Abstract
Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies—determined by electron microscopy—and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.
Highlights
Current advanced cancer therapy includes surgery, chemotherapy, and radiation therapy; glioblastoma multiforme (GBM) re mains the most treatment-resistant malignant primary brain tumor, with a median survival of approximately 1.5 years [1]
Numerous potential boron delivery systems based on macromolec ular aggregates have been reported in the Boron neutron capture therapy (BNCT) research field, partic ularly liposomes and water-in-oil-in-water (W/O/W) emulsions [20,21,22,23]
Small unilamellar liposomes composed of a pure synthetic phospholipid and cholesterol encapsulating water-soluble ionic boron compounds (B10H10(2-), B12H11SH2, B20H17OH4, B20H19(3-), B20H18(2-)); distearoylphosphatidylcholine (DSPC) liposomes and DSPC–PEG liposomes with nido-carborane lipid; and small, unilamellar BSH-encapsulating, transferrin (TF)-conjugated polyethyleneglycol li posomes (TF-PEG liposomes) as colon cancer and brain tumor targeting system have been reported [24,25,26]
Summary
Current advanced cancer therapy includes surgery, chemotherapy, and radiation therapy; glioblastoma multiforme (GBM) re mains the most treatment-resistant malignant primary brain tumor, with a median survival of approximately 1.5 years [1]. Boron neutron capture therapy (BNCT) is one of the most promising GBM treatments. BNCT is based on the neutron capture and fission reactions that 10B atoms undergo with low-energy neutrons on the irradiation of brain tumor tissues with thermal or epithermal neutron beams [4]. One of the greatest challenges in BNCT has been developing new boron drugs for application to several malignant tumors—in addition to BPA [11]. BPA (4‐borono-L-phenyl alanine) is the leading BNCT boron drug for treating malignant mela noma and is based on an amino acid analogue fused boron. New boron drugs with different intracellular uptake pathways for combined use with BPA are essential for developing BNCT efficacy [16]
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