Newsletter

From KING SKYFRONT to the world - NanoMedical Innovation

March
2018

5

Vol.

Innovative Minimally Invasive
Treatment led by “Nanomachines×
Medical Equipment”
Contents
2

6
8

Talking about Theme 5

Pursue the Goal of Realization of Revolutionary
Diagnostic Imaging and Treatment using
Nanomachines

Nobuhiro NISHIYAMA, Yoshihiro MURAGAKI,Ｉｃｈｉｏ AOKI

Interview with Researcher

Aim at Damageless Imaging and Therapy using
Near-Infrared “Biological Window”  

Kohei SOGA

Research Highlights

Study on the Practical Application of Sonodynamic Treatment
with the Concurrent Use of Nanomachines and Ultrasound to
Actualize Minimally Invasive Cancer Treatment
Yoshiyuki KONISHI, Kazuhisa TAKEMAE

Japanʼs Leading Innovative Medical Technology
Boron-mounted nanomachines for boron neutron
capture therapy
Takahiro NOMOTO

12 Listen to COINS’ Members
What we treasure

Wataru KUROSAWA, Yuki HORISE, Naohiko SHIMADA, Sayaka SHIBATA

14 Activity Report

・4th COINS Symposium・4th Retreat Camp・9th General Meeting
・Editor’s noteTalking about
Theme 5

Pursue the Goal of Realizationof Revolutionary Diagnostic
Imaging and Treatment using
Nanomachines

Center of Open Innovation Network for Smart Health (COINS) Theme 5 is carrying out the research on how
to use nanomachines which circle around the body for diagnostic imaging and treatment targeting affectedareas.Including sonicodynamic therapy (Sonodynamic Therapy: SDT), which began to move toward practicaluse already, three people who lead the research group on the current situation talk about R&D, clinicalapplication, challenges and future prospects etc.

Yoshihiro MURAGAKI

Nobuhiro NISHIYAMA

Ichio AOKIProfessor,
Faculty of Advanced Techno-Surgery /Department of Neurosurgery,Tokyo Women's Medical University· Institute of Advanced Biomedical
Engineering and Science

Professor,
Laboratory for Chemistry and Life Science,
Institute of Innovation Research,
Tokyo Institute of Technology /Principal Research Scientist,
Kawasaki Institute of Industrial Promotion
Innovation Center of NanoMedicine

He was born in Osaka in 1962. He graduatedfrom Kobe University School of Medicine in 1986,
and after working as intern and then an assistant,
he went to Pennsylvania University Pathology
School in USA (Professor Trojawnoski, Professor
Lee) from 1992–1995. He became a directorof Neurosciences Center of Tokyo Women’sMedical University when he returned. In 2006, hemoved to Faculty of Advanced Techno-Surgery/ Department of Neurosurgery, Tokyo Women'sM e dic al U nive rsit y · I nstitute of Adva n c e dBiomedical Engineering and Science. He is incurrent position from 2011.Doctor of Medicine /Certifying physician of the Neurosurgical Society/ Cancer treatment certified doctor.

He was born in Wakayama in 1974. He completed
the doctoral program of Graduate School ofEngineering, The University of Tokyo in 2001.
He became a postdoctoral fellow at Faculty of
Pharmaceutical Sciences, Prof. Kopecek Lab, The
University of Utah, USA and an assistant professorof di vision of Tissue Engineering of The Universityof Tokyo from 2001 to 2003. In 2009, he became
an associate professor of Center for Disease
Biology and Integrative Medicine, Graduate Schoolof Medicine, The University of Tokyo and at thecurrent position from January in 2013. His areaof specialty is the development of drug delivery
system (DDS) utilizing polymer assemblies. In
2007 he received Award for Young Investigator in
Polymer Science, the Society of Polymer Science,
Japan, the 1st The Japan Society of Drug Delivery
System Young Investigator Award (Basic) in 2009,and in 2012, the Young Investigator Award of theJapanese Cancer Association.

Group Leader, Group of Quantum-state
Controlled MRI,National Institutes for Quantum andRadiological Science and Technology(QST) /
Team Leader, Functional and Molecular
Imaging Team,
Department of Molecular Imaging andTheranostics,
National Institute of Radiological Sciences(NIRS), QST

2 | NanoSky VOL.05 MARCH 2018

He was born in Kita Kyushu City, Fukuoka Pref.
In 1999, after obtaining Ph.D. in the research offunctional MRI contrast agent, he did his researchon biomedical application of ultra-high magnetic
field MRI and functional contrast agent at thelaboratory of functional molecular imaging, NIH /NINDS (Koretsky AP Chief). In 2007, he works at
National Institute of Radiological Sciences (NIRS)
as a team leader and advances R&D of functionaland nano contrast agents using high field MRI
and the application of pathological conditions. In
2016, the NIRS has been renewed as the National
Institutes for Quantum and Radiological Scienceand Technology (QST). He received 2017 R&D
Achievement Award of QST.

Combining nanomachines andfocused ultrasound,investigator-initiated researchon pancreatic cancer are being
planned.
■ First, please introduce yourself.

■ To what extent has the development of therapies
that combine SDT with nanomachines progressed?
Muragaki: In this treatment, nanomachines equippedwith the anthracycline anticancer drug epirubicin are
accumulated in the tumor, to which focused ultrasoundis then applied. After confirming its safety throughtreating four diseased animals five times last year, aclinical trial was performed in 12 patients with progressive unresectable pancreatic cancer. We are now
planning an investigator-initiated Phase I study and aregoing to set the boundary intensity between effect andadverse reaction for focused ultrasound from now on,
sharing information with companies. We are also investigating the mechanism of the SDT effect using nanomachines.

Nishiyama: I am engaged in research on nanomachinetechnology, a medical technology using polymers in the
Laboratory for Chemistry and Life Science, Institute of
Innovative Research, Tokyo Institute of Technology. In
COINS Theme 5, developments of minimally invasive
treatment systems and imaging systems that integrate
nanomachines and medical devices are ongoing (Fig. 1).
■ Linking research on actions and biokinetics ofSpecifically, combining nanomachines with treatments
nanomachines to“diagnose and treat at the sameusing physical energy such as photodynamic therapytime”or“diagnosis more linked to treatment”is(PDT), boron neutron capture therapy (BNCT, p.10),
also a great theme in Theme 5, isn’t it?
and sonodynamic therapy (SDT) using high intensity
focused ultrasound (HIFU) equipment is being attempted, to dramatically enhance safety and efficacy (Fig.2).
Nishiyama: I sometimes hear from clinicians that the
While other Themes are focused on medication, we are
current diagnostic performance of MRI is sufficient andseeking a novel day-treatment that is less invasive andthat no contrast agent of higher performance is needed,
poses fewer burdens on patients in this Theme. Anothbut I think such opinions will be changed if its linkage
er one is the development of imaging methods that alto treatment is considered. If you can predict the effectlow the visualization of a cancer’s status without a biof the treatment that will be performed in the diagnosopsy. This study identifies how nanomachines act in
tic imaging stage, you can provide a big advantage tovivo and is relevant to all COINS nanomachine rethe patient. This allows the selection of the optimal
searches. This research is also needed to realize precitreatment for each patient. Visualizing the biokinetics
sion medicine.
of nanomachines may be very useful for both diagnosis
Muragaki: I am engaged in the treatment of malignant
and treatment.
brain tumors in the Department of Neurosurgery, ToAoki: Diagnosis and treatment are essentially different
kyo Women's Medical University, while developing a
in their concepts: diagnosis requires absolute safety,
precisely-guided treatment having the functions of awhile the risks of treatments in patients, such as side
surgeon’s eyes, hands, and brain in Institute of Adeffects and complications, are assumed. The clinician
vanced Biomedical Engineering and Science. In COINS
actually wishes to avoid using a contrast agent in diagTheme 5, I conduct research
1. Summary of devices fusing pharmaceutical and equipment actualizingon the combination of two Figure
図 -1 サブテーマ5「ナノ低侵襲治療システムの創成」の概要
ultra-minimally invasive therapy
targeted therapies, namely,
Reduction of risk by treatment planning andMultimodality navigation→Precise guiding
medication and HIFU.
evaluation of treatment effectPre-confirmation of the treatment site
Aoki: I work with researchand development focusing on
diagnostic technology using
Treatment planningmagnetic resonance imaging
Treatment planning using
information from various sources(MRI) in the National InstiPrecisely navigated treatment
support technology
tutes for Quantum and RaEvaluationofdiological Science and Techtreatment effect（Validation of Safety
nology (QST) which was
New HIFU system
and Efficacy）
Multichannel transducer
established two years ago.
Photosensitizer-equipped nanodevices
Intelligent animal
In COINS, I’d like to visualoperating room
Diseased animals
ize how nanomachines are（Dogs/cats）
distributed and act in vivo
Endoscopic laser
Endoscopic
photosensitizer-equipped polymer
laser
and optimize the nanomaMicellar nanodevices
chine function to contributeto the realization of secure
Nanodevice for visual superficial lesions
Remote-operated deep lesion nano devices
Precisely navigated treatment
Precisely navigated treatment
treatment utilizing imaging.

