Novel Hyaluronan Formulation Enhances the Efficacy of Boron Neutron Capture Therapy for Murine Mesothelioma

MASAO SASAI; HIROYUKI NAKAMURA; NAGAKO SOUGAWA; YOSHINORI SAKURAI; MINORU SUZUKI; CHUN MAN LEE

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Figure 1.
Competitive inhibition of various compounds of the binding of fluorescein-labeled hyaluronan (HA) to malignant pleural mesothelioma cells. From left to right, the percentage inhibition of a cluster of differentiation 44-neutralizig antibody (CD44 NA), HA 132 kDa (2.0 mg/ml), sodium borocaptate (BSH), BND-S lacking HA [HA(−)-BND-S], HA-BND-S (2 mg/ml HA), and HA-BND-S (0.2 mg/ml HA). The binding was inhibited 20% more with HA-BND-S than with HA(−)-BND-S. The HA binding was inhibited by HA-BND-S in a concentration-dependent manner. Data are mean values±SEM.
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Figure 2.
Cytotoxicity of boron neutron capture therapy (BNCT) with each boron compound for malignant pleural mesothelioma (MPM) cells. The percentage of dead cells after BNCT(% T/C) is shown for MPM cells treated as follows: sodium borocaptate (BSH) 1-h incubation, not washed; BSH 1-h incubation, washed; hyaluronan containing BSH formulation (HA-BND-S) 24-h incubation, washed; and no-boron control. HA-BND-S led to the strongest cytotoxicity. Neutron irradiation was performed to a total fluence of 1.8×10¹² neutrons/cm² at Kyoto University Research Reactor. Data are mean values±SEM.
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Figure 3.
Survival of malignant pleural mesothelioma (MPM)-bearing mice treated with boron neutron capture therapy (BNCT). All mice were observed for 28 days after tumor inoculation. Survival curves are shown for phosphate buffered saline-treated control, irradiation (IRR) alone, sodium borocaptate (BSH) (10,000 ppm), hyaluronan containing BSH formulation (HA-BND-S) (2,000 ppm) and HA-BND-S (10,000 ppm). The mean survival time was 15.1±1.7 days, 15.3±1.3 days, 19.8±2.5 days, 21.2±7.0 days, and 28 days, respectively. HA-BND-S (10,000 ppm) versus control group was significantly different at p<0.05. Data are mean values±SEM.
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Figure 4.
Macroscopic views of the thorax of malignant pleural mesothelioma (MPM)-bearing mice with and without boron neutron capture therapy (BNCT) treatment with hyaluronan containing sodium borocaptate (BSH) formulation (HA-BND-S). In the untreated control group (left panel), pleural mesothelioma invaded the mediastinum, the heart, and the uninjected side of the pleural cavity. The black and white arrows indicate massive pleural mesotheliomas. In the high-dose HA-BND-S BNCT-treated group (right panel), no mesotheliomas were detected in the pleural cavity 28 days after tumor transplantation. In the BNCT-treated BSH group and low-dose HA-BND-S group, 28 days after tumor transplantation tumors were detected in the thorax of all mice (not shown).