A biomarker is aliving body-derived marker for understanding the physiological condition anddisease state. The so-called tumor markers are examples of biomarkers.

NanoSky VOL.03 MARCH 2017|5

Interview

Interview with Researcher
Connecting Exosomes and miRNA
research to an understanding ofBiological phenomenon and Healthcare
Takahiro OCHIYA
Chief, Division of Molecular and Cellular Medicine
Advanced Medical Biology Research, Treatment
Development Group
National Cancer Center Research Institute

The diagnostic device being developed in Theme 4 in COINS aims to analyze
miRNAs encapsulated in exosomes secreted from cancer cells. Takahiro Ochiya,
Chief in the Division of Molecular and Cellular Medicine, National Cancer Center
Research Institute is supporting basic research in this project. I asked Chief Field
Manager Dr. Ochiya, who leads world exosome research, about current exosome
research and the spread of exosome research.

To deepen our understanding of
exosomes and elucidate mechanisms of
diseaseOnce looked upon as the "cell trash can", exosomes have beenstudied on a smaller scale. Exosomes have been a major global
topic in biology and medicine over the last 10 years since 2007
when it was first reported that exosomes contain miRNA (Figure 1).
Exosomes are nano-sized vesicles having a diameter of about
100 nm that encapsulate miRNAs as well as mRNAs and carryproteins and DNA information (Figure 2). Exosomes are conformed by a lipid bilayer similar to the one of the cell membrane, they have molecules such as proteins present on theirsurface and these are thought to be involved in exosome secretion and cellular uptake.
A function of exosomes that is currently drawing attention istheir relationship with cancer malignant transformation including metastasis.
Chief Ochiya says“Many cancers metastasize to specific organs. In terms of which organ cancer metastasizes to, a new
finding has been shown that this depends on the type of surface
integrin on exosomes secreted from cancer cells. Integrin is a
protein known to be a cell adhesion substance. It is speculated
that exosomes are taken up into cells in organs that are metastatic targets guided by the exosome integrin, and various molecules in exosomes create an environment to draw in cancer
cells.”Furthermore, he explained that“our research results also
clarified that specific exosomes are involved in brain metastasisof breast cancer. Exosomes destroying the brain blood barrier
were secreted from breast cancer cells that are easily metastaFigure 1. Basic Research into Exosomes and Scope of Application

sized to the brain.”(Figure 3).
Thus, secretion of exosome that conveys the signal of disease
onset and deterioration, and inhibiting efforts on target cells
may lead to the prevention of disease which is the subject ofdrug discovery.
On the other hand, so to say“good exosomes”that do a goodjob has been studied.“In the field of regenerative medicine, forexample, the use of mesenchymal stem cell exosomes and miRNAs that have the ability to differentiate into bone, blood vessels, and myocardial cells is being investigated”. That is,strengthening the exosome working physiologically within the
body helps maintain health. Originally exosomes were a communication tool secreted in response to the physiological statusof the body and it is thought that the miRNA encapsulated
therein is important. One reason is that there are two types ofmiRNA, one that emerges from dead cells into bodily fluid andcirculates unchanged and one that circulates within the exosome, and it is speculated that the latter is a "spontaneous" message. Chief Ochiya et al calculate that about 37 % of the total
RNA amount in the blood is contained in exosomes in the formof secretory miRNA. "I think that about 40 % of this miRNA is
specifically encapsulated in exosomes and I believe this has
meaning and has an important role. It is possible to understandthe complexity of the body by understanding the important role
carried out by exosomes. I also expect that it’ll lead to an understanding of diseases for which effective medicines have notbeen developed, for example, mental disease like depression andautism, and lead to the development of therapeutic agents.”
This seems to be a world apart from the image of exosomes
which was once said to be a“cell’s trash bin".

Figure 2. miRNA Secreted from an Exosome

Basic exosome research (disease)
Disease exosome analysis

Exosome analysis techniques

Understanding the mechanism of
diseases in which exosomes participate

Tissue regeneration carried out by
exosomes, disease healing ability(function, markers etc.)

CancerChronic diseaseAging(isolation, purification etc.)

Mesenchymal stem cell
Immunocompetent cell

Correspondencewith illness

Verification withclinical sample

Disease biomarker
Cancer metastasis treatment

Drug Delivery Technology (DDS)
Regenerative medical

Destruction of bad exosomes

Use of exosomes for treatment of disease

Realize application to diagnosis of diseases/treatment

The development of diagnostic/therapeutic methods targeting exosomes (badexosomes) from cancer cells and the therapeutic application of exosomes (goodexosomes) from mesenchymal stem cells in regenerative medicine are anticipated.
DDS development of exosomes is also an important subject.

6 | NanoSky VOL.03 MARCH 2017

Membrane protein

Cell

Endosome

Diameter
40-200 nm

ExosomeA small vesicle ofabout 100 nm diameterencapsulated in a lipid
membrane released from cells
miRNA
Non-coding RNA（20-25 bases）

miRNA is encapsulated by exosome and is stable over a long
period even in blood. The presence of more than 700 miRNAs
has been confirmed and it is possible to identify the primarycancer organs with relatively high accuracy only by analyzing a
relatively few expression patterns.