NanoSky VOL.05 MARCH 2018

|3

TALK
nosis because it increases risk. There will be twotrends in future diagnostic imaging: an increase in thesafety of contrast media and the addition of new values
useful in treatment.

■ Will there be any difference depending on themodality (medical imaging device)?

Aoki: I agree. I think that the need for a contrast
agent used only for diagnosis is high if it is safe, and I
believe companies will be interested in it if it is a diagnostic method that can be used in popular modalities
such as MRI. Recently, several contrast agents have
had their patents expired, and it seems that there is ademand for new products. However, if the range of target diseases is narrowed too much, the number of target patients will be too small for the companies to takeaction.
Muragaki: The key is whether or not we can, as academics, prove indications and depict a business model
to persuade the companies.
Aoki: To this end, it is important to share R&D processes with companies.

Aoki: Currently used modalities
each have advantages and disadvantages, and all of them are necessary in clinical settings. In Japan, for example, CT has broadly
been introduced compared to other countries, however it has the
disadvantage of high medical radiBeyond R&D, there are barriers
ation exposure. Radiation exposure should always be considered
to clinical popularization evenin terms of balance between theafter the diagnosis andbenefits of medical care and thetreatment are approved.
risks. However, given the recent nervous situation toradiation exposure after the powerplant accident in Fu■ Are there any difficulties in development,
kushima, it is necessary to suppress frequent CT use. I
approval, or clinical use of the treatment method
think methods without radiation exposure, such as
wit h integ rated n a nomac hin es a n d medical
MRI and ultrasound, and modalities that can be useddevices?
easily, safely, and inexpensively will be more popular.
Nishiyama: Companies have a wait-and-see attitude toNishiyama: The Pharmaceuticals and Medical Devices
ward the use of nanomachines to enable advanced imAgency (PMDA), an independent administrative instituaging that would be difficult to achieve with the existtion in charge of directions and reviews, seems to be
ing contrast media. We believe that our success incooperative in the development of epoch-making treatconcurrent diagnosis and treatment will be a breakments originating in Japan in states from development
through.
to approval.
Aoki: That would be nice if we could make it possible
Muragaki: Sometimes, new treatments cannot be manto switch diagnosis and treatment by changing what isaged in accordance with conventional regulations, andcarried on nanomachines.
we ask to respond to such cases flexibly. After approvNishiyama: Without the added value of visualizingal, on the other hand, one may fall into unexpected pittreatment, in addition to diagnosis, the practical applifalls of the Drug Price system and Health Insurance.
cation of the combination of nanomachines and imaging
We were able to expand the indications of PDT to matests may図
be-2
difficult.
手術、放射線、化学療法につぐ第4の最新治療

ダブルターゲッティングによるケモサーマル治療
treatment following operation, radiotherapy, and chemotherapy
Figure 2. The 4th and latest— chemothermal therapy through double-targetingー

Photosensitizer

Cancer accumulation
Drug accumulation in
Administration oflesions
ultrasound-sensitive drugs

Acoustic chemotherapy with MRI-guided,
focused ultrasound irradiation and acoustic
luminescence (Chemothermal treatment)

Navi-guiding

Double-targeting

Cancer

1 Focused ultrasonic ablation

DDS

Cancer accumulation
Ultrasound-sensitive drugs

4 | NanoSky VOL.05 MARCH 2018

2 Sonochemical effectAccumulation of
DDS in cancer

Nocomplication

Complete
control

lignant brain tumors in 2014 by conducting investigator-initiated clinical studies. However, the photosensitizer used in PDT for the price proportional to theamount for nearly 2 years after the approval was thencovered by the DPC (diagnosis, procedure, combination)system as one of the so-called “lump” drugs used in
hospitalization for malignant brain tumors, and thedrug cost was not applied. Although the treatment isbeneficial for patients, it is difficult to provide in thecurrent Health Insurance system. We are requesting
the MHLW to improve this issue. I realize that it is difficult to change the determined framework once atreatment has been launched. This may also be thecase in diagnosis and treatment using nanomachines.
In addition, if nanomachine DDS targeted to the affected site is actualized, it reduces the dose and amount ofdrug use in companies and hospitals, that is to say, it
reduces a company’s profits, and therefore, the incentive for companies to go toward DDS becomes smaller.
Successful matching of patients' benefits to corporate
profits is important.
Nishiyama: Developments and clinical studies can be
conducted in consultation with the PMDA, but systems
providing no incentive to companies and hospitals areproblematic. We have to consider business models in
the early stage. Dr. Muragaki's experiences in the approval of PDT and its clinical use will be utilized in
COINS in the future.
Muragaki: Pharmaceutical companies
and medical device companies havetheir own management policies and different profit-making structures, so they
are not ready to enter the developmentof such new treatments. Medical devicecompanies sell devices to medical institutions to make profits and they wantto raise the price (of the medical devices), while pharmaceutical companies
want them to sell medical devices atlower prices to increase use of thedrugs. Such a situation was present for PDT, and eventually, the problem was resolved by integrating the
PDT division of the medical device companies into thepharmaceutical company. For SDT, we foresee futurebusiness models and have been asking several companies to discuss among themselves from the beginning,
because academia is not good at things like this.
Nishiyama: Health care is a service and medical institutions and companies should be paid for patients' benefits. Such systems should be adopted.
Aoki: Despite the growing number of diagnosis andtreatment methods that use medicinal products andmedical devices as a unit, there has been no organization to evaluate them together, posing obstacles to
R&D and their practical application. I hope that the Japan Agency for Medical Research and Development(AMED) established in 2015 will make a cross-cutting
effort to promote the R&D for the methods.

■ New treatments combining pharmaceuticalproducts and medical devices pose various issues,
including the development of R&D strategy,
funding, mode of information sharing withcompanies, patent strategy, and management fromapplication for approval to post-marketing, andthere is know-how to overcome these challenges.
Muragaki: Yes. The project we are involved in has
been advanced by lucky, coincidental encounters. However, for our next-generation researchers, we have toconsider the Japanese system from R&D to practicalapplication.
Nishiyama: Separately from the optimization of nanomachines, it is important to retain the findings for the future purposes. Everyone may do thesame things and make mistakes atthe same points. There are manythings that you don’t understandthrough successful stories only. Sharing information on failures will raise
the level of nanomachine research.
Aoki: COINS functions as a place toshare such information, doesn’t it?
Muragaki: Today, our gathering is exactly the place
like that too (laughter).
Aoki: COINS gathers researchers who are conscious ofsocial implementation. I hope that we will also cooperate with people out of our specialties, coordinators, andcompanies to proceed to the same goal.

■ Lastly, what are your future aspirations?
Nishiyama: Dr. Muragaki will advance the investigator-initiated research on SDT, and the research on
BNCT will further be deepened. However, it is still along way to achieve the “In-body hospital”. When
COINS enters Phase III of the research aiming at practical application of the research in the 2019 fiscal year,
I would like to develop simple, high-performance, andsafe smart nanomachines capable of social implementation using not only combinations of existing materials
but also new materials.
Muragaki: COINS intends to investigate the mechanism of SDT in detail and establish an investigator-initiated clinical trial protocol in a method that enables its
benefits to be actualized, leading to approval by regulatory authorities and adoption as the standard treatment.
Aoki: We would like to seek precision medicine by imaging with nanomachines to predict treatment effects
and perform treatment based on the predictions.

■ Thank you very much.
(Interviewer: Science Writer Ayumi KOJIMA)

NanoSky VOL.05 MARCH 2018|5

Interview

Interview with Researcher
Aim at Damageless Imaging andTherapy using Near-Infrared “Biological
Window”
Kohei SOGA
Professor, Department of Materials Science andTechnology, Tokyo University of Science,
Imaging Frontier Center, Tokyo University of Science
Research Institute for Biomedical Sciences, Tokyo
University of Science

Professor Kohei Soga of the Department of Materials Science and Technology, Faculty ofIndustrial Science and Technology, Tokyo University of Science / Imaging Frontier Center,Research Institute for Science and Technology, joined COINS Theme 5 as new member
in 2016 and he is a pioneer of bioimaging using near-infrared light. We asked him about
the background and recent results of the research on near-infrared bioimaging, which is
expected to be applied clinically, as well as on the integration of bioimaging and therapy.

