OU-MRU Vol.14 September 2015

Okayama University Medical Research Updates （OU-MRU）

2015.09 Vol.14

Source: Okayama University, Center for Public Affairs and Communications
For immediate release : 16 September 2015
Okayama University research : Simplified boron compound may treat brain tumours(Okayama, 16 September) Effective and targeted uptake among malignant cells
demonstrates the promise of a simplified boron compound for neutron radiation therapy,
report researchers at Okayama University and Kinki University.
“Glioblastoma multiforme is the most common malignant central nervous system primary
tumour that has been incurable for decades,” explain Hideki Matsui and colleagues atOkayama University Graduate School of Medicine and Kinki University in their recent report.
Treatment with ‘boron neutron capture therapy’ (BNCT) has been found to double theduration of patient survival, but finding effective compounds for it has been challenging.
Now Michiue and colleagues have demonstrated - both in cell lines and mice - a readily
made boron compound that targets and penetrates tumour cells for effective BNCT [1].
The compound BSH is high in boron content and has the advantage of accumulatingprimarily in tumour tissue rather than healthy tissue. However BSH does not penetrateinside the tumour cells limiting the therapeutic effects of BNCT using it.
Previously Michiue and a collaboration of researchers in Japan demonstrated they could
enhance cell penetration by fusing BSH with a large peptide comprising up to 11 amino acid‘arginine’ groups [2]. However with the large added peptide it was difficult both to produce
the compound and track its effects in the body.
Studies of protein transcription aided by a smaller version of the peptide suggested that acompromise in size may allow effective BSH cell penetration without the need forprohibitively complicated synthesis techniques. [3]. The latest results from Michiue andcolleagues have now shown that while peptides with just one or two arginine groups wereineffective, three arginine groups were enough to improve cell uptake.
The BSH fused with a peptide of three arginine groups was simpler to produce and they
could also track the drug in the body using positron emission tomography. They conclude,“In our present study, we discovered that BSH-3R overcame many obstacles to develop aBSH-peptide suitable for future clinical use.”

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OU-MRU Vol.14 September 2015

Background
Boron neutron capture therapy
One of the challenges with treating glioblastoma multiforme is removing all cancer cells
without causing damage to the brain. The destruction of nearby healthy cells is a significant
side effect for traditional radiation therapy.
BCNT has attracted particular interest because the radiation caused is highly localised.
When boron is delivered to malignant cancer cells, irradiation with low-energy thermal
neutrons then triggers boron fission into a high energy alpha particle and lithium atom.
While lethal to cells in their direct path the high-energy alpha particle and lithium atom
produced cannot travel further than roughly a cell length before their energy is absorbed
leaving nearby healthy cells intact.
BNCT has already been used clinically for treating brain tumours, malignant melanoma,
head and neck cancers, and hepatoma. Hospital sources for low-thermal-energy neutrons totrigger the fission are in continued development. However clinical use so far has highlighted
shortcomings in the boron delivery drugs currently available.
Boron delivery drugs
Previous clinically used drugs for BNCT include an essential amino acid analog p-boronoLphenylalanine (BPA) and disodium mercaptoundecahydrododecaborate ([B12HnSH]2-2Na+,BSH). BPA readily delivers high boron content to cells but it does not target malignant cells
alone and is not taken up by slowly proliferating malignant cells.
In contrast accumulation of BSH is greatly enhanced in tumour regions but it is presentbetween the cells making it less effective for BNCT. Simulations in previous work havehighlighted the limitations of BNCT from outside the cell.
Arginine
Arginine is a type of amino acid. Previous work has shown that with an 11-arginine-strong
peptide the cancer killing effect of the BSH compound was greater than with a dose 100
times stronger of BSH without the added peptide. However it is difficult to synthesise BSH
with the 11-arginine peptide and it cannot be readily tracked to monitor its effects in thebody. The results of this latest work resolve some of the practical issues around usingarginine groups to improve BSH cell penetration for cancer treatment using BNCT.