Front-line Research for miRNAs andexosomes
Chief Ochiya’s research in this field began with a view to
exploring the relationship between miRNA and cancer andapplying it to therapy. From the latter half of the 2000s toaround 2010, he examined miRNAs whose expression change incancer cells and proved the therapeutic effect by replenishingthose miRNAs to cancer cells in a mouse model that caused
cancer and suppressing by administering nucleic acids ofcomplementary sequence. After that, he analyzes the functionof miRNAs whose expression is altered in cancer cells, andstudied the relationship between drug resistance ability andmiRNA and the relationship with cancer stem cells.
From 2007 onwards the scope of research has also expanded
to exosomes. In 2010 he clarified, for the first time in the world,that exosomes envelop miRNA and function as an informationtransmitter, that mother's milk contains maternal miRNA andworks in children's cells. Apart from studying the relationshipbetween cancer malignancy and exosomes, he is also currently
creating a database of exosomes and miRNAs from samples
held in The National Cancer Research Center, searching forproteins in specific exosomes from cancers, and is developing
early diagnosis methods using these samples. One of them isthe method of early diagnosis of about 140 kinds of miRNAs
with high sensitivity microarray chip on examination site for 13
kinds of cancer and dementia, and industrialization has come tobe seen. "We will calculate combinations and detection
frequencies of miRNAs with artificial intelligence, and willfurther give sensitivity and specificity. Anyhow, I would like tohave the ability to investigate all 2500 miRNAs even at home.”
Chief Ochiya expects that in the future new knowledge will
be forthcoming from a combination of transcriptomes to analyze
epigenetic DNA changes and mRNA and other biologicalinformation and, in doing so, thinks that the use of artificial
intelligence in analysis is essential.
In COINS, he is developing technology for the detection andanalysis of exosomes and miRNA for participation in Theme 4
and, using exosome surface molecules as clues, he is in theprocess of developing methods to find and measure exosomes(see p. 2, 8, and 10). "In COINS, natural nanoparticles such as
exosomes and artificial nanoparticles such as polymeric micelles
are studied at the same time. I am applying them to prevention
and from ultra-early diagnosis to treatment and am focusing on
their industrialization. Measurement methods cannot be
developed nor can they be industrialized with only researchers
Figure 3. Novel Mechanism of Breast Cancer
Metastasis to the Brain by Exosomes（1）
Action of Exosomes（3）Inﬁltration

Exosomes
Cancercell（2）Blood-brain barrier penetration

working in basic research centered on biology such as
ourselves. COINS has gathered researchers in engineering,
pharmaceutical science and medicine and experts in manydifferent fields such as business and intellectual property toform a particularly unique and useful project. If smart life carein daily life is achieved while unconsciously monitoring changes
occurring within our bodies, we will be able to make acontribution to Japan which will have an aging society andincreased medical expenses.”

Exosomes may also be related tothe evolution of living organisms
Chief, Ochiya is currently mainly studying cancer as a target
but, of course, other diseases too as well as broadening his fieldof vision relating to the maintenance of homeostasis in humans
and other living organisms, environmental factors andexosomes.
"Exosomes and miRNAs are present in many biologicalorganisms regardless of their species. Moreover, the possibility
that exosomes and miRNAs can transfer between different
species began to be reported. Although it is known that miRNA
inhibits bacterial invasion and promotes growth in plants, plantderived miRNAs may act similarly in our bodies so exosome
and miRNA research may lead to the development of
supplements and superfoods that will make our bodies
healthier."
Furthermore, Chief, Ochiya also predicts the involvement ofspecies differentiation, the evolution of living things such as
spontaneous mutations, and extracellular vesicles such as
exosomes. "As I mentioned earlier, exosomes are conserved inmany biological species. Exosomes also contain DNA fragments
as well as transposases. It would be interesting to think of using
them as a tool to create diverse evolution by incorporating a
specific genomic unit into the genome of another person."
Although listening to the details of“cells chatting to eachother” through studies of exosomes and miRNAs thenelucidating the physiology of living organisms and making useof them in medical care and health broadens our interests, "Iwould like to put more emphasis on fundamental research as
this is a research field where applications are expected”saysOchiya Chief expressing his ambitions.
(Notes: science writer Ayumi KOJIMA)PROFILE
Takahiro OCHIYAIn 1988, he obtained PhD after completing the doctorial course at Graduate School of
Medicine, Osaka University. After working as an assistant professor at Osaka University
Institute for Molecular and Cellular Biology, he became a researcher at La Jolla Cancer
Research Foundation in the United States in 1991 and chief researcher at the National
Cancer Center Research Institute in 1992. In 1993 he was a director of the Laboratoryof Molecular Oncology at the same institute and in 1998 he took on his present positionas Head of the Cancer Metastasis Laboratory of the same institute. He has been serving
both as a visiting professor in the Department of Advanced Science and Engineering at
Waseda University since 2004 and a visiting professor at the School of Life Scienceand Technology, Tokyo Institute of Technology since 2008.

References
1. Kosaka N et al., The Journal of Clinical Investigation, 126（4）:1163-72（2016）（4）Brain metastasis(1) Exosomes secreted by breast cancer cells act on cells making up the blood-brain barrier,and (2) destroy the blood-brain barrier. (3) Cancer cells infiltrate the damaged blood-brain
barrier and eventually (4) brain metastasis is established.

2. Tominaga N, et al., Nat Commun. 6, Article number: 6716（2015）
3. Kosaka N et al., Silence 1:7（2010）（3）:326-34（2016）
4. Shimomura A et al., Cancer Science, 107
5. Akagi T, et al., PLoS ONE, 10, e0123603（2015）

NanoSky VOL.03 MARCH 2017|7

Reserch
Highlights

1

Theme 4

New light on cancer diagnosis!
Success in capturing nanoparticles
released from cancer cells“Cancer”was discovered. However, it was detected early so it can be treated.”
The biggest therapeutic agent for cancer may actually be early diagnosis. It has recently been found that
exosome secreted by cancer cells are useful in early diagnosis and this has attracted attention. In this study,
a novel method to capture and detect exosomes secreted by cancer cells into the blood using an antibody
was developed and possibility of early cancer detection was demonstrated. I hope that the number of people
suffering from cancer will decrease in the future with early diagnosis using exosomes.

Yusuke YOSHIOKA
Researcher,
Division of Molecular and Cellular Medicine,National Cancer Center Research Institute

Currently, cancer is treatable if found early so the development of diagnostic methods aiming at early diagnosis and the search for biomarkers are being actively
conducted. Nanoparticles of around 100 nm in diametersecreted by various cells have recently attracted attention as new biomarkers. This nanoparticles are called
exosomes and contain nucleic acids such as mRNA andmiRNA and various proteins and circulates in body fluids[1]. Since exosomes secreted by cancer cells envelop
specific molecules, attempts have been made worldwide
to use these specific molecules in diagnosis by detecting
exosomes secreted by cancer cells in body fluids suchas blood and urine.
We focused on the protein present on the lipid bilayer
membrane of exosomes and worked on the development of a new exosome detection method[2]. Conventional exosome detection methods mainly focused on Western blotting ＊1 so it was necessary to purify andconcentrate exosomes using an ultracentrifuge. However, purification of exosomes by ultracentrifuge is time
consuming, labor intensive and has a low throughput.
When clinical application is intended, a high throughput
method that eliminates the need for purification of exosomes, a highly sensitive detection system and multisample treatment are required. We developed a method
to detect exosomes in a short period of time using anantibody that specifically recognizes proteins present on
the exosome membrane and two types of beads (Figure
1 ExoScreen). As it was possible to detect exosomes using this method by simply mixing an exosome-containing solution (body fluid), antibody, and beads on a 96well plate, high throughput was achieved and exosomes