Challenge in the area where no one
has gone, leading to success in thelive imaging of nematodes
Prof. Soga has been conducting his research on nanoparticle lightemitters (ceramic nanoparticles containing rare earth elements such as
ytterbium and erbium, 10 to 200 nm in diameter) since 2004, and has usedthem to actualize bioimaging with near-infrared light. The rare-earthdoped ceramic nanoparticles emit fluorescence when subjected to nearinfrared light with photon energy lower than that of visible light, and also
emit visible light through up-conversion (conversion from long-wavelength
light to short-wavelength light).
He majored in metallurgy in the Faculty and Graduate School of The
University of Tokyo, where he researched the structure and physicalproperties of rare-earth-element-containing glass, particularly glass lasermaterials. Thereafter, he energetically started to research on nanoparticles
containing rare earth elements in parallel with optical fiber materials andthe physical properties of boron icosahedral cluster solid (boron).
The reason he began researching and developing bioimaging using nearinfrared light was an approach from bio-researchers in Tokyo Universityof Science who were interested in the research of rare-earth-containing
ceramic nanoparticles. Fluorescence imaging with fluorescent dyes canuse abundant colors and provide sensitive and dynamic imaging, while
excitation light degrades the dye and attenuates the fluorescence in ashort time, resulting in a short observation time. They asked Prof. Soga if
there were any measures taken for this short observation time.
While he was examining the actualization of bioimaging by improving

Figure 1. Light loss spectrum of human skinthis rare-earth-element-containing ceramics nanoparticle for about a year,
Prof. Soga thought that“bioimaging uses visual light in excitation andimaging, but must visual light be used? How about near-infrared light?”In
optical communication, which he had studied for a long period, infrared
light is used, taking advantage of its low light loss. Prof. Soga is familiar
with the properties of near-infrared light and was interested in using nearinfrared light for fluorescent bioimaging.
He studied near-infrared light and learned that it is called a“biological
window”because its wavelength is as long as 700 to 1500 nm, allowing
greater observation depth with little light loss. Particularly, wavelengths
from 1000 to 2000 nm have high penetration ability with respect to thebody (Fig. 1).
Conventional bioimaging uses fluorescent dyes that emit light in thevisible range excited by short-wavelength UV light (wavelength 380 to
450 nm) and blue light (wavelength 450 to 495 nm). This method has the
disadvantages not only of rapid discoloration of the dyes, but also an
observation depth as shallow as a few millimeters, which is difficult todistinguish from autofluorescence, as described above. On the other hand,using near-infrared light may prolong fluorescent light duration andincrease observation depth from a few millimeters to several centimeters.
However,“ No study of fluorescent bioimaging with excitation andobservation by near-infrared light with a wavelength longer than 1000 nm
was available. This may be because there were no favorable fluorescentprobes or there was no camera for biological materials to detect the nearinfrared light. I decided to take the challenge while wondering whether
research on a theme studied by nobody would be successful,”said Prof.
Soga.
The camera commonly used in fluorescent bioimaging is a Si-CCD
camera, which images by transforming light to electrical signals with asilicone device as charge-coupled device (CCD). This camera allows
observation from the visible light range to near-infrared light around 900
nm. However, it cannot be used in any wavelength range over 1000 nm,

In（I I0）（cm−1）
300

Light loss

Visual Light
200

Near infrared light

Si-CCD

InGaAs-CCD

All

Figure 2. Fluorescent bioimaging images

Diﬀusion

1st biological
window
100

Degree ofabsorption

2nd biological
window

ICG
0

500

1000
1500
Wavelength（nm）

2000

R. Rox Anderson, John A. Parrish
Journal of Investigative Dermatology, Vol. 77, Issue 1, p13–19 redesigned
Light of shorter wavelength applied to human skin results in stronger lightscattering, and longer wavelengths result in greater absorption. Wavelengths 500
to 1000 nm from the visible range to near-infrared range has been known as the“biological window,”allowing great observation depth under the skin surface since
1980s. Prof. Soga and his colleagues developed InGaAs CCD cameras anddemonstrated that wavelengths longer than 1000 nm (over a thousand nanometers:
OTN) has far higher penetrating ability. They named this near-infrared range OTNNIR and call it“the second biological window.”

6 | NanoSky VOL.05 MARCH 2018

Ytterbium-containing ceramic nanoparticles are injected in mice and fluorescentimaged with Fluorescent Imaging Device SAI-1000, developed by Prof. Soga andhis colleagues. The blood vessels are clearly imaged.

which is suitable for imaging of the deep in vivo area. Thus, Prof. Sogaand his colleagues developed a system that enables in vivo observation inthis wavelength range using an InGaAs (indium-gallium-arsenide) CCD
camera, which is used to detect near-infrared light in the opticalcommunication area.“It was lucky that the optical communication bubbles
had collapsed, and cameras and other devices were available at lower
costs.”
Then, they created a prototype fluorescent microscope system that
excites rare-earth-doped ceramic nanoparticles with 980 nm near-infrared
light to have them emit near-infrared light fluorescence with a wavelengthof 1550 nm, and successfully imaged live nematodes in 2008. This was thefirst live imaging in this wavelength range in the world. Prof. Soga lookedback to that time and said“Probes other than fluorescent dyes, such as
rare-earth-doped ceramic nanoparticles, were unfamiliar to biologists andwe wanted to show how to use them.

Developing and marketing a device
for small animal observation
Next, he worked on developing this imaging system to observe small
animals such as mice. Saving money by turning the laboratory light off
without buying a dark box, a prototype of fluorescence animal imaging
system with a laser excitation was developed. He felt great pleasure in2010 when the gastrointestinal tract of was clearly imaged in a mouse fed
with the rare-earth-doped ceramic nanoparticles. The device was refinedin cooperation with Shimadzu Corporation in expectation of its practicalapplication, and it was marketed in 2014.“The first prototype created in
インタビュー用
図 2 Ce6+UCNPの構造
Figure3. Structuresof Ce6+UCNP

Near infrared
photoexcitation（980 nm）

3
Ce6

O2
1

O2

Ce6

Therapy
Ce6
Ce6

Diagnosis

Up-conversion
Red emission（660 nm）
OTN near-infrared emission（1550 nm）

インタビュー用 図 1

がん腫瘍への攻撃の仕組み

Mechanism of attack of cancer/tumor
200

400

Ultraviolet

Skin tissue surface

UV

600

visible light

1000

Wavelength（nm）

Near-infrared radiation

VIS
NIR
980 nmVisible light Near-infrared
excitation photoexcitation

High
Permeability
1

O2

Deep

800

Efficientcell deathcooperation with Shimadzu was in refrigerator size, but I requested ofthem to make the device lighter and smaller so that it could be brought
into the small animal laboratory, and they created a device the size of a
printer and weighing 17 kg. We were advised by the professor ofdesignology from Department of Design at Nagoya Zokei University etc.
about the computer software screen, creating a user-friendly design.”
Figure 2 shows an image of mouse blood vessels obtained by injecting
rare-earth-doped ceramic nanoparticles using this image system. Rareearth-doped ceramic nanoparticles used in this system have already beenlaunched as well.

The goal is to link near-infrared
fluorescent light imaging to therapy.
Currently, Prof. Soga and his colleagues are focusing efforts ondeveloping fluorescent probes. They are developing the rare-earth-doped
ceramic nanoparticles that they have long carried on their research,quantum dots, and carbon nanotubes as well as probes containing organic
fluorescent dyes, and they are also investigating to confirm the stability
and safety in the tissues for each device.
Recently, they successfully performed photodynamic therapy (PDT) inmice by modifying ytterbium/erbium-containing ceramic nanoparticles
with PEG and binding them to photosensitive substances that generate
active oxygen when illuminated (Fig. 3)＊1. In this method, the EPR effect(Enhanced Permeability and Retention effect) of PEG-modified
nanoparticles is expected to accumulate the nanoparticles in cancer,
allowing imaging to simultaneously determine the size of the cancer inparallel with cancer therapy with PDT.
Currently, the PDT covered by Health Insurance for indications such aslung cancer, esophageal cancer, and malignant brain tumor uses laser atwavelengths as short as 400 to 600 nm. Therefore, the PDT is used only
for exposed lesions on the body’s surface or in the lumen and performed
endoscopically or in conjunction with craniotomy. If that can be performed
with the use of near-infrared light, noninvasive imaging and PDT from the
body’s surface become possible. Professor Soga says,“I would like to leadto clinical research within a few years.”
COINS Theme 5 is planning to put nano-thermal imaging into practice.
In this method, pH and temperature are measured in the environment
where the phosphor is placed with use of near-infrared light having great
observation depth, and the measurements are mapped and used inthermal therapy. A basic experiment for thermometry has already been
performed successfully using PEG-modified ceramic particles containing
ytterbium.＊2
His elder brother is the conductor Mr. Daisuke Soga, and Professor
Soga also has an art lover side and likes colorful works such as theartworks of Joan Milo and the musical pieces of Maurice Ravel, and heloves to collect potteries made by Living National Treasures.“I likeconsidering original solutions for an issue and often come up with ideas
while walking because the brain fully works then. I feel happy to be a
researcher in such moments.”
There is no doubt that Professor Soga will, while he is commuting or
taking a walk, generate ideas on utilizing the advantages of near-infrared
light that causes no exposure and hazard to human body, and that further
progress will be made in the applications of near infrared light tobioimaging and clinical practice.
(Notes: science writer Ayumi KOJIMA)O2PROFILE

