Journal
ACS APPLIED BIO MATERIALS
Volume 5, Issue 12, Pages 5953-5964Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsabm.2c00883
Keywords
anticancer drugs; tumor-selective drug accumulation; glycolysis inhibition; boric acid; styrene-maleic anhydride copolymer; glucosamine
Funding
- Japan Society for the Promotion of Science (JSPS)
- Czech Academy of Sciences (CAS) [29400001]
- Japan Society for the Promotion of Science [P21407]
- JST CREST [JPMJCR18H5]
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The development of a multifunctional water-soluble anticancer polymer drug, the SGB complex, has been shown to have tumor-selective accumulation and therapeutic effects on cancer cells by inhibiting lactate secretion. Chemical structure analysis confirmed the rational design of the SGB complex and its stability in the presence of serum.
The development of effective anticancer drugs is essential for chemotherapy that specifically targets cancer tissues. We recently synthesized a multifunctional water-soluble anticancer polymer drug consisting of styrene-maleic acid copolymer (SMA) conjugated with glucosamine and boric acid (BA) (SGB complex). It demonstrated about 10 times higher tumor-selective accumulation compared with accumulation in normal tissues because of the enhanced permeability and retention effect, and it inhibited tumor growth via glycolysis inhibition, mitochondrial damage, and thermal neutron irradiation. Gaining insight into the anticancer effects of this SGB complex requires a determination of its structure. We therefore investigated the chemical structure of the SGB complex by means of nuclear magnetic resonance, infrared (IR) spectroscopy, and liquid chromatography-mass spectrometry. To establish the chemical structure of the SGB complex, we synthesized a simple model compound-maleic acid-glucosamine (MAG) conjugate -by using a maleic anhydride (MA) monomer unit instead of the SMA polymer. We obtained two MAG-BA complexes (MAGB) with molecular weights of 325 and 343 after the MAG reaction with BA. We confirmed, by using IR spectroscopy, that MAGB formed a stable complex via an amide bond between MA and glucosamine and that BA bound to glucosamine via a diol bond. As a result of this chemical design, identified via analysis of MAGB, the SGB complex can release BA and demonstrate toxicity to cancer cells through inhibition of lactate secretion in mild hypoxia that mimics the tumor microenvironment. For clinical application of the SGB complex, we confirmed that this complex is stable in the presence of serum. These findings confirm that our design of the SGB complex has various advantages in targeting solid cancers and exerting therapeutic effects when combined with neutron irradiation.
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