8 | NanoSky VOL.03 MARCH 2017

were extracted from 5 µL of healthy serum＊2.
We then searched for proteins specifically containedin exosomes secreted by cancer cells in order to detect
exosomes secreted by cancer cells. It was consequently
found that a membrane protein called CD147 was common in exosomes secreted by colon cancer. As a resultof attempting to detect serum exosomes from 194
colorectal cancer patients and 191 healthy volunteers
using CD147 as a marker, it was shown that CD147-positive exosomes are extremely common in the sera ofcolorectal cancer patients. It is thought that colon cancer cells secrete this protein as CD147-positive exosomes decrease when tumor tissue is removed by surgery. Furthermore, as CD147-positive exosomes aredetected in early colon cancer, which cannot be detected using the conventional biomarkers of CEA andCA19-9＊3, new diagnostic methods using exosomes havedemonstrated utility in early diagnosis (Figure 2).
If this is limited to colorectal cancer alone and if earlycancer (stage I) can be diagnosed, then the 5-year survival rate will be almost 100%. However, as discovery isdelayed because there are few subjective symptoms in
the early stage, it is desirable that cancer can be accurately discovered by a less invasive blood test such as
this method. By advancing our research results in the
future, it is thought that it can be applied not just tocolorectal cancer but also to pancreatic cancer which issaid to be difficult to detect early. Day to day we areworking on the development of diagnostic methods using exosomes aiming at “early diagnosis is the besttreatment".

Figure 1. Summary Figure of ExoScreen Method

Exosomes secreted from cells bind to 2
kinds of bead (donor bead and acceptorbead) via an antibody. The oxygen molecules around the donor beads are converted to singlet oxygen (1O2 ) when irradiatedwith light at 680 nm. When this singlet oxygen reaches the acceptor beads, the acceptor beads emit light. The amount of
exosomes present in body fluids can bemeasured from the intensity of this emission. In this case, the amount of exosomesfrom cancer cells can be measured by using antibodies against specific molecules
present in the exosomes secreted by cancer cells and this is usable in diagnosis.

Excitation
wavelength

Fluorescencewavelength

200 nm or less

680 nm1O

Antibody

2615 nmAntibody

Diameter250 nm

ExosomeDonor beadAcceptor beadModiﬁed from Yoshioka Y. et al . Nat Commun, 2014

Figure 2. Specific Exosomes Secreted by Cancer Cells

Diameter 40〜200 nm

Colon cancer cells

On the exosome membrane
Transpanin
Lipid raft
Adhesion molecules etc.

Cancer cell-derived
exosomes

Within the exosome
miRNA
mRNA
Signal transmitters etc.

Stromal cells(immune cells, ﬁbroblasts etc.)

Exosome

Tumor

CD147
Speciﬁc molecules encapsulated byexosomes secreted by cancer cells

Normal cell-derived
exosomes

Exosomes are secreted not only from cancer cells but
also from normal cells and circulate in human body
fluids. The exosomes secreted by cancer cells,
however, contain specific molecules and, as an

Blood vessel

example, exosomes secreted by colon cancer cells
contain CD147. Early colon cancer can be discovered
by detecting exosomes in blood using this molecule asa marker.

Terminology＊1 Western blotting (immunoblotting)A typical method to detect specific proteins. Proteins are separated according
to molecular weight by electrophoresis using polyacrylamide gel and are thentransferred onto a membrane. The target protein is detected on this membrane byimmunostaining using an antibody that recognizes the protein.

＊3 CEA, CA19-9
Both are used as tumor markers of gastrointestinal carcinoma. However, since
they are difficult to detect in early patient blood, they are often used in theevaluation of therapeutic effect by treatment intervention, and are not used inblood tests such as examinations.

＊2 Serum
The liquid component of blood after the cellular component has been removed.
It contains no coagulation factors since blood cell components coagulate andclots precipitate upon centrifugation. It is used in many biochemical blood tests.

References[1] Raposo G. & Stoorvogel W., J Cell Biol, 200, 373-383（2013）[2] Yoshioka Y, et al, Nat Commun, 5, 3591（2014）

NanoSky VOL.03 MARCH 2017|9

Reserch
Highlights

2

Theme 4

Starry sky observations in microspaces?
Development of a revolutionary
nanoparticle analysis system

The development of diagnosis and treatment using particles (nanoparticles) having a diameter of about 100 nm suchas exosomes and polymer micelles is advancing. The importance of analyzing individual particles is increasingin the development of nanoparticle applied technology. Nevertheless, in conventional instruments it was not easy
to measure these particles individually. In our research, we have developed a system that tracks and analyzes the
movement of nanoparticles in microchannels using scattered light. This system is expected to speed up researchand development of nanomedicine and contribute to the realization of new diagnostic methods and treatments.

Takanori AKAGIProject Associate Professor
Department of Bioengineering, Graduate School ofEngineering,
The University of Tokyo

The development of medical technology using 100 nm
diameter particles such as exosomes and polymer micelles has been actively conducted recently. For example, if it is possible to detect exosomes secreted from abnormal cells such as cancer cells among the exosomespresent in blood, the presence of abnormal cells in the
body can be determined. Moreover, in drug delivery
systems (DDS) using polymer micelles, drugs can be delivered to specific sites only, so effective drug treatment
can be carried out. In the development of technologies
for medical applications of these nanoparticles, the importance of single particle measurement technology inanalyzing various nanoparticle clusters is increasing. It
was, however, not easy to measure nanoparticles individually using conventional apparatus so I have developed a single-particle detection system for nanoparticles
that uses a microfluidic chip by combining laser darkfield illumination with high-sensitivity imaging. This system consists of a polydimethylsiloxane (PDMS) polymer
microfluidic chip and a platinum electrode, a high voltage power supply, a laser light source, and a high sensitivity camera. The equipment configuration and a prototype system are shown in Figure 1.
After introducing the nanoparticle sample into theflow path, scattered light is generated by the particles
when an incident laser beam is shone from the side of
the chip. When this scattered light is focused with anobjective lens and imaged with a high sensitivity camera, the bright spots of twinkling and flickering nanoparticles are observed in microspace as shown in Fig. 2a.
Quantitative information on particle concentration,