Ce6

Tumor

Ce6 ＋ UCNP

Rare-earth-doped ceramic nanoparticles have the disadvantage of easy aggregation
at biological salt concentration, and the particles modified with polyethylene glycol(PEG, blue) are stably dispersed. This actualizes the EPR effect to accumulate theparticles in the cancer. Ce6 is a photosensitive substance and releases active
oxygen to destroy cancer cells when Ce6 is exposed to near-infrared light.
Concurrent use with an imaging system allows simultaneous cancer therapy with
PDT (adapted from Reference 1).

Kohei SOGA
He was born in Tokyo in 1967. He grew up in both Osaka and Tokyo. He graduated from
Department of Metallurgy, Faculty of Engineering, The University of Tokyo in 1990 andcompleted Department of Materials Engineering, Graduate School of Engineering, The
University of Tokyo in 1995 and obtained PhD. He worked at the Graduate School ofEngineering, The University of Tokyo as a research associate, also at Rutgers University,
New Jersey State as a postdoctoral fellow, and at Department of Materials Sciences
and Technology, Tokyo University of Science as a lecturer and became an associate
professor in 2007. He is in current position from 2012.

Reference＊1 M. Kamimura, K. Soga, et al., Chem. Lett., 46 (2017) 1076.
＊2 M. Kamimura, K. Soga et al., J. Mater. Chem. B (2017)

NanoSky VOL.05 MARCH 2018|7

Reserch
Highlights

1

Theme 5

Study on the Practical Application ofSonodynamic Treatment with the Concurrent Useof Nanomachines and Ultrasound to Actualize
Minimally Invasive Cancer Treatment
Aiming surgery, drug therapy, radiation therapy and social implementation of a minimally invasive therapy thatis both“friendly to the body”and“intense”, researches are underway to unveil the mechanism of action ofsonodynamic therapy with the concurrent use of nanomachines and ultrasound. Faced with the challenge of filing
two applications for approval as a pharmaceutical product and medical device at the same time, the industry andacademia are working together to tackle the challenge.

Yoshiyuki KONISHI

Kazuhisa TAKEMAE

Research Assistant Professor,
Faculty of Advanced Techno-Surgery,
Institute of Advanced Biomedical Engineeringand Science,Tokyo Women’s Medical University

Principal Investigator,Research Strategy Dept.
Global R&D Dept.
Pharmaceutical Division
Kowa Company Limited

In recent years, interest in minimally-invasive treatments has increased. Advances in engineering andphysical science have made progress in diagnostic andtherapeutic equipment. Among them, we are conducting researches aimed at the practical application of sonodynamic treatment using ultrasound and nanomachines. Treatment using ultrasound has been put into
practice, and High-Intensity Focused Ultrasound (HIFU)
treatment, among others, treats the affected area withthermal effects. HIFU treatment is used for a variety of
diseases and has been approved by the pharmaceuticalauthorities for indications of pain relief in prostatomegaly, hysteromyoma, and bone metastases. While HIFU
therapy alone exerts effects, it requires higher energy
to obtain thermal energy and is associated with the riskof radiation to an unintended site because it is refracted
and reflected by the effects of air and bones in the body.
We are therefore conducting, in an experiment facilityof iCONM, research and development of a minimally invasive treatment system with sonodynamic therapy(SDT) that combines a nanomachine and ultrasound, asa treatment to reduce the risks of HIFU therapy andpotentiate cytotoxicity (Fig. 1). This R&D will elucidate
the combination effects of nanomachines and ultrasound,allowing less invasive treatments than HIFU treatment
alone (Fig. 2). Specifically, the combined effects of HIFU
irradiation and nanomachines were examined by administering them to immunodeficient mice with mouse-derived colorectal cancer cells (Colon26) or human pancreatic cancer cells (MIA PaCa 2) implanted in them. The
results showed that the combination of both treatments
had growth suppression effects superior to those by theuse of HIFU irradiation or nanomachines alone, at doses
lower than those in HIFU irradiation or nanomachinetechnique alone (Fig. 3). The effect of active oxygen that

8 | NanoSky VOL.05 MARCH 2018is also noted in photodynamic treatment has been reported as a mechanism of action of SDT. Thus, in thepresent research, we are conducting basic studies to
identify reactive oxygen species generated by the combined use of HIFU irradiation and nanomachines andtheir effects.
A major barrier to social implementation is the approval by regulatory authorities of medicinal products,
medical devices, and regenerative medicine products.
The recent legal revisions in Japan have resulted in priority reviews of innovative pharmaceutical products,
medical devices, and regenerative medicine products.
Applications for approval of pharmaceutical products
are reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA). It is important to develop optimal non-clinical and clinical plans via thorough discussions with the PMDA not only in application process
but also from the preclinical stage. The key to the present treatment is how the filing of both“medicinal products”and ＂medical devices”applications will be, and themechanism of action of the treatment is essential for
discussions in this process. Information on the mechanism of action is very important not only in terms of efficacy, but also from the point of view of how safety
should be evaluated.
Previous studies suggest that several types of active
oxygen may be involved in the mechanism of this treatment, in addition to nanomachines equipped with anticancer drugs and the thermal treatment effects of ultrasound. We will further study the effects of active
oxygen, which have not been well understood until now,
using the latest assessment devices in the iCONM fromboth in vivo and in vitro aspects, and further deepen
our knowledge of pharmaceutical strategies required forsocial implementation.

Figure 1. Overview of sonodynamic therapy (SDT)
Administration of
1. ナ
ノマシン投与nanomachines

2. HIFUHIFU照射radiation

3. 癌根治Cure of cancer
Repeated treatment

Production of reactive
活性酸素産生oxygen species

必要に応じて繰返しas needed (unlike
radiotherapy,
HIFU
治療（放射線と異なり
can be delivered
HIFUは何度でもmultiple times)
照射可能）

Cancericidal
殺癌作用effectAccumulated in
癌細胞に集積the cancer cells

Figure 2. DDS drugs and high-intensity focused ultrasound (HIFU)

HIFU prototype model

HIFU clinical model

Epirubicin（Anticancer drugs＋ Ultrasound-sensitive drugs）

Polymer nano-micelle of about 50 nm diameter

Epirubicin-equipped nanomachines［mm3］

human pancreatic cancer cells（MIA PaCa-2）［mm3］

Figure 3. Non-clinical
Mouse colon cancer cells（Colon26）
therapeutic effect3500
of SDT (mouse3000
subcutaneoustransplantation model)

800

1000
500

0

2

4

6

8

500

DDS

Tumor volume

HIFU

1500

400
300
200
100
0

10

Days after treatment［days］

HIFU

600

2000

0

900

700

DDS

Tumor volume

2500

1000

0

3

6

9

12

15

Days after treatment［days］

group1（Control）

group2（DDS）

group3（HIFU‒360W/cm2）
group5（HIFU‒270W/cm ）2group4（SDT DDS＋HIFU‒360W/cm2）
group6（SDT DDS＋HIFU‒270W/cm2）

Reference
M. Maeda, Y. Muragaki, J. Okamoto, S. Yoshizawa, N. Abe, H. Nakamoto, H. Ishii, K. Kawabata, S. Umemura, N. Nishiyama, K. Kataoka, and H. Iseki, SONODYNAMIC
THERAPY BASED ON COMBINED USE OF LOW DOSE ADMINISTRATION OF EPIRUBICIN-INCORPORATING DRUG DELIVERY SYSTEM AND FOCUSEDULTRASOUND.Ultrasound in Med. & Biol. (2017)

NanoSky VOL.05 MARCH 2018|9

Reserch
Highlights

2

Theme 5

Japan's Leading Innovative Medical Technology
Boron-mounted nanomachines for boron
neutron capture therapy

Radiotherapy ＊1 is an excellent technology capable of pinpointing cancer with X-ray ＊2 or particle beam＊3 andaiming at curing with minimal systemic side effects. However, if many small cancers are scattered, it is not easy
to treat each cancer one by one through this method. In this study, we aim to treat such cancers in an ultraminimally-invasive manner, without surgery, and develop neutron-responsive nanomachines for boron neutron
capture therapy, which has been clinically studied mainly in Japan, to create an innovative medical technology
originating in Japan.

