BNCT is a cell-selective radiation technique that depends on α-rays emitted from boron-10 (10B) atoms when neutrons hit the atoms [103,104]. When boron delivery agents enter tumor tissues and enrich tumor cells, the thermal neutrons trigger fission of boron atoms, which leads to release of 10B atoms and then release of α particles (4He) and recoil lithium particles (7Li) [104,105]. The released α particles are toxic for cells and can result in cell destruction, bouncing out up to 10 µm, which is almost the size of the cells; for this reason this technique is called cell-selective radiation therapy [106]. The first clinical use of sodium borocaptate (BSH) for BNCT was reported by the Japanese scientist Hiroshi Hatanaka in 1960; boronophenylalanine (BPA) was introduced for clinical use by another Japanese scientist Y. Mishima in 1988–1989 [107]. Clinical trials of BNCT for treatment of glioblastoma multiforme and/or melanoma and, more recently, head and neck tumors and liver metastases, with BPA or BSH as the 10B carrier, have been performed in many countries including Argentina, Europe, Japan, Taiwan, and the United States [96,103]. Thus, BNCT is not a modern concept, although clinical progress with this method has been quite slow, probably because of the lack of tumor-selective drug accumulation and terrible adverse effects [16,103,108]. Conventional borono-drugs, which are commonly used in clinical settings, are low-molecular-weight drugs that are distributed indiscriminately throughout the body, particularly in the skin, when given intravenously [16,68]. As a result, when neutrons are used to irradiate the whole body these low-molecular-weight drugs produce adverse effects such as skin damage and mucositis, among others [96,103]. Macromolecular drugs, however, have the advantage of tumor-selective accumulation because of the EPR effect [6]. Figure 6A illustrates the problems with conventional BNCT and strategies for successful BNCT. Our group had a breakthrough in our studies to address the clinical drawbacks related to BNCT: we developed a novel multifunctional polymer conjugate drug—the SGB-complex [68]. This SGB-complex formed spontaneous micelle, manifested a single peak by gel permeation chromatography, and had a diameter of 10–15 nm by transmission electron microscopy and dynamic light scattering [68]. We found that intravenously injected SGB-complex bound with albumin during circulation and had a plasma half-life of 8 h in mice; it accumulated in tumor tissues about 10 times more than in normal tissues [68,109]. We developed the SGB-complex primarily for BNCT, but surprisingly we found that it can inhibit cancer cell growth effectively under mildly hypoxic conditions (pO2, 6–8%), which resemble tumor microenvironments [48,68]. In addition, the SGB-complex significantly suppressed tumor growth in various mouse tumor models (e.g., mouse sarcoma S180 and colon carcinoma C26) even without neutron irradiation [68]. We hypothesized that, as a possible mechanism, the SGB-complex inhibited glycolysis in cancer cells and affected mitochondrial functions [68,108]. We noted that the SGB-complex released free BA in tumor tissue (pH 5.5–6.5); liberated BA may compete with phosphate in the phosphorylation of glucose to glucose 1-phosphate and may thus inhibit glycolysis in cancer cells [29,68,110]. According to the Warburg effect, under hypoxic conditions cancer cells depend predominantly on energy production via glycolysis instead of the tricarboxylic acid cycle [111]. Thus, suppression of glycolysis in cancer cells will lead to cell death. To confirm our hypothesis, we measured glucose uptake, lactic acid production in hypoxia-adapted HeLa cells, and tumor tissue pH in vivo and found that the SGB-complex significantly inhibited glucose uptake and lactic acid secretion in HeLa cells [68]. Moreover, tumor pH after intravenous injection of the SGB-complex shifted from slightly acidic to neutral, which indicates inhibition of lactic acid production [68]. All the data presented above provide consistent evidence that the SGB-complex inhibited glycolysis in cancer cells. Our data suggest that the SGB-complex is more sensitive in hypoxic conditions than normoxic condition, which means that this nanomedicine is ideal for advanced late-stage cancers, which have low pO2, in clinical settings.We also confirmed excellent anticancer effects of the SGB-complex after neutron irradiation in vitro and in vivo. We used human oral squamous carcinoma cells in vitro and we found, surprisingly, that the cells treated with the SGB-complex at 8 μg/mL (BA equivalent) demonstrated about 16-fold greater cytotoxicity after 10 Gy neutron irradiation when compared with the group treated with the same dose of neutron irradiation alone (no drug) [68]. We also investigated the antitumor effect of the SGB-complex after neutron bombardment in C3H mice bearing human oral squamous cells carcinoma (SCC VII), and we found that the SGB-complex at 10 mg/kg significantly suppressed tumor growth at days 14 and 21 after a single neutron irradiation dose compared with irradiation alone (6 × 108 n/cm2/s for 30 min) or compared with the SGB-complex alone treatment group [68,108]. One hallmark result we observed that neutron irradiation of SGB-complex-treated mice did not affect the skin of the mice, nor were other common toxic effects of BNCT treatment (e.g., mucositis, systemic toxicity) [16,68,108]. These common phenomena were seen in treatment with BPA + neutron irradiation or other conventional borono-drugs [16,29,68,103,108]. These results indicate the promising future of the SGB-complex for BNCT in clinical settings. Figure 6B illustrates the multiple modes of action of the SGB-complex.