10 | NanoSky VOL.03 MARCH 2017

particle diameter distribution, surface potential (zeta po＊1
tential ), and surface molecules (surface markers) canbe obtained for each particle by tracking and analyzingthese bright spots.
Figure 2b shows an example of exosome analysis carried out as a model experiment. The exosome sample
was prepared from a cultured human breast cancer-derived cell line (Sk-Br-3 cells) by purification from culture
supernatant with density gradient centrifugation using
fraction ultracentrifugation and a density gradient centrifugation medium (OptiPrep). The exosome sample
was allowed to react with an anti-CD9＊2 antibody or acontrol antibody (IgG) not bound to CD9, and this wasthen introduced into a microfluidic chip for measurement. There was no significant difference in particle diameter distribution between exosomes reacted with anti-CD9 antibody or control antibody. A significant
difference was, however, observed for the zeta potential
of exosomes that reacted with the control antibody having negative potential and exosomes that reacted withthe anti-CD9 antibody having a positive potential. The
difference in zeta potential is thought to be because of
the positive charge of the anti-CD9 antibody bound to
the exosome surface. It was demonstrated in this experiment that a small amount of CD9 protein present on
the exosome surface can be evaluated using a change inzeta potential as an index. This system will accelerate
the research and development of medical technology using nanoparticles, and it is anticipated that new diagnostic methods and treatments will materialize.

Figure 1. Device Configuration of a Microfluidic Chip-type Nanoparticle Analysis System

Platinum electrode

ExosomeDC power supply

Flow reservoir
Laser light source

Fluid path height :100 μm＊3

Rayleigh scattered

Fluid path width :200 μmlight

Objective lensThis is composed of a laser dark-field microscope opticalsystem and a microfluidic chip made of PDMS. The laser
beam that forms a sheet-like shape is shone from the sideof the flow path, the scattered light generated by particles
in the flow path is focused by an objective lens below theflow path, an image is formed with a high sensitivity camera
and a high contrast dark-field image results. In dark fieldimaging＊4 , it is possible to individually detect nanoparticles
with a size less than the diffraction limit of light that cannot
be detected by illumination using general transmitted light.

Fluid path length : 1000 μm

MirrorHigh sensitivity camerab20

Number

a

10
5

15

20

35
30

b. Particle diameter measurement by Brownian motion analysis
and zeta potential measurement by electrophoretic analysis are
performed consecutively for individual exosomes so that themeasured values of particle diameter and zeta potential are associated with individual particles. This shows an example ofanalysis of exosomes derived from the culture supernatant of
human breast cancer Sk-Br-3 cells. Measurement is carried out
after treatment with the exosome markers, anti-human CD9 antibody and control antibody, and a change in zeta potential
caused by binding of antibody to the marker protein on the exosome surface is observed.

10

-20

Zeta potential（mV）

a. When a sample having exosomes dispersed within it is introduced and positioned in a dedicated measurement device, theexosomes can be detected and it is possible to see an image
which is like a starry sky.

Number

10

100μm

0

0
-25

5

25
20
15
10
5
0

15

NumberFigure 2. Example of Analysis of Exosomes Derived from Human Breast Cancer Sk-Br-3 Cells

-15
-10
-5
0
5
10
15

0

200

400

600

800

1000

Diameter（nm）

NumberExosome reacted with control antibody (IgG)
Exosome reacted with anti-CD9 antibody

Terminology＊1 Zeta potential
An electric potential that attracts and fixes ions with opposite charges in anelectrolyte due to the charge generated on the surface of the substance. The zeta
potential of an exosome can be understood from measurement of the speed of
exosome migration when a voltage is applied to a solution in an electric field inwhich exosomes are suspended.
＊2 CD9A type of tetraspanin protein assumed to mark exosomes.

＊3 Rayleigh scattering
Light scattering by tiny particles smaller than the wavelength of light.
＊4 Dark-field imaging
A method of observing high contrast and microstructures in observations using a
microscope by observing scattered light generated in a sample being observed.

References

Akagi T, et al., PLoS ONE, 10, e0123603（2015）

NanoSky VOL.03 MARCH 2017

| 11

Listen to

COINS'
Members

Kazuo HOSOKAWA
Analysis of miRNA and DNA in body fluids isthought to be useful in the diagnosis of cancer
and the like. We are developing a microfluidic
chip to simply conduct such analysis.

m ed into protein, contains about 22

iRNA is an RNA which is not translat-

bases, and regulates gene expression incells. It has recently been found that miRNAis also present in body fluids such as bloodand it is thought possible to diagnose cancers by analyzing specific miRNAs in blood.
Conventionally, quantitative PCR has beenused for this purpose but requires a complex
procedure taking 2-3 hours and this is difficult to conduct in the clinic or at home.
We are developing microfluidic chips
where miRNA analysis takes about 20 minutes by simply introducing samples and reagents. The chip is made of rubber andglass known as PDMS and there is a Y-

Ryo KOBAYASHI

o you know the sport of orienteering?

around successive check points drawn on a
map and competing on a time basis to thegoal. In Japan, the image of camping school
recreation is deeply rooted but it is, in fact, avery tough competition competing for even a
1 second advantage by running practicallyfrom the start to the goal. The areas where
the competition takes place are often in forests near villages but recently competitions
have also been held in parks and on university
campuses. I came across this sport when I
was a student and I have been enthusiastic intravelling overseas to represent Japan. Even
after becoming an adult, I frequently find a

12 | NanoSky VOL.03 MARCH 2017

Senior Research Scientist
RIKEN
Maeda Bioengineering Laboratory

Analysis of a nucleic acid biomarker
using an original microfluidic chipshaped microchannel on the bonded surface. PDMS takes in air so samples and reagents placed by the entrance of thechannel automatically flow into the chip.
The specific miRNA present in the sample
binds to DNA immobilized on the glass surface and then binds a fluorescently labeledreagent molecule for detection.
Recently however, we have tried to apply
microfluidic chips not only to the analysis of
miRNA but to DNA methylation as well.
DNA derived from cancer cells is also present in blood and it has been found that it
has a characteristic methylation abnormalitythat is related to the type of cancer and malignancy. When the methylation of DNA isanalyzed using a microfluidic chip, a specificsequence of DNA is bound to the DNA on
the glass surface and the methylated cytosine base binds to antibody. We are aiming
at practical application of this chip as soon
as possible and we are pushing our researchforward every day.

