Okayama University


Okayama University Medical Research Updates (OU-MRU) Vol.88

February 22, 2021

Source: Okayama University (JAPAN), Public Relations Division
For immediate release: 22 February 2021
Okayama University research: Nanotechnology for making cancer drugs more accessible to the brain

(Okayama, 22 February) In a study reported in the Journal of Controlled Release, researchers from Okayama University describe the use of nanocarriers in selectively transporting anticancer drugs to brain tumors.

Glioblastoma is an aggressive form of brain cancer that is best treated with boron neutron capture therapy (BNCT). BNCT involves the use of an agent that delivers boron into tumor tissues. When subsequently hit with radiation, boron (typically the 10B isotope is used) emits particles that kill neighboring cells. However, current methods do not cargo boron into cancer cells homogenously. Now, Associate professor MICHIUE Hiroyuki and Okayama university Neutron Therapy Research Center (NTRC) team have successfully used a nanocarrier that selectively delivers boron into brain tumors.

The carrier, known as the A6K peptide, is a nano-scale structure that spontaneously clusters to form hollow tubes when immersed in water. The peptide has a positively charged core, which attracts any negatively charged molecules in the vicinity and traps them inside it. Another bonus feature is that the assembled tubes easily pass through cell membranes. The researchers first combined varying concentrations of the A6K peptide and BSH (disodium undecahydro-mercapto-closo-dodecacarborate), a negatively charged boron-containing chemical. The ensuing complexes formed were observed under the electron microscope.

At high ratios of A6K: BSH a chaotic mess of branched complexes were produced, whereas at concentrations of 1:5 and lower, ordered spherical complexes were created. Seemingly, the BSH particles had been engulfed. These low concentration complexes were then introduced into glioma cells to find that they effectively penetrated the cancerous cells. However, the localization of only BSH into glioma cells was almost ten times less. A6K was thus highly competent in ushering BSH particles into the cells. Additionally, A6K-BSH did not induce any toxicity in the cells by itself.

To then investigate how the complexes were transported in the body, A6K-BSH was injected into the tails of mice with glioblastoma. Within 2 hours the levels of A6K-BSH peaked within the brain tumors of these mice. What’s more, no drug complex was found in healthy tissues. Finally, the tumor-killing properties of A6K-BSH were assessed by treating cells with the complex and then bombarding the cells with radiation for 30 minutes. Within 24 hours, cells irradiated for 15 minutes or more stopped proliferating. The BSH-containing nanotubes were successful in targeting and preventing the growth of cancer cells.

“We aimed to demonstrate a new boron delivery system based on A6K peptide and BSH, and open up a novel direction for boron agents in the next generation of BNCT,” claim the researchers. They also point out the convenience of using this system which simply involves one mixing step before use. While the system remains to be fully tested in animals, it paves the way for directed killing of hard-to-reach tumors.

Boron neutron capture therapy (BNCT): BNCT is a commonly used combination of drug and radiation therapy for cancers that are hard to target with traditional chemotherapy. BNCT involves transferring boron-containing compounds into cancer cells, and subsequently irradiating the cells with neutron beams. However, there are several challenges associated with traditional BNCT, such as ensuring that boron is escorted into tissues uniformly.

Pharmaceutical scientists are now designing novel delivery systems for these boron-containing compounds. A vast array of synthetic polymers has been investigated for this purpose, but these pose additional issues such as toxicity and degradation of the boron agents. The A6K nanotube is a small peptide molecule that has been used to deliver gene therapy in the past. This study demonstrates that the peptide can usher many more substances.

Hiroyuki Michiue, Mizuki Kitamatsu, Asami Fukunaga, Nobushige Tsuboi, Atsushi Fujimura, Hiroaki Matsushita, Kazuyo Igawa, Tomonari Kasai, Natsuko Kondo, Hideki Matsui, Shuichi Furuya. Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture therapy (BNCT). Journal of Controlled Release, 2020 Nov 11;330:788-796.
DOI : 10.1016/j.jconrel.2020.11.001

Reference (Okayama Univ. e-Bulletin): Professor MICHIUE’s team
OU-MRU Vol.14:Simplified boron compound may treat brain tumours

Correspondence to
Associate professor MICHIUE Hiroyuki, M.D., Ph.D.
Neutron Therapy Research Center, Okayama University,
Shikata-cho 2-5-1, Okayama-city, Okayama 700-8558,
E-mail: hmichiue(a)md.okayama-u.ac.jp