Takahiro NOMOTOAssistant Professor,
Laboratory for Chemistry and Life Science,
Institute of Innovative Research,
Tokyo Institute of Technology

When boron ( 10 B ) is irradiated with thermal neutrons＊4 , boron and a neutron undergo nuclear reaction
to produce a high-energyα particle and a Li atomic nucleus. When this nuclear reaction occurs in the cell, αparticles and Li nuclei damage the cellular nuclei to induce cell deaths. This principle has been applied tocancer therapy as boron neutron capture therapy(BNCT) (Fig. 1). BNCT is a technique that selectively
kills cancer cells by causing the aforementioned nuclear reactions between boron and neutrons through theaccumulation of boron in cancer cells, followed by irradiation of the diseased area with slow neutrons (thermal neutrons and epithermal neutrons). Although boron and slow neutrons have no significant biologicaleffect when they are used alone, strong cytotoxic activity is obtained only if the two are combined. In addition, the range of α particles and Li nuclei in the cells
is within 10 μm, which is almost the same as the cell
diameter. Therefore, this technology can target a single cell.
BNCT was first attempted by U.S. researchers between 1951 and 1961, but at that time, the technique
for selectively delivering boron to cancer cells was notdeveloped enough, with the low quality of neutron radiation sources. Thus, the therapeutic effects that could
have been expected from the above theory was not
eventually obtained. Thereafter, Japanese researchersbegan to play a central role in improving boron formulations and neutron radiation sources in Japan, and
BNCT with boron clusters (BSHs) and boronophenylalanine (BPA) has succeeded in achieving excellent therapeutic effects. However, these formulations are still

10 | NanoSky VOL.05 MARCH 2018

accumulated in a limited number of cancer species,and new technologies to selectively deliver boron tocancer cells are essential to expand the indications of
BNCT.
We are developing nanomachines to deliver boron,
in an effort to explore further possibilities of BNCT.
Figure 2 shows a polymeric nanomachine, equippedwith multiple boron clusters that we have recently developed. Compared with polymeric micellar nanomachines, these polymeric nanomachines are very smallin size, accumulate efficiently in tumors, and disappear
in a short time from the blood. In BNCT, boron remaining in the blood and normal tissues causes adverse reactions in normal tissues when neutrons areirradiated, and its early excretion from the body istherefore essential. In addition, as described above, theranges of α particles and Li nuclei are within 10 μm,
and boron should be delivered as uniformly as possible
to all cells in the tumor. Because of their small size, thepresent polymeric nanomachines can penetrate deep
into the tumor and are expected to kill all the cancer
cells. In fact, the polymeric nanomachines we developed have shown tumor accumulation superior to theconventional boron agent (BSH) in subcutaneous tumor
models, and neutron irradiation has produced a remarkable anti-tumor effect.
We aim to create innovative medical technologies
that originate in Japan and can be exported worldwide
through the integration of BNCT technology, developed over a long period in Japan, with the nanomachine technology we have developed.

Figure 1 Principle of BNCT

3. Cell killing by α-ray and Li- nuclei produced
through nuclear reactions between neutronsand boron accumulated in the tumor.

1. Injection of a boron（ B） 2. Neutron irradiation
to the diseased site
formulation
10

Thermalneutron10

B Li nucleus

α-ray

10

B

Cell killing

nucleus

10

B

10

B

nucleusnucleus

Boron formulations that have beenused in BNCT

Target diseases for BNCTBSH

For almost all types of cancer.
*Diﬃcult to be applied forrecurrent/multiple tumors

BPA（Mercaptoundecahydrododecaborate） （4-Borono-L-phenylalanine）

Recurrent head and neck cancer
Multiple brain metastases

Conventional radiotherapy

Particlebeam
radiotherapy

Solitary liver cancer
Early stage lung cancer
Prostate cancer

HOOC

BNCT

Recurrent malignant melanoma
Malignant pleural mesothelioma
Multiple lung metastasis
Localized recurrent breast cancer

B

Multiple liver cancer

OH

OH

Bladder carcinoma in situ
Primary malignant brain tumor

Choroid melanoma

There are not many cancers whereparticle beam radiotherapy is deﬁnitely more
eﬀective than conventional radiotherapy.

NH2

Recurrent malignant brain tumors
Boron neutron
capture therapy

B

Fresh malignant melanoma

＝ BH

SH

Bone/soft tissue tumor/sarcoma
Radiotherapy-resistant head and neck cancer

Cited from Minoru Suzuki. Expanded indications of BNCT. Radioisotopes 64, 59-66 (2015).

S

HN
C
O
O

O
l

N
H

H
N
m

O

N
Hn

S

B

O

H

COOH

Biocompatible polyethylene glycol and polyglutamic acidare used as the backbone, and BSH is introduced topolyglutamate side chains via a disulﬁde bond.

Amount of boron
accumulated in tumors
9.0

Conventionalboron formulation

8.0

Polymericnanomachines

7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0

10

＝ BH

Biodistribution in subcutaneous tumor models

B existing in the blood per 1mL / Administered 10B（％）

Polymeric nanomachine equippedwith multiple boron clusters
Accumulated 10 B was administered in tumor per 1g（％）

Figure 2

0

10

20

Time after administration（h）

Nanomachines are capable ofdelivering more boron than BSH,
to keep a high concentration of
intratumor boron for a long period.

Amount of boronin blood
20

Conventionalboron formulation

18

Polymericnanomachines

16
14
12
10
8
6
4
2
0

0

10

20

Time after administration（h）

Both BSH and nanomachines are
eliminated rapidly from the blood.

Terminology＊1 Radiation
Radiation is a collective term indicating particles that flow with high energy (particle rays)and high-energy electromagnetic waves. For example, one of the particle beams, α-ray, isthe flow of helium nuclei, composed of two protons and two neutrons, which are referred
to as α-particles. On the other hand, X-ray is high-energy electromagnetic waves (light).
＊2 X-ray
It is radiation with high transmittance capable of obtaining an anti-tumorous effect bypointing radiation at the cancer.
＊3 Particle beam
In addition to α-ray (α particle beam), there are proton beams (hydrogen nuclei [protons])beam) and carbon ion beams (carbon nuclei beam). Particle beams of nuclei heavier thanprotons such as carbon nuclei are referred to as heavy particle beams. Radiotherapies
utilizing proton beams and heavy particle beams are gathering attention.

＊4 Thermal neutron
A neutron is an uncharged particle that makes up a nucleus. A neutron, with its kinetic
energy similar to that of thermal motion at ordinary temperature (about 0.025 eV), isreferred to as a thermal neutron. In a broader sense, a neutron with energy not more than
0.5 eV is referred to as a thermal neutron as well as a high temperature thermal neutron.
An epithermal neutron is a neutron with energy 0.5 to 10 keV.

Reference
1. Hiroyuki Nakamura. History and Current Status of Boron Compounds/Formulations
Radioisotopes 64, 47-58. (2015)
2. Minoru Suzuki Expanded indications for BNCT. Radioisotopes 64, 59-66. (2015)
3. Mi, P., et al. Block copolymer-boron cluster conjugate for effective boron Neutron
capture therapy of solid tumors. J. Controlled Release 254, 1- 9 (2017)

NanoSky VOL.05 MARCH 2018

| 11

Listen to

COINS'
Members

Wataru KUROSAWA
He is engaged in R&D on medical materials
to realize minimally invasive treatmentb y a p p l y i n g A j i n o m o t o ’s a m i n o a c i dtechnologies.

What w

Manager, AJIPHASE Group,
Business Strategy & Planning Dept.,
AminoScience Division,
AJINOMOTO CO., INC.