Microfluidic chip under development.

NIKON Corporation
R&D Department, Medical Business Promotion

The appeal of cutting a way throughwithout a roadD This competition is a sport of navigation

What w

nearby race and take part. Although roads arealso shown on orienteering maps they are notnecessarily the fastest route. I often you goover a mountain ridge, go through thickets,and jump over streams. The real thrill of this
sport is instantaneously reading topography
and aiming at the goal by cutting a way
through by oneself, and this is the thing I’m
addicted to.
In my company, I am in charge of developments in the medical field, which is a new
business for us, and we are collaborating with
the Ichiki Laboratory which is my old laboratory. While using cutting-edge equipment at
iCONM, we open new paths and push research and development forwards day by day

We are developing in vitro diagnostic devices
for POCT (Point of Care Testing) that canprocess a sample and return the results in ashort time.

in order to realize“rapid diagnosis". The more
you research, the more the things you don’tknow emerge on a daily basis and, although
this is serious, I’m filled with excitement, I really enjoy it and I feel fulfilled every day.

The situation at Yatsugatake’s race. I run hard without aroad.

e treasure
Akira MATSUMOTO

Associate Professor
Tokyo Medical and Dental University Institute of
Biomaterials and Bioengineering

Aiming to develop "boronic acid engineering" having
outstanding compatibility with biomolecules
B cules, and its selectivity is syntheticallyoronic acid interacts with various biomole-chemically variable. It is also known as“boronolectin”because of its binding to carbohydrate. Molecular recognition involving boronic acid causeschanges in physical properties synchronous withits dissociation equilibrium and this can lead to various functionalities by incorporating them into material design.
I am fascinated by this characteristic and conducting medical engineering research by paying a
lot of attention to "making it readily available". We
have recently focused on the development of an
artificial pancreas by application of boronate gel inparticular. An existing artificial pancreas for thetreatment of diabetes comprises a machine

equipped with a power supply, a motor, a microcomputer etc. but we have created an artificial
pancreas-like, blood sugar-dependent insulin supply mechanism using only boronate gel and havealready demonstrated its safety and therapeutic efficacy in small animals. It is inexpensive and robust
and, because it has high affinity for existing medical devices such as needles and catheters, it ispossible to create a“just pierce and paste artificial
pancreas”. It is expected to form the next-generation technology to solve unmet medical needs indiabetes (long-term blood sugar control, avoidanceof hypoglycemia, reduction in patient burden). I feelstrongly about the potential of "boronic acid engineering" which involves superb affinity to biomolecules and creates dynamic function. I would like to

Fumi TOSHIOKA
I have been affiliated with the Ichiki Laboratory
since April 2016 and am carrying out research
into diagnostic devices aiming at achieving
minimally invasive cancer diagnosis using
miRNA testing.

I cancer diagnostic markers and im-have been engaged in research into

proved drugs for lifestyle diseases in thearea of biochemistry such as protein analysis using cultured cells. When I heard about
the COINS project, I initially wondered what
diagnostic devices, which were in a completely different field of engineering researchfrom mine, were? It was a starting point.
When I went to visit the Innovation Center of
NanoMedicine, I didn’t know what some of
the instruments measured although I’dheard the names from familiar devices, and I
was curious about this interesting place. Researchers from many institutions are conducting research all under one roof and it

When the molecular recognition ability of boronic
acid is skillfully combined with materials, it ispossible to achieve multi-level environmental
responsiveness and functionality. We areconducting biological measurement and DDS
research which cleverly utilizes this system.

contribute to the realization of an 'in-body hospital'
while proposing a unique method of use for them.
Skin adhesion site

Insulin reservoir

Subcutaneous
injection site
Needle, catheter etc.

Insulin

Glucose-responsive gel(boronate gel)Image of a“just paste artificial pancreas" which combines
boronate gel and minimally invasive subcutaneous
injection technology.

Research AssistantIchiki Laboratory
Innovation Center of NanoMedicine, Kawasaki
Institute of Industrial Promotion

As a working mother, I want to respondto my daughter's smile
was extremely open and I felt the closenessof the gap with society. When I worked in aclinical investigation company, conventional
cancer diagnosis was made by biopsy of apathology sample and diagnosis took 2-3
days with cytodiagnosis by a pathologist.
Furthermore, it is likely that mistakes withsamples occur as samples pass through thehands of many people in preparing them. It
was actually a chilling moment. If diagnostic
devices linked to research are placed in hospitals, accurate and rapid diagnosis may bepossible.
I have a 5-year-old daughter who has
been to nursery school since she was lessthan one year old. Although I am anxious

about working while trusting small children,each morning she send me on with a smileand say,“Good luck with your work today!" I
want to cherish
the time spent withmy child and one
day I can say that
“ Yo u r m o t h e r
helped create thisdiagnostic device”.

My 5-year-old daughter full ofenergy.