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Okayama University Medical Research Updates (OU-MRU)
The whole volume : OU-MRU (1- )
Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testing
Vol.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
Vol.14:Simplified boron compound may treat brain tumours
Vol.15:Metamaterial absorbers for infrared inspection technologies
Vol.16:Epigenetics research traces how crickets restore lost limbs
Vol.17:Cell research shows pathway for suppressing hepatitis B virus
Vol.18:Therapeutic protein targets liver disease
Vol.19:Study links signalling protein to osteoarthritis
Vol.20:Lack of enzyme promotes fatty liver disease in thin patients
Vol.21:Combined gene transduction and light therapy targets gastric cancer
Vol.22:Medical supportive device for hemodialysis catheter puncture
Vol.23:Development of low cost oral inactivated vaccines for dysentery
Vol.24:Sticky molecules to tackle obesity and diabetes
Vol.25:Self-administered aroma foot massage may reduce symptoms of anxiety
Vol.26:Protein for preventing heart failure
Vol.27:Keeping cells in shape to fight sepsis
Vol.28:Viral-based therapy for bone cancer
Vol.29:Photoreactive compound allows protein synthesis control with light
Vol.30:Cancer stem cells’ role in tumor growth revealed
Vol.31:Prevention of RNA virus replication
Vol.32:Enzyme target for slowing bladder cancer invasion
Vol.33:Attacking tumors from the inside
Vol.34:Novel mouse model for studying pancreatic cancer
Vol.35:Potential cause of Lafora disease revealed
Vol.36:Overloading of protein localization triggers cellular defects
Vol.37:Protein dosage compensation mechanism unravelled
Vol.38:Bioengineered tooth restoration in a large mammal
Vol.39:Successful test of retinal prosthesis implanted in rats
Vol.40:Antibodies prolong seizure latency in epileptic mice
Vol.41:Inorganic biomaterials for soft-tissue adhesion
Vol.42:Potential drug for treating chronic pain with few side effects
Vol.43:Potential origin of cancer-associated cells revealed
Vol.44:Protection from plant extracts
Vol.45:Link between biological-clock disturbance and brain dysfunction uncovered
Vol.46:New method for suppressing lung cancer oncogene
Vol.47:Candidate genes for eye misalignment identified
Vol.48:Nanotechnology-based approach to cancer virotherapy
Vol.49:Cell membrane as material for bone formation
Vol.50:Iron removal as a potential cancer therapy
Vol.51:Potential of 3D nanoenvironments for experimental cancer
Vol.52:A protein found on the surface of cells plays an integral role in tumor growth and sustenance
Vol.53:Successful implantation and testing of retinal prosthesis in monkey eyes with retinal degeneration
Vol.54:Measuring ion concentration in solutions for clinical and environmental research
Vol.55:Diabetic kidney disease: new biomarkers improve the prediction of the renal prognosis
Vol.56:New device for assisting accurate hemodialysis catheter placement
Vol.57:Possible link between excess chewing muscle activity and dental disease
Vol.58:Insights into mechanisms governing the resistance to the anti-cancer medication cetuximab
Vol.59:Role of commensal flora in periodontal immune response investigated
Vol.60:Role of commensal microbiota in bone remodeling
Vol.61:Mechanical stress affects normal bone development
Vol.62:3D tissue model offers insights into treating pancreatic cancer
Vol.63:Promising biomarker for vascular disease relapse revealed
Vol.64:Inflammation in the brain enhances the side-effects of hypnotic medication
Vol.65:Game changer: How do bacteria play Tag ?
Vol.66:Is too much protein a bad thing?
Vol.67:Technology to rapidly detect cancer markers for cancer diagnosis
Vol.68:Improving the diagnosis of pancreatic cancer
Vol.69:Early gastric cancer endoscopic diagnosis system using artificial intelligence
Vol.70:Prosthetics for Retinal Stimulation
Vol.71:The nervous system can contribute to breast cancer progression
Vol.72:Synthetic compound provides fast screening for potential drugs
Vol.73:Primary intraocular lymphoma does not always spread to the central nervous system
Vol.74:Rising from the ashes—dead brain cells can be regenerated after traumatic injury
Vol.75:More than just daily supplements — herbal medicines can treat stomach disorders
Vol.76:The molecular pathogenesis of muscular dystrophy-associated cardiomyopathy
Vol.77:Green leafy vegetables contain a compound which can fight cancer cells
Vol.78:Disrupting blood supply to tumors as a new strategy to treat oral cancer
Vol.79:Novel blood-based markers to detect Alzheimer’s disease
Vol.80:A novel 3D cell culture model sheds light on the mechanisms driving fibrosis in pancreatic cancer
Vol.81:Innovative method for determining carcinogenicity of chemicals using iPS cells
Vol.82:Making memories — the workings of a neuron revealed
Vol.83:Skipping a beat — a novel method to study heart attacks
Vol.84:Friend to Foe—When Harmless Bacteria Turn Toxic
Vol.85:Promising imaging method for the early detection of dental caries
Vol.86:Plates and belts — a toolkit to prevent accidental falls during invasive vascular proceduresa
Vol.87:Therapeutic potential of stem cells for treating neurodegenerative disease