Polymer-conjugated glucosamine complexed with boric acid shows tumor-selective accumulation and simultaneous inhibition of glycolysis

Waliul Islam; Yoshitaka Matsumoto; Jun Fang; Ayaka Harada; Takuro Niidome; Katsuhiko Ono; Hiroyasu Tsutsuki; Tomohiro Sawa; Takahisa Imamura; Kazuo Sakurai; Nobuyoshi Fukumitsu; Hirofumi Yamamoto; Hiroshi Maeda

doi:10.1016/j.biomaterials.2020.120631

Polymer-conjugated glucosamine complexed with boric acid shows tumor-selective accumulation and simultaneous inhibition of glycolysis

Biomaterials. 2021 Feb:269:120631. doi: 10.1016/j.biomaterials.2020.120631. Epub 2020 Dec 26.

Authors

Affiliations

¹ Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; BioDynamics Research Foundation, Kumamoto, 862-0954, Japan.
² Radiation Oncology, Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan and Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba, Japan.
³ Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
⁴ Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.
⁵ Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁶ Department of Nutritional Science, Shokei University and Department of Molecular Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁷ Department of Chemistry and Biochemistry, The University of Kitakyushu, Kitakyushu, Japan.
⁸ Department of Radiation Oncology, Kobe Proton Center, Kobe, Japan.
⁹ Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan and Department of Molecular Pathology, Division of Health Sciences, And Graduate School of Medicine, Osaka University, Osaka, Japan.
¹⁰ Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan and Department of Molecular Pathology, Division of Health Sciences, And Graduate School of Medicine, Osaka University, Osaka, Japan; BioDynamics Research Foundation, Kumamoto, 862-0954, Japan; Tohoku University, Sendai, Japan. Electronic address: maedabdr@sweet.ocn.ne.jp.

PMID: 33450582
DOI: 10.1016/j.biomaterials.2020.120631

Abstract

We synthesized unique water-soluble synthetic-polymer, styrene-maleic acid copolymer (SMA) conjugated glucosamine (SG); which formed a stable complex with boric acid (BA). This complex had a mean particle size of 15 nm by light scattering, and single peak in gel permeation chromatography. The particles were taken up by tumor cells five times faster than free BA in vitro and liberated BA at acidic tumor pH (5-7). Liberated BA inhibited glycolysis and resulted in tumor suppression in vivo. Intravenously injected SGB-complex did bind with albumin, and plasma half-life was about 8 h in mice, and accumulated to tumor tissues about 10 times more than in normal organs. IC₅₀ of SGB-complex for HeLa cells under pO₂ of 6-9% was about 20 μg/ml (free BA equivalent), 150 times more potent than free BA. Neutron irradiation of human oral cancer cells with SGB-complex resulted in 16 times greater cell-killing than that without SGB-complex. In vivo antitumor effect was evaluated after neutron irradiation only once in SCC VII tumor bearing mice and significant tumor suppression was confirmed. These results indicate that SGB-complex is a unique multifunctional anticancer agent with much more potent activity under low pO₂ conditions as in large advanced cancers.

Keywords: BNCT; Glycolysis inhibition; Mild-hypoxia; Multifunctional; Treatment of advanced tumor; Tumor selective.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Boric Acids
Cell Line, Tumor
Glucosamine*
Glycolysis
HeLa Cells
Humans
Mice
Polymers*

Substances

Boric Acids
Polymers
Glucosamine
boric acid