NanoSky VOL.03 MARCH 2017

| 13

ACTIVITY REPORT
3rd COINS International Symposium

Towards Smart Health Society〜Challenge of Kawasaki based Medical Innovation〜
The first international symposium in Kawasaki was held on Thursday, December 15 with the theme of“Towards Smart Health Society 〜 Challenge of Kawasaki based Medical Innovation 〜”at Kawasaki City Industrial Promotion Hall. The number of theparticipants has reached nearly 300, and it was a great success toopen up the spare second floor seats. Unlike the past two symposiums, the proportion of visitors from industries and general was
higher than that of universities and research institutions. We could
see that the interest in COINS efforts was very high.
The symposium started with opening remarks of Dr. Yuzuru Matsuda, Vision 1 Visionary Leader, JST Center of Innovation (COI)
program (Former president of Kyowa Hakko Kirin Co., Ltd.). After introducing COI program, he expressed high expectation to COINS
and Kawasaki city.
In session 1「Medical Innovation/Forefront of Technology」, after
introducing COINS’major research outcome, Dr. Xiaoyuan Chen,
Senior Investigator and Lab. Chief (NIH) and Professor Wim Hennink, Department of Pharmaceutics, Utrecht University gave talk on“Albumin-Binding Evans Blue Derivatives as Theranostics”and“Polymeric Micelles for Targeted Drug Delivery”.
In session 2「Forefront of Medical Innovation Eco-System」, after
COINS effort being introduced, Mr. Peter Takizawa, Senior commercial officer of Life Science, Danish Embassy gave talk on“Medicon Valley – A Danish-Swedish Life Science Cluster”.He explainedthat 60% of the employment in the life sciences field in Denmarkand Sweden is in Medicon Valley, that 99% of the markets targetedby companies in Medicon Valley are overseas markets, and it iseasy to change job or start up new business because the move between the companies is flat. This indeed impressed the audience.
In poster session, 28 posters were presented by COINS participating researchers, organizations and local government and there
were active discussions and exchanges between the participantsPeter Takizawa

Ryuta Nomura

Osamitsu Yamada

Chairman of the Board and chief Chairman, Kawasaki Chamber
Senior commercial officer,
executive officer, Central Institute for o f C o m m e r c e a n d I n d u s t r yLife Science, Danish Embassy Experimental Animals (CIEA)(Kawasaki CCI)

with coffee in hands.
In final panel discussion, as theme of Innovation through community collaboration, the session started with greetings by Mr. Ryuta
Nomura, Chairman of the Board and chief executive officer, Central
Institute for Experimental Animals (CIEA) and Mr. Osamitsu Yamada, Chairman, Kawasaki Chamber of Commerce and Industry (Kawasaki CCI) and followed with short presentations by Mr. Kazuhiko
Tamai, Department Director, Headquarters International Strategy
Promotion Department, Kawasaki City Coastal Area International
Strategy, Mr. Hideki Kaji, Vice Chairman, Kawasaki Chamber ofCommerce and Industry (Kawasaki CCI) Senior Adviser, Mr. Toru
Kawanishi, Director General, National Institute of Health Sciences(NIHS) and Mr. Keitaro Takebayashi, Division Director, DaiwaHouse
Industry Co., ltd. After short presentation, there was a panel discussion, having Dr. Hiromichi Kimura as a moderator, with Mr. Hideki
Kaji, Mr. Toru Kawanishi, Mr. Keitaro Takebayashi, Mr. Peter Takizawa Ahlenius and Prof. Kazunori Kataoka as panelists. There was areal intention discussion on future of King SkyFront and the task
was shared with all including the audience.
In the questionnaire, almost 90% of participants said they weresatisfied with the symposium, and there were many positive feedback such as "I'm expecting the activities of COINS based in Kawasaki" "I want to have some kind of relationship" "I want you tohold a symposium in Kawasaki from now on". COINS is in the stageof advancing social implementation of the research outcome of
Phase 2, and the contact with society is more important than ever.
This symposium was a great opportunity for people and companies to be interested in research of COINS and it was a meaningfultime to further strengthen determination towards the realization of asmart life care society that departed from Kawasaki.
（Report by Takashi SUGIMOTO）

Xiaoyuan Chen

Wim Hennink

Panelist

Panelist

Panelist

Panelist

Panelist

Moderator

Director General &COINS Research Leader,
Kawasaki Institute of Industrial Promotion
Innovation Center of NanoMedicine

Senior commercial officer,
Life Science section,
Danish Embassy

Division Director,
Building division, Tokyo Head officeDaiwa House Industry Co., ltd

Director General,
National Institute of
Health Sciences

Vice Chairman,
Kawasaki Chamber of Commerceand Industry (Kawasaki CCI)COINS Project Leader,
Kawasaki Institute of Industrial Promotion
Innovation Center of NanoMedicine

Yuzuru Matsuda
Visionary Leader,
COI Program Vision 1

Senior Investigator andLab Chief,NIH

Kazunori Kataoka

Panel discussion

14 | NanoSky VOL.03 MARCH 2017

Professer, Department ofPharmaceutics, Utrecht University

Peter Takizawa

Keitaro Takebayashi,

Toru Kawanishi

Hideki Kaji

Hiromichi Kimura

Activity Report
TopicsJune 2016 – December 2016◦6.30 – 7.1.2016【Award】Mitsuru Naito, Visiting Researcher, Center for
Disease Biology and Integrative Medicine, Graduate School of Medicine, The
University of Tokyo received an Excellence Presentation Award (oral) at the32nd Annual Meeting of the Japan Society of Drug Delivery System on June
30 – July 1. Award title:「Organic/inorganic hybrid multilayered nanocarriers with controllable ligand density for targeted siRNA delivery」（Co-author:
Ryota Azuma、Hiroyasu Takemoto, Mao Hori, Shigehito Osawa, Kim HyunJin, Takehiko Ishii, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka）.
◦7.5.2016【Activity】 14 members of OSONG Medical Innovation Foundation from Korea visited iCONM.
◦7.19.2016【News】 The paper“Nanomedicines Eradicating Cancer Stemlike Cells in Vivo by pH-Triggered Intracellular Cooperative Action of
Loaded Drugs" of Dr. Hiroaki Kinoh, Principal Research Scientist (Deputy
Head, Kataoka Kinoh Lab./ Visiting Scientist, The University of Tokyo) andDr. Horacio Cabal, Associate Professor, Department of Bioengineering,
Graduate School of Engineering, The University of Tokyo (Visiting Scientist,
iCONM) et al. which was published online of ACS Nano, one of the top journal within Nanotechnology field was introduced as most read article in one
month in“Most Read Articles”column.
◦7.29.2016【News】The research outcome of iCONM was carried in“Research highlight corner”of WEB newsletter Kawasaki SkyFront i-Newsletter
Vol.7 which is run by Kawasaki city.
◦7.29.2016【Activity】 Students from Kawasaki city high school for Scienceand Technology visited iCONM.
◦7.31.2016【News】 The related article of Joint Press Conference thattook place in 5.16 was published in Kanagawa Shimbun. Title: New contrast
agents with Nanotechnology - Cancer tissue structure clearly visible◦9.30 – 10.1.2016【Activity】COINS retreat camp was held at Shonan International village.
◦10.6.2016【Activity】Students from Fukuoka Kasumigaoka High School visited iCONM as a part of extracurricular activities.
◦10.7.2016【Activity】COINS Seminar #19 was held at iCONM.
Lecturer：Prof. Won Jong Kim (Department of Chemistry Polymer ResearchInstitute, Pohang University of Science and Technology (POSTECH) Center
for Self-assembly and Complexity, Institute for Basic Science (IBS)
Title：“Polymer-based Nitric Oxide Delivery System for Bioapplication”◦10.8.2016【Activity】Students from Fukuoka Kasumigaoka High School
visited Ichiki Lab. The University of Tokyo which is one of the COINS participating institutions as a part of an extracurricular activities.
◦10.12.2016【News】The article of Nanomachines which has been developedby Dr. Kazunori Kataoka, Professor, Graduate School of Engineering, The
University of Tokyo was put on Newsweek website.
◦10.13.2016【Activity】Students from International Section, Kawasaki
Tachibana High School visited iCONM as a part of extracurricular activities.
◦10.13.2016【Activity】The delegation of Academic Research & Industry Academia - Government Collaboration, Nagoya University and The University of Minnesota with the connection to Nagoya University visited COINS.
◦10.20.2016【Activity】The delegation of Healthcare Innovation visited
COINS from Netherland.
◦10.20.2016【Activity】COINS Seminar #20 was held at iCONM.