Importance of timing

T counter the related situations not only in
hey say“timing is important”. We often en-

our daily lives but also in research lives. I suppose
most of the researchers have similar experiences
when they got stuck in the research, such as“Ithappened to lead the solution when I listened to
the lecture at the conference,”or“I got an idea atthe social gathering after the conference.”etc.
It looks like social implementation of research
results is also similar to these cases. It is a given
fact that excellent research results are available,
however, in many cases social implementation isrealized through companies. So even cutting-edge
technologies would not always lead to social implementation, if there is no merit for companies interms of intellectual property, or the social infra-

structure is not improved enough, which mightmake you disappointed. It is put into practical use
only when the needs of the society and the invented technologies are fully matched. Outdated technologies are out of the question, however, too futuristic technologies might be difficult to realizesocial implementation. It really makes me feel timing is important.
I had been engaged in various R&D projects in
the research institute for 15 years since I joined
the company. During the time, I could have precious experience, such as creating the cuttingedge technologies with COINS members, success, failure, and encounter with many excellent
researchers. This time, I moved to the headquarters and am currently challenging business devel-

opment based on our company’s technologies.
For a corporate researcher, it is surely worthwhile
to contribute to
the health of human beings
through businessand to grow companies as well. I
will strive to provide new value tothe world, while
paying attention to
the importance oftiming.
Created by my daughters.“Badtiming, I was on my business trip.”

Yuki HORISE

Project Assistant Professor,
Faculty of Advanced Techno-Surgery (FATS),
Institute of Advanced Biomedical Engineering and Science,
Tokyo Women’s Medical University

Medical-engineering integrationand human connection
F (FATS) is consisted of medical and engiaculty of Advanced Techno-Surgery

neering staff, sharing the same time and spaceby arranging desks in one room, and various projects are progressing here with "medical and engineering integration" a motto. Institute of Advanced
Biomedical Engineering and Science with FATS
locates a walking distance to the university hospital and thus closer to clinical practice, involving a
lot of medical staff such as doctors and nurses.
So, it is the best environment to know about whatis actually happening in clinical site.
We are developing a robotic microscope forbrain surgery at one of the parts of Smart Cyber
Operating theater (SCOT)® project. In the Human Resources Development Project, we orga-

12 | NanoSky VOL.05 MARCH 2018

nize seminars and clinical site tours for businesspeople, establish a foundation to promote the creation of domestic medical equipment, etc. In addition, promotion of new projects in collaboration
with major and small enterprises, etc. from development to education and collaborative research.
Since I often meet so many people on a daily basis, I feel that "connection with others" is very important in promoting things in every projects.
I participate in COINS project from FY 2016
and we are developing a sonodynamic
therapy (SDT) using DDS. When SDT was implemented to a pet dog suffering from spontaneous cancer, we could not only confirm the safetyof SDT but also get result that suggest effectiveness. In October 2017, first-in-human clinical

She joined FATS in May 2015 as a postdoctoral
researcher and works as a project assistant professor
from April 2016. As having a motto of medical andengineering integration, she has been engaged in
medical device development and human resource
development, etc. beyond the framework of engineering.

study which started at Tokyo Medical University
was successfully completed. We will keep up ourwork for the development of SDT, believing that it
will drastically change human cancer treatment.

SDT Team conducted clinical study at Tokyo Medical
University

e treasure
Naohiko SHIMADA

Assistant Professor,
School of Life Science and Technology,
Tokyo Institute of Technology

When I move my bodyW become older. As a result, weight ine humans, metabolism falls when wecrease, and it gets easier to become a lifestyle-related disease such as high bloodpressure and hyperlipidemia. Like other people in my age, I also gained my weight drastically compared to my younger days, then,although I did not like exercise, I started going to a nearby sports gym. There are various machines in the gym and you can exercise at your own pace. I succeeded in losing
2 kg in two months with 30 minutes muscle
training and 30minutes aerobic exercise!
What's even better was that I was able tothink while doing an aerobic exercise suchas an aero bike. Since I often think while I

am sitting, when I think while I am moving, I
come up with something different from usual. As well as losing weight, I really feel it
was good that I started to go to the gym.
Now usually, we are conducting research
on a polymer“thermo-responsive polymer”
which undergoes solubility change in response to temperature change. Especially,
thermo-responsive polymers that cause
compatibilization and change in aqueous
solution are widely used as biomaterials
such as drug delivery bases and cell cultureboards. Most of these were phase separation type which was heated by somethingcalled LCST type. However, we have foundthat UCST-type polymers with ureido groups

He has found that polymers with ureido groups
exhibit temperature responsive behavior in hightemperature dissolution (UCST) type in aqueous
solution. He is doing molecular design of UCST
type polymers and its application to biomaterials.

were extremely unusual macromoleculesthat causes phase separation by cooling under physiologicalconditions contrary
to LCST type.
I will continue
working toward application of this unusual ureido polymer to biomaterials
at my daily gym exercise.

Right now, I am thinking whilepedaling!

Sayaka SHIBATA
She is an engineer supporting animal testing by
preclinical MRI.She assists to create diseasemodel animal, operate on animals necessaryfor MRI imaging, administer an anesthetic,
make vital management and stain tissue inorder for research to proceed smoothly.

“T compound, this is a mouse for this”,
hree months for the synthesis of thissometimes unlikely words are said before theexperiment. In animal testing using MRI, techniques such as contrast medium administration with a long catheter line, anesthesia management in continuous photography forseveral hours, methods for fixing to animals
during that time are necessary. For various experiments, prepare and practice as much as
possible to raise the success rate, meet frequently with researchers, and try not to failwith maximum attention at the real stage. It is
my job to help experiments of the synthesizedcompound with a lot of time and effort and experiments of precious model animals not toEngineer,
National Institutes for Quantum and Radiological Scienceand Technology (QST),
Department of Molecular Imaging and Theranostics,
National Institute of Radiological Sciences (NIRS), QST

Because I never failfail although it is not like the TV drama“I never fail.”I enjoy the process that the paper iscompleted with the hint of this experiment result and“things that are not yet science”become“science”.
“What is important is planning, checking
the current location, not giving up.”This iswhat I cherish with the mountain walking
which I started after twenty years old. If research goal is the peak of far away mountain,
the experiment is just a step. The peak of a
big mountain is far away, I can’t reach no
matter how much I walk. Even if I become
anxious along the way, I continue walking
without giving up. There are so many things
that I can’t control in the mountain such as

unstable weather and trouble, however, when
I am moved by superb view beyond my imagining in a few occasions, thatmakes me feelthat I would liketo climb again.
The road to research is also
steep and I getlost sometimes.
However, now I
think it is not that
bad.
Azumayama, Ohtakizawa, 2 days
and one night trip to the mountain.

NanoSky VOL.05 MARCH 2018

| 13

ACTIVITY REPORT
4th COINS Symposium

Nanotech → In-body hospitals → Smart Life
〜 Future Health care with Nanomachine 〜
On Friday, December 8, the 4th COINS Symposium was held at
Kawasaki City Industrial Promotion Hall on the theme of nanotech →In-body hospitals → Smart Life 〜 Future Health care with Nanomachines 〜
As this time was the second time which was held in Kawasaki, we
aimed for a symposium that would be an opportunity to build environments and networks that could accelerate future social implementation and networks while sharing the concept of“In-body hospitals”
and cutting-edge outcomes that would contribute to its realization.
Unlike the previous symposium, most of the participants werecompanies those were not from our participating companies andgeneral. Particularly, it seemed that interest in“In-body hospitals”
and COINS’s efforts were increasing among the society here in
Kawasaki.
In oral sessions“Overcome Cancer by Nanotech”and“Healthy life
span with“In-body hospitals”, there were presentations about the latest research results leading to the development of innovative diagnostic and therapeutic technologies and realization of“In-body hospitals”
by DDS using nanotechnology. The voices of admiration and expectation were raised from the venue. In the poster session, 34 researchersand companies gave presentations and active discussions were held
between participants and presenters.
In the final panel discussion, on the theme of“Health care in smart
life care society”, after a keynote lecture / short presentation frompanelists, there were active discussions on one of the future healthcares“In-body hospitals”, how it could be accepted by society andimportant points and way of thinking also with the participants at thevenue.
It became avery meaningful
symposium togive momentum
to the progress of
research and development / social
implementation
toward the final Twan Lammers
Liangfang Zhangp h a s e o f COI Full Professor, Department
Professor, Department ofof Nanomedicine and
NanoEngineering, University(2019-2021).
Theranostics, ExMI, RWTH
Aachen University Clinicof California San Diego

Panelist

Panelist

Panelist

Panelist

Moderator

Professor, Department of Materials Engineering,
Graduate School of Engineering, The Universityof Tokyo
COINS Theme 4 Leader

Executive Advisor,
Asahi Kasei Corporation
COINS Advisor

Director, Johnson &Johnson Innovation
New Ventures Japan

Editorial Board Member,
Science Department, Editorial Office
Yomiuri Shimbun

Kawasaki Institute of Industrial Promotion
Innovation Center of NanoMedicine
COINS Project Leader

