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

• Published in: Biomaterials 2021-02, Vol.269, p.120631-120631, Article 120631
• Main Authors: Islam, Waliul, Matsumoto, Yoshitaka, Fang, Jun, Harada, Ayaka, Niidome, Takuro, Ono, Katsuhiko, Tsutsuki, Hiroyasu, Sawa, Tomohiro, Imamura, Takahisa, Sakurai, Kazuo, Fukumitsu, Nobuyoshi, Yamamoto, Hirofumi, Maeda, Hiroshi
• Format: Article
• Language: English
• Subjects: BNCT; Glycolysis inhibition; Mild-hypoxia; Multifunctional; Treatment of advanced tumor; Tumor selective
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2020.120631

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. [Display omitted] •A multifunctional anticancer-drug of synthetic polymer conjugate with glucosamine and boric acid (BA) was developed.•After iv injection it exhibits long plasma t1/2 (24hr) thus good EPR effect: tumor/blood ratio more than 30.•The polymer conjugate released BA in acidic tumor pH and inhibited both glycolysis of tumor cells and tumor growth.•This complex showed 16 times more potent tumor killing after neutronirradiation in vitro and no damage to skin in vivo.•This polymer BA complex exhibited much higher antitumor effect in low pO2 (6–8%), implying potent effect on large tumors.