◦8.9.2016【Activity】“King SkyFront Summer Science Event 2016”was organized by Kawasaki city. 300 primary students visited iCONM.

Lecturer: Dr. Michael Sprenger (Senior adviser for IT & innovation, National
Institute for IT in Healthcare, Technical University of Eindhoven)
Title：“The Implementation and Strategy of ICT in Healthcare in the Netherlands”◦8.13.2016【News】 The article of research that Dr. Kazunori Kataoka, Professor, The University of Tokyo (COINS Research Leader) and Dr. Yasutake
Anraku, Assistant Professor, Department of Materials Engineering, Graduate
School of Engineering, The University of Tokyo (COINS Theme 2 Leader)are pursuing as playing a central role was published in Nikkei Shimbun.

◦10.25.2016【Activity】COINS Seminar #21 was held at iCONM.
Lecturer: Dr. Emmanuelle MARIE (Researcher, The National Center for Scientific Research)
Title：“Polymer coatings for dynamic adjustment of specific and non-specificinteractions for cell culture”◦8.17.2016【News】 The article of development of anticancer agent by oneof the COINS’participating companies Nanocarrier Co. Ltd. was publishedin Nikken Shimbun.

◦11.1.2016【Award】Dr. Keiji Itaka, Leader of Theme 3 (Project Associate
Professor, Center for Disease Biology and Integrative Medicine, Graduate
School of Medicine, The University of Tokyo /Principal Research Scientist,
Innovation Center of NanoMedicine(iCONM) was awarded Best Abstract
Presentation Award at the 4th International mRNA Health Conference.

◦8.23.2016【Activity】Mr. Katsuaki Watanabe, Advisor of Toyota Motor Corporation and Mr. Sadayuki Tsuchiya, former Deputy Minister of MEXT visitediCONM.
◦8.25 – 8.26.2016【Activity】“JST Fair 2016 – Creation of Future Industries
by Science and Techology”organized by JST was held in Tokyo Big sight.
COINS set up a booth for project introduction exhibition and introduced theresearch outcome.
◦8.31.2016【Activity】Mr. Paul de Jersey, Governor of Queensland Australia
visited iCONM.
◦9.7 – 9.9.2016【Activity】JASIS - an Asia’s largest Analytical instruments
and scientific instruments special exhibition was held at Makuhari Messe International Exhibition Hall. Ichiki Lab. from COINS exhibited.
◦9.11.2016【Activity】Science and Technology Department of Embassy of theSocialist Republic of Viet Nam to Japan visited iCONM.
◦9.14.2016【Activity】Mr. Moshe Bar-Siman-Tov, Vice Director General, Israel Ministry of Health Mission, a chief scientist of Israel Ministry of Healthand Embassy of Israel visited iCONM.
◦9.15.2016【Activity】 "Medicine-Engineering collaboration Forum in Kawasaki" organized by Kawasaki City was held and iCONM tour was arranged.
◦9.19.2016【News】Interview article of Dr. Liu, Xueying, Research Scientist
was published on WEB Newsletter“Kawasaki Innovation Gateway”Vol.3
which is run by Kawasaki city.
◦9.21.2016【News】Thomson Reuters reported that iCONM Senior Research
Associate Yasuhiro Matsumura (Division Head, Division of Developmental
Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Japan) was awarded in the Thomson Reuters Citation
Laureates 2016 as a likely candidate to win a 2016 Nobel Prize.

◦11.11.2016【News】The paper (refer to News report of 7.19)published in
ACS Nano was chosen as one of the Frequent Downloaded Articles and its
video was distributed.
◦11.15 – 11.17.2016【Award】Mitsuru Naito, Visiting Researcher, Center
for Disease Biology and Integrative Medicine, Graduate School of Medicine,
The University of Tokyo received Kawahara prize at the 2nd Annual Meeting of Nucleic Acids Therapeutics Society of Japan held on November 15– 17, 2016. Awarded title:「Design and characterization of multilayered
hybrid nanocarriers with controllable peptide ligand density」（ Co-authors:
Hiroyasu Takemoto, Kim Hyun-Jin、Mao Hori, Shigehito Osawa, Nobuhiro
Nishiyama, Kanjiro Miyata, Kazunori Kataoka）.
◦11.16.2016【Activity】Danish International Market Development Committee
visited COINS.
◦12.1.2016【Activity】Institut Teknologi Bandung, ITB, Research Center for
Nanosciences and Nanotechnology（NRCN）visited iCONM.
◦12.1.2016【Activity】COINS seminar #22 was held at iCONM.
Lecturer: Dr. Ernst Wagner (Professor and Chair, Pharmaceutical
Biotechnology, Ludwig Maximilians-Universität München, Nanosystems
Initiative Munich:NIM）
Title: Nucleic Acid Nanoparticles for Cancer Therapy◦12.9.2016【News】The paper "Poly(ethylene glycol) crowding as criticalfactor to determine pDNA packaging scheme into polyplex micelles for enhanced gene expression" which was published online Biomacromolecules
was introduced in ACS Editors’Choice.