Takanori ICHIKI

Toshio ASANOTaro TSURUKAI

Hiroshi MASUMITSU

Hiromichi KIMURA

panel discussion

TopicsJuly – December, 2017◦7.3.2017【News】An issue regarding of Prof. Kazunori Kataoka, Director
General of iCONM (COINS Research Leader) was introduced. The title: Realization of nanomachines“Fantastic Voyage”changes health care.
◦7.6.2017【News】Article of Dr. Kazunori Kataoka, COINS Research Leader,
Dr. Yasuhiro Matsumura, Exploratory Oncology Research & Clinical Trial
Center, National Cancer Center (COINS Theme 1), Dr. Ichio Aoki, Team
Leader, National Institutes for Quantum and Radiological Science and Technology, Functional and Molecular Imaging Team, Department of Molecular
Imaging and Theranostics, National Institute of Radiological Sciences (COINS
Theme 5)’s interview and its research were introduced in Yomiuri Shimbun
Evening paper P. 6“Research Front”. The title: Drugs that target cancer◦7.7. 2017【Award】Ms. Wakako Sakamoto (D1), Ms. Satomi Azuma (M2),
Mr. Takuro Ochiai (M1), Dr. Naohiko Shimada (Assistant Professor) and Dr.
Atsushi Murayama (Professor) from Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology received The Best Oral Presentation Award from The 33rd Annual Meeting of the Japan Society. Dr. Takuro
Ochiai, Dr. Naohiko Shimada and Dr. Atsushi Murayama received The Best
Post Presentation Award as well.
◦7.13.2017【News】Article of Dr. Kazunori Kataoka (COINS Research Leader) ’s interview was introduced in Yomiuri Shimbun Evening Paper P.3. The
title: Drugs that target cancer – flexibility, cheerfulness and passion

14 | NanoSky VOL.05 MARCH 2018◦7.19 . 2017【Activity】COINS Seminar #26 was held.
Speaker: Prof. Alexander Wei（Department of Chemistry and Materials Science & Engineering, Purdue University ）Title: Adventures in Drug Delivery, Diagnostics, and Additive Manufacturingwith Engineered Metal Nanoparticles◦7.20.2017【News】Article of Dr. Yasuhiro Matsumura (National Cancer
Center)’s interview was introduced in Yomiuri Shimbun evening Paper P.6
The title: Drugs that target cancer – Be nice with data
◦7.23.2017 【News】Article related to iCONM was introduced in Kanagawa
Shimbun P.19. The title: Developing Kanagawa Prefecture Coastal Area
◦7.24.2017【News】Article related the research of Dr. Takahiro Ochiya,
Chief, Division of Molecular and Cellular Medicine Advanced Medical Biology
research, Treatment Development Group, National Cancer Center ResearchInstitute (COINS Theme 4) was appeared in Yomiuri Shimbun Morning Paper P.2. Moreover, it was appeared in Sankei Shimbun, Nikkei Shimbun,
40 other local newspapers and TV News as well. It triggered a large public
response. The title: Diagnosis of 13 types of cancer with a drop of blood –New test by National Cancer Center – Start clinical test from next month◦7.27.2018 【Award】Dr. Shigehito Osawa (COINS Theme 1) received Young
Scientist Encouragement Lecture award from The 27th Symposium on Biopolymers Science, The Society of Polymer Science, Japan (SPSJ).

Activity Report◦8.3.2017【News】Article of King SkyFront Summer Science event 2017
was introduced in Kanagawa Shimbun P.19. The title: Elementary and JuniorHigh School students’have job experience – doctor, politician and researcher – just like adults.
◦8.17.2017【News】Article of Dr, Ichio Aoki (National Institutes for Quantum
and Radiological Science and Technology, National Institute of Radiological
Sciences) ’s interview about COINS research was posted on New Medical
Life Science website. The title: Preclinical research using 1 Tesla desktop
MRI◦ 8.23.2017【News】Article of Dr. Kazunori Kataoka, iCONM Director General and COINS Research Leader’s interview was published in Asahi Primary
School Student Newspaper. The title: Nanomachines for the bright future –“In body hospitals”with micro capsule◦8.23.2017【News】Interview of Dr. Kazunori Kataoka, iCONM Director General, Research Leader of COINS was posted in EMIRA website. The title:
Will there be“In-body hospitals”!? The great revolution of cancer treatment
brought by nanotech◦8.31 – 9.1. 2017【Activity】“ The JST Fair – Future Industrial Creation with
Scientific Technology”which was organized by JST was held at Tokyo Big
Site. COINS exhibited our research contents at our booth and introduced
COINS challenges and results.
◦9.1.2017【Award】Dr. Takanori Akagi, Project Assistant Professor, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo (COINS Theme 4) received Best Presentation Award from The
9th Annual Meeting of the Japanese Association for RNAi (JARI)/ The 4th
Annual Meeting of Japanese Society of Extracellular Vesicles (JSEV).
◦9.2.2017【News】Dr. Kazunori Kataoka, iCONM Director General (COINS
Research Leader) was appeared on TBS TV“EARTH Lab. – Think about
next 100 years – COINS and iCONMS’approach and effort was introduced.
◦9.5.2017【News】Interview of Dr. Kazunori Kataoka, iCONM Director General (COINS Research Leader) was posted on website“mugendai”. The title:
Soon it will be realized! Stun the world with“In body hospitals”Ultimate
nanomachines which patrol around the body, detect, diagnosis and treat thedisease◦ 9.6.2017 【Award】Dr. Kensuke Osada, Project Associate Professor, Department of Bioengineering, Graduate School of Engineering, The Universityof Tokyo (COINS Theme 1,2,3) received Asahikasei Award 2017 of The Society of Polymer Science, Japan. Title: Control of higher order structures ofplasmid DNA by block copolymers and its application toward gene delivery
system
◦9.8.2017【News】Research result of Dr. Sabina Quader, iCONM SeniorResearch Scientist (COINS Theme 1) was posted in the research highlights
segment in the Kawasaki City-operated web newsletter“Kawasaki SkyFront– News Letter”The title: Surface modification of nanomedicines enhances
their therapeutic effect on brain tumors◦9.12.2017【Activity】COINS Seminar #27 was held.
Speaker: Dr. Kohei Yamamizu, Center for iPS Cell Research and Application,
Kyoto University
Title: Application of iPS cell derived blood brain barrier (BBB) model to drug
discovery

immunostimulatory double stranded messenger RNA with maintained translational activity through hybridization with poly A sequences for effective
vaccination. Biomaterials 150: 162 (2018)”.
◦10.12.2017【News】Article of the press conference which was held on
October 11 was posted on JIJI COM and Medical NEWS etc. The title: Development of mRNA vaccine that increased immunopotentiating effect –iCONM and others◦10.18.2017 【Activity】Press Conference was held by iCONM, The University of Tokyo and Tokyo Medical and Dental University on the paper
presented by Dr. Yasutaka Anraku, Project Assistant Professor, Departmentof Bioengineering, Graduate School of Engineering, The University of Tokyo(COINS Theme 2 Leader), Dr. Takanori Yokota, Chairman and Professor and
Dr. Hiroya Kuwabara, Project Assistant Professor, Department of Neurology and Neurological Science Tokyo Medical and Dental University, and Dr.
Kazunori Kataoka, iCONM Director General (COINS Research Leader) andothers“Glycaemic control boosts glucosylated nanocarrier crossing the BBB
into the brain. Nature Communications 8: 1001 (2017)”.
◦10.20 – 29【News】Article about the press conference was appeared in Nikkei Shimbun P.8, Nikkan Kogyo Shimbun P.21, Kanagawa Shimbun P.21.
The title: BBB- crossing nanomachines efficiently reach neurons Kawasaki
Institute of Industrial Promotion etc. (Nikkan Kogyo Shimbun) on October
18. It was reported in NHK News on October 29. The title. Development ofMicro capsule that deliver drug to the brain.
◦10.29.2017【News】Dr. Kazunori Kataoka, iCONM Director General (COINS
Research Leader) appeared on BS JAPAN“Shock! Future Technology –World will change like this”. The challenge of COINS and iCONM were introduced. The title: Japan made nanomachines slip into human body. That SF
movie“Fantastic Voyage”finally become a reality.
◦10.30.2017【News】Dr. Akira Matsumoto, Associate Professor, Tokyo
Medical and Dental University (COINS Theme 4)’s research was appearedin Nikkei Shimbun P.9. The theme:
Artificial pancreas, compact and easy to use◦11.1.2017【Activity】Braizon Therapeutics Inc., iCONM and Tokyo Medical
and Dental University made an announcement at the press conference on
the establishment of Braizon Therapeutics that venture company responsible for social implementation of research result of COINS Theme 2. The
Title: Revolutionary medical innovation using DDS technology to the brain.
◦11.17-18【Activity】4th Retreat Camp was held at Shonan Village Center.
(detailed report in P.16)◦11.18.2017【 Award】Dr. Kazunori Kataoka, COINS Research Leader
earned the honor as“2017 Highly Cited Researchers (Top 1% most citedresearchers in this area) by Web of Science.
◦11.29.2017 【Award】Dr. Kazunori Kataoka, COINS Research Leader received John G. Wagner Memorial Lectureship Award by College of Pharmacy, the University of Michigan. He gave a memorial lecture. The title: SelfAssembled Supramolecular Nanosystems for Smart Diagnosis and Targeting
Therapy of Intractable Diseases.
◦12.6.2017【News】Article related to COINS by Mr. Toshio Asano, COINS
Advisor (Standing Advisor, Asahi Kasei Corporation) was posted on websiteof the Pharmaceutical Society of Japan“Katsuyaku no hito”.

