EPR-effect driven tumor delivery of multifunctional boron nanomedicine for neutron capture therapy

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We synthesized a water-soluble micellar drug called styrene maleic acid (SMA) copolymer conjugated glucosamine and boric acid (SGB-complex). It showed tumor selective accumulation based on EPR effect and excellent tumoricidal activity in vitro as well as various mouse tumor models. However, the precise chemical structure of SGB-complex and the detailed mode of action of cytotoxicity without neutron irradiation was not understood.During FY2022 period, I focused on the determination of molecular structure of SGB-complex by UV-vis, IR, NMR spectroscopy and liquid chromatography mass spectroscopy. We confirmed that the SMA-polymer bound to the glucosamine via amide bond and the boric acid was attached to glucosamine by di-ol bond (This works we reported at ACS Applied Biomaterials journal). Next, we try to find out the possible mechanism of in vitro cytotoxicity of SGB-complex. We hypothesized that SGB-complex might induce ER or mitochondrial stress in mild-hypoxia state. To support our hypothesis, we measure the ER stress marker phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2), C/-EBP homologous protein (CHOP), and Caspase 3 and 7 expressions after treating of our drug. Interestingly, we found the SGB-complex significantly increased various ER stress markers that confirmed our drug induces ER stress in hypoxia adapted cancer cells. We also measured the mitochondrial membrane potential after treatment of our drug, and data showed very less changes occurred compare to non-treated group. TEM image will be able to confirm whether any mitochondrial damage occur or not.