◦9.30.2016【News】Dr. Kazunori Kataoka, Director General (Professor
Emeritus, The University of Tokyo) and Dr. Yasuhiro Matsumura, Principal
Research Scientist, (Division Head, Division of Developmental Therapeutics,
National Cancer Center Exploratory Oncology Research & Clinical Trial Center) were introduced as the Kawasaki based world class scientists who haveoutstanding research results in Kanagawa Shimbun.

NanoSky VOL.03 MARCH 2017| 15

Activity Report
3rd Retreat Camp
ternational Strategy Promotion Department, Kawasaki City Coastal Area
A retreat camp was held under the theme of“How to implement InInternational Strategy, and Dr. Tatsuro Irimura, COINS Advisory Board,
body hospitals”at Shonan Village Center on Friday, September 3 andProfessor, Graduate School of Medicine, Juntendo University.
Saturday, October 1, 2016.
In this retreat, participants who actively discussed while crossing the
For this time, with the aim of strengthening the team building toward
theme and age barriers, interworking knowledge gained from the lecture
the realization of“In-body hospitals”, we set a goal to deeply discuss andstand out. The retreat was meaningful to deepen understanding by sharshare the image and tasks at the time of realization of“In-body hospitals”.
ing the way to realize in body hospital and issues to be overcome in theOn the first day, there were group discussions on“Image of In-bodyfuture.
hospitals you draw”and“Task of social implementation with innovative(Left) Daisaku Sato
technology”responding to a talk“Tasks of practical realSafety measures manager, Health and Medical
ization of innovative technology (regenerative medicalcare, Ministry of Health, Labor and Welfare
products et al. as examples) of Mr. Daisaku Sato, Safety(Center) Koichi Murashita
measures manager, Health, Medical care, Ministry ofVice Director (in charge of research) and Professor,
Hirosaki University / Strategy Advisor, COI
Health, Labor and Welfare
Research Promotion Organization (Graduate School
On second day, responding to Dr. Koichi Murashita,of Medicine)
Vice Director (in charge of research) and Professor, Hiro(Right) Tetsuo Hasegawa
Manager for External Affairs for Global Technology
saki University / Strategy Advisor, COI Research PromoR&D Engineering Management Headquartertion Organization (Graduate School of Medicine)’s talkNissan Motor Corporation“Aim to realize“Lifetime Innovation”– Challenge of Hirosaki COI, where industry, academia and government gather as returning short-lived prefecture as a banner markand Mr. Tetsuo Hasegawa, Manager for External Affairs
for Global Technology, R&D Engineering Management
Headquarter, Nissan Motor Corporation’s talk“ Various
problems accompanying introduction of automatic driving
technology”, there were group discussions on how to
overcome the problem, presentation of their summary andfinally we had three talks of Mr. Haruhiko Manabe, Assistant of Vision 1 Visonary Leader, COI program, JST, Mr.
Kazuhiko Tamai, Department Derector, Headquarters InWith heated two days, the tie of COINS became even stronger toward the realization of in body hospital.

7th General Meeting
The 7th Group Meeting was held in the main conference room at theLife Science & A Environment Research Center (LiSE) on Thursday,
January 27, 2017.
This meeting is held semi-annually with participation of all participating
institutions.
In this time, we held a panel discussion after the presentations oftheme leaders and participating organizations on the themes of this fiscal year's results and future plans.
The active discussion on new research theme and venture efforts was
exchanged towards “In - body
hospitals”. Moreover, there wasa lecture of Professor Kohei
Soga, Tokyo University of Science which will participate in
COINS from next year on“Biomedical Imaging on NIR II/II (IOTN-NIR)”and report about intellectual property policy by research promotion organization.
Lecture by Prof. Kohei Soga,
Project Professor,
Tokyo University of Science

30 posters were presented for the poster session and active discussions
were held in front of the posters. At the conclusion of the meeting, Dr.
Tatsuro Irimura, COINS Advisor and Project Professor of Juntendo University, Mr. Toshio Asano, Standing Counsellor of Asahi Kasei Co., Ltd.
and Mr. Hiroshi Misawa, Medical Technology Association of Japan gave
review of the meeting. It became a fruitful meeting for the participating
institutions to further strengthen the unity toward realization of "In-bodyhospitals".
Review by COINS Advisers

Tatsuro Irimura
Project Professor,
Juntendo University

Toshio Asano
Standing Counsellor,
Asahi Kasei Co., Ltd.

Hiroshi Misawa
Managing Director,
Medical technology
Association of Japan

Editor’s Note
The theme 4 team is responsible for the development of diagnostic technology that is accurate and less burdens on the body,which is indispensable for an "in-body hospital”(see Vol 2, p2, 3) that will realize a“Smart life care society”COINS is aimingfor. If this is achieved, there is the possibility of changing society and lifestyle significantly by shifting medical care from sickcare to health care. With this issue of NanoSky. I hope readers will be able to get the drift of a sense of the progress of researchand development over a wide range from fundamental research to practical application while the team is sharing a specific vision. COINS entered Phase 2 this fiscal year and is pressing on with its social implementation. This social implementation includes not simply practical application but also activities such as information dissemination that increase social acceptability.
While being conscious of its importance, we are excited about delivering "NanoSky" to everyone next year as well.
(Editor Takashi SUGIMOTO)

Edited by NanoSky Editorial Board (Takashi SUGIMOTO, Takanori
ICHIKI,Takanori AKAGI, Ryo IIZUKA and Yusuke YOSHIOKA)
Writer： Ayumi KOJIMA
Camera: Aki TANAKA
Design: Studio L Co., Ltd.
Copyright: KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION

Vol.

Published by Center of Open Innovation Network for Smart Health (COINS),
Innovation Center of NanoMedicine (iCONM),
KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION,
3-25-14, Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa Pref. JAPANTEL: +81 44 589 5785 / FAX: +81 44 589 5789
http://coins.kawasaki-net.ne.jp/