◦9.21.2017【News】Research of Dr. Kazunori Kataoka, iCONM Director
General (COINS Research Leader) was posted on GIZMODO Japan, excite
News and LINE NEWS MAGAZINE. The title:“In body hospitals”has finallycome this far. Towards the era where the disease is found automatically inthe body and treated◦12.7.2017 【Activity】COINS New letter Vol.4 was published.

◦9.24.2017【News】Dr. Kazunori Kataoka, iCONM Director General (COINS
Research Leader) appeared on Nihon TV“Nittere Update!”.

◦12.8.2017【Activity】4th COINS Symposium was held at Kawasaki City Industrial Promotion Hall.

◦10.8.2017【Appointment】Dr. Kazunori Kataoka, iCONM Director General(COINS Research Leader) attended an appointment ceremony of National
Academy of engineering: NAE as a foreign member, which was held at Headquarters in National Academy in Washington DC, USA.

◦12.12.2017【Activity】“RIKEN Symposium: RIKEN/iCONM/NIMS Medical
Engineering Network”was held at iCONM and next door LiSE.

◦10.10.2017 【News】Article of Dr. Kazunori Kataoka, iCONM Director General (COINS Research Leader)’s interview was published in weekly magazine SPA! (Vol. 10/10・17 P.41). The title: Fairy bright“Paradox”Japan’s
future Excellent health is available inexpensively in 2032 A healthy lifespanis dramatically extended – A society without becoming senile!
◦10.11.2017 【Activity】Dr. Satoshi Uchida, Project Assistant Professor,
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo (COINS Theme 3), Dr. Keiji Itaka, Professor, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (COINS
Theme 3) ,Dr. Kazunori Kataoka, iCONM Director General (COINS Research
Leader) and others held a press conference about their paper“Designing◦12.7.2017 【News】Article related the press conference on October 18 was
posted on Mainichi Shimbun P.12. The tile: BBB crossing nanomachines Expected to be used for a treatment of Alzheimer’s disease.

◦12.12.2017【Appointment】Dr. Kazunori Kataoka, COINS Research Leader
earned the honor of Fellow of the National Academy of Inventors (NAI).
NAI Fellow status is the highest professional accolade bestowed solely toacademic inventors who have demonstrated a prolific spirit for innovation increating or facilitating outstanding invention that have made a tangible impact on quality of life, economic development and the welfare of society.
◦12.22.2017 【Award】Dr. Kazunori Kataoka, iCONM Director General (COINS
Research Leader) received“Princess Takamatsu Cancer Research Fund
Prize”of 2017 for his pioneering research on“The Development and Clinical Translation of Delivery Systems of Anti-Cancer Reagents based on Polymeric Micelles”.

NanoSky VOL.05 MARCH 2018

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Activity Report
4th Retreat Camp ━ Lean“R&D”“Commercialization”“Intellectual Property”“Strategy”
On Friday, November 17 – Saturday, November 18, a retreat camp washeld on the theme of“Strategy towards realization of In-body hospitals”
at Shonan International Village Center in Kanagawa Pref. To promote social implementation of research results to realize“In-body hospital”, it isimportant to foster the strategic viewpoint of the COINS members andcreating a chance to review current efforts, thus we organized a workshop on“R&D”,“Business, Social Implementation”and“Intellectual
Property”this time. First, Dr. Tomohiro Anzai, Theme 6 Leader gave atalk as a theme on“Strategy”and afterwards "R&D Strategy Workshop"
was held as facilitated by Dr. Shintaro Sengoku, Tokyo Institute of Technology.
Followed by“Commercialization and Social Implementation strategy
workshop”in response to the special lecture“How to commercialize andput innovative research outcome into practical use”by Dr. Chikafumi Yokoyama, CEO, ReproCELL Inc.
Subsequently, Mr. Hirokazu Iwasaki, COINS Research Promotion
Leader conducted“Intellectual strategy workshop”and this was followed
by group presentations. Excellent
groups and individuals were awarded. Three COINS advisors, Prof.
Tatsuro Irimura , CO I N S Advisor(J u nte n d o U nive r sit y G ra d u a te
School), Mr. Toshio Asano (Asahi
Kasei Corporation), Mr. Hiroshi Misawa (Medical Technology Association Japan) and an observer, Mr. Hiroshi Kono, Kawasaki Institute ofIndustrial Promotion, and Prof. Hiromichi Kimura , C O I N S ProjectSpecial lecture by Chikafumi Yokoyama,leader and Prof. Kazunori Kataoka,
CEO, ReproCELL Inc.

COINS Research leader gave feedback with expectation for the years tocome. Some research results have already moved to social implementation; therefore, it is necessary to promote the project even more strategic
way. We are planning to organize a retreat camp on entrepreneurship human resources development.
Feedback by COINS Advisors and observers

Toshio Asano,Executive Advisor,
Asahi Kasei
Corporation

Hiroshi Kono,
Tatsuro Irimura,
Hiroshi Misawa,
Project Professor,
Executive Director, Chief Coordinator,
Life Science,
Juntendo University Medical Technology Kawasaki Institute of
Association Japan Industrial Promotion

Through the two days case study workshop, the members have become further united.

9th General Meeting ━Toward final third phase
The 9th General Meeting was held at the main conference room in theLife Science & Environment Research Center (LiSE) on Thursday, January 25, 2018.
In this meeting, to share the progress of Phase II (2016 – 2018) plans
and 2018 plans toward Phase III (2019-2021) as a purpose, after presentations of theme leaders and participating companies, a panel discussion was held on the theme of social implementation of research resultand points to build a structure to accelerate it. The members shared thepoints that cooperation across the themes and strategic use of regulatory
measures and intellectual property etc. were very important to maximize
the use of results and further promotion of In-body hospitals.
In special session, Mr. Shigeyuki Shiratori, Director of International
Strategy promotion, Coastal Area International Strategy Headquarters,
Kawasaki City gave a talk on the title of“Establishment of Center at Tonomachi International Strategic Zone King SkyFront”and Mr, Haruhiro
Okuda, Vice-Director of the National Institute of Health Sciences (NIHS)
introduced NIHS.

Participants raised expectation that COINS’s efforts will accelerate in the
future by accumulating important institutions in social implementation at
King Skyfront.
Prof. Tatsuro Irimura, Juntendo University, COINS Advisor, Mr. Hiroshi
Misawa, Medical Technology Association of Japan and Mr. HaruhikoManage, JST, COI vision 1,
visionary leader gave feedback such as the point andstance to promote social implementation from research
result. It was very fruitful opportunity to share theawareness of making best
effort for realization of Inb o dy h os pitals by e ntire
Shigeyuki Shiratori,
Haruhiro Okuda,
COINS.
Diretor, Kawasaki City Vice-Director, NIHS

Editor’s NoteThe mission of COINS Theme 5 is“No hospitalization · Realization of day treatment”. We aim to develop a system that can
combine detection, diagnosis, and treatment by combining the functions of nanomachines and medical devices, and we are trying
our best every day. In point of integrating the functions of treatment and diagnosis, it can be said that it is closer to“In-bodyhospitals”than other themes, and some results are already in the clinical trial stage, so that it may be the Theme that feels therealization of“In-body hospitals”. On the other hand, as the social implementation is progressing, the differences from current
healthcare systems and business situations started to be seem as a big problem. You might be able to catch a part of the problem
in“Talking about Theme”. Theme 5 and eventually COINS's overall efforts will overcome such challenges and expect to be thedriving force to build economic and social systems that will support Japan in the near future. We will continue to strive to makethis“NanoSky”reports the progress and the heat of people involved in that progress.
(Chief Editor Takashi SUGIMOTO)

5

Edited by NanoSky Editorial Board (Takashi SUGIMOTO, Nobuhiro
NISHIYAMA, Ken MASAMUNE, Miyako YOKOYAMA)
Writer： Ayumi KOJIMA
Camera : Kazuyuki OTSUBO
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/