Press Release
A Therapeutic Option for Glioblastoma using pHSensitive Nanomicelles
Summary:
Using practical nano-DDS technology, a polymeric nanomicelle that effectively delivers thepotent mitotic inhibitor desacetyl vinblastine hydrazide (DAVBNH) to glioblastoma (GBM)
was developed. GBM, which grows rapidly under anaerobic conditions, causes acidosis due
to enhanced glycolysis, and the developed nanomicelle accurately senses the pH lowering
to release the contained anticancer drug. Vinca alkaloids, represented by vinblastine, arelong-known anticancer agents that strongly inhibit mitosis of cells, but they are highly toxic
to normal cells and poorly tolerated for treatment. This major issue was greatly improved by
our nano-DDS technology. In the experiment using mice with GBM transplanted intracranial,
the DAVBNH loaded nanomicelle treated group containing improved 100% survival rate by
2 times and 50% survival rate by 2.6 times in comparison with the free DAVBNH treatedgroup. This result, published in “Biomaterials” (IF = 10.317, 2019) on October 23, suggeststhat it may be clinically applicable to cancers with rapid disease progression other thanglioblastoma.

https://doi.org/10.1016/j.biomaterials.2020.120463

Main Body:
November 12, 2020, Kawasaki in Japan: The Innovation Center of NanoMedicine (DirectorGeneral: Prof. Kazunori Kataoka, Location: Kawasaki-City in Japan, Abbreviation: iCONM)
announced in “Biomaterials” (Impact Factor: 10.317 in 2019) that polymeric nanomicelles
that selectively releases anti-cancer drugs by utilizing the acidity in the cells of glioblastoma(GBM) has been developed focusing on the fact that the hydrogen ion concentration (pH) ofGBM cells is lower than healthy tissues. GBM is a brain tumor with extremely fast diseaseprogression and poor prognosis (5-year survival rate: 10.1%). Although some drugcandidates are under clinical trials, there are currently no drug therapies that cansignificantly improve the overall survival. Besides, it is difficult to completely remove it bysurgery keeping the brain function as much as possible while the boundary with normal
tissues is unclear.
Recently, it has been noted that as a treatment method for GBM, a method using anelectromagnetic pulse called Tumor Treatment Fields (TTF) improved the overall survival(10-14 months to 16-24 months). The mechanism is known to be mitotic inhibition based on
the destruction of the mitotic spindle that occurs during cell division. Therefore, we focusedon the vinca alkaloids represented by vinblastine, an anticancer drug, which has been used
as a mitosis inhibitor for decades. This type of drug suppresses mitosis by inhibiting thepolymerization of intracellular microtubules and shows strong cytotoxicity, but it also affects
not only cancer cells but also normal cells, and results in various types of serious adverse
events including myelosuppression. Therefore, we considered the selective delivery of
vinblastine to tumor tissue using nano-DDS (drug delivery system) with polymeric micelles.
In this system, the drug must be released after reaching the tumor tissue. Cancer cells areusually placed in an anaerobic environment, unable to successfully run the TCA cycle tosustain their lives, and obtain the life energy exclusively from glycolysis. This nature makes
cancer tissues accumulate acidic molecules and result in acidosis. This is more pronounced
in faster-growing cells and is more acidic in rapidly developing cancers such as GBM. We
wanted to take advantage of this property for drug release from micelles.
Hydrazone bonding was chosen as a linker that causes acidic cleavage and prepared by
selecting a block polymer with carbonyl group such as ketones or aldehydes and using
desacetyl vinblastine hydrazide (DAVBNH) as a vinca alkaloid. It is known that DAVBNH is
6 times more potent than vinblastine in suppressing the growth of glioblastoma. Selfassociation of a PEG-PAA block copolymer with DAVBNH attached to an aliphatic ketone
residue in water was able to produce nanomicelles with an average diameter of 31 nm,
containing DAVBNH in its inner core. Examining the stability of these micelles in solutions
at various acidities from pH 6.0 to pH 7.4, the amount of free DAVBNH was significantlydifferent between pH 6.9 and pH 7.4. In other words, it was found that the drug can bereleased on the slightly acidic side by accurately capturing the subtle difference in pH. It wasalso found that when the ketone residue is changed to an aldehyde residue, the drug is notreleased until the pH drops below 5.0.
Using mice in which GL261-Luc cells, which are a type of GBM cells, were transplanted
intracranially, a micelle preparation of DAVBNH or a free drug was injected through the tailvein and the antitumor effect was examined. Compared with the free drug administrationgroup, the 100% survival rate was improved by 2 times, and the 50% survival rate wasimproved by 2.6 times.

Public Interest Incorporated Foundation KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTIONKAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION was established in 1988 funded 100%from Kawasaki City for the purpose of coping with the hollowing out of industry and changes in thedemand structure.
In order to realize a higher level of market development, transforming R&D type companies, training
technological capabilities to support it, human resources development, understanding market needs,etc., by utilizing the functions of the Kawasaki, KAWASAKI INSTITUTE OF INDUSTRIALPROMOTION has been contributing to revitalize the local economy by promoting exchanges of localindustry information, advancing technology and corporate exchanges with establishment of a R&D
institutions, developing creative human resources through workshops and promoting businesses suchas expanding sales channels through exhibition business.
https://www.kawasaki-net.ne.jp/

Innovation Center of NanoMedicine (iCONM)
Innovation Center of NanoMedicine (iCONM) started its operation in April 2015 as a core research
center in life science field at King SkyFront on the request of Kawasaki city that KAWASAKIINSTITUTE OF INDUSTRIAL PROMOTION utilized national policies as a business operator andproposer.
It is a unique research center that the world has ever seen which is designed for the purpose ofpromoting open innovation through industry-academia-government/medical-engineering

collaboration, prepared with state-of-the-art facilities and experimental equipment, that enables
comprehensive research and development from organic synthesis / microfabrication to preclinicaltesting.
https://iconm.kawasaki-net.ne.jp/en/index.html

Center of Innovation Program (COI)The COI program is a research and development program under the Ministry of Education, Culture,Sports, Science and Technology and the Japan Science and Technology Agency. The program
employs the backcasting approach and set interdisciplinary and collaborative R&D themes thatshould be challenged at the present from the issues that are underlying in the future society. Eighteen
centers have been established nationwide to realize radical innovation through industry-academia
collaboration which cannot be accomplished by industry and academia alone.
The Kawasaki center is the only COI center managed by local governments, not universities, and theresearch projects carried out there are called COINS (Center of Open Innovation Network for Smart
Health).
COI: https://www.jst.go.jp/tt/EN/platform/coi.html
COINS: https://coins.kawasaki-net.ne.jp/en/index.html

November 12, 2020