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1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 Japan© OKAYAMA University

OU-MRU Vol.14 September 2015

Figure caption
Chemical structures of the readily synthesised BSH fused with comparatively short ‘nR’
peptides, where R is the arginine group and n is the number of arginine groups. When fusedwith 3R the BSH penetrates the cell for effective BNCT. The chemical is additionally readily
fused with a fluorescent moiety, Tmr (a), and DOTA for positron emission tomography scans(b) to track the drug in the body.
References
1. Yoshiya Iguchi, Hiroyuki Michiue, Mizuki Kitamatsu, Yuri Hayashi, Fumiaki Takenaka,
Tei-ichi Nishiki and Hideki Matsui. Tumor-specific delivery of BSH-3R for boron
neutron capture therapy and positron emission tomography imaging in a mousebrain tumor model. (2015) Biomaterials 56 10e17
doi: 10.1016/j.biomaterials.2015.03.061.
http://www.ncbi.nlm.nih.gov/pubmed/25934274
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1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 Japan© OKAYAMA University

OU-MRU Vol.14 September 2015

2. Hiroyuki Michiue, Yoshinori Sakurai, Natsuko Kondo, Mizuki Kitamatsu, Feng Bin,
Kiichiro Nakajima, Yuki Hirota, Shinji Kawabata, Tei-ichi Nishiki, Iori Ohmori, Kazuhito
Tomizawa, Shin-ichi Miyatake, Koji Ono and Hideki Matsui. The acceleration ofboron neutron capture therapy using multi-linked
mercaptoundecahydrododecaborate (BSH) fused cell-penetrating Peptide. (2014)
Biomaterials 35 3396e3405
doi: 10.1016/j.biomaterials.2013.12.055.
http://www.ncbi.nlm.nih.gov/pubmed/24452095
3. Takashi Hitsuda, Hiroyuki Michiue, Mizuki Kitamatsu, Atsushi Fujimura, Feifei Wang,Takahiro Yamamoto, Xiao-Jian Han, Hiroshi Tazawa, Atsuhito Uneda, Iori Ohmori,Tei-ichi Nishiki, Kazuhito Tomizawa, Hideki Matsui . A protein transduction method
using oligo-arginine (3R) for the delivery of transcription factors into cell nuclei.
(2012) Biomaterials 33 4665e4672
doi: 10.1016/j.biomaterials.2012.02.049.
http://www.ncbi.nlm.nih.gov/pubmed/22465335

Correspondence toAssistant Professor Hiroyuki Michiue, M.D., Ph.D.
Department of Physiology, Okayama University
Graduate School of Medicine, Dentistry andPharmaceutical Sciences, 2-5-1 Shikata-Cho,Okayama, 700-8558, Japan.
E-mail: hmichiue@md.okayama-u.ac.jp

Further information
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OU-MRU Vol.14 September 2015

Okayama University Medical Research Updates （OU-MRU）
Vol.1：Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells
from blood samples for genetic testingVol.2：Ensuring a cool recovery from cardiac arrest
Vol.3：Organ regeneration research leaps forward
Vol.4：Cardiac mechanosensitive integrator
Vol.5：Cell injections get to the heart of congenital defects
Vol.6：Fourth key molecule identified in bone development
Vol.7：Anticancer virus solution provides an alternative to surgery
Vol.8：Light-responsive dye stimulates sight in genetically blind patients
Vol.9：Diabetes drug helps towards immunity against cancer
Vol.10：Enzyme-inhibitors treat drug-resistant epilepsy
Vol.11：Compound-protein combination shows promise for arthritis treatment
Vol.12：Molecular features of the circadian clock system in fruit flies
Vol.13：Peptide directs artificial tissue growth

About Okayama UniversityOkayama University is one of the largest
comprehensive universities in Japan withroots going back to the Medical Training
Place sponsored by the Lord of Okayama
and established in 1870. Now with 1,300
faculty and 14,000 students, the University
offers courses in specialties ranging frommedicine and pharmacy to humanities
and physical sciences. Okayama
University is located in the heart of Japan
approximately 3 hours west of Tokyo byShinkansen.

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