Therapeutic Efficacy and Radiobiological Effects of Boric-Acid-Mediated BNCT in an Osteosarcoma-Bearing SD Rat Model.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignancy of the bone and is notoriously resistant to radiation therapy. High-dose cytotoxic chemotherapy and surgical resection have improved the survival rate and prognosis of patients with OS. Nonetheless, treatment challenges remain when the tumor cannot be removed by surgery. Boron neutron capture therapy (BNCT) provides high linear energy transfer (LET) radiation, and its internal targeted characteristics make BNCT a novel therapy for removing OS and reducing radiation damage to adjacent healthy tissues. METHODS: In this study, a UMR-106-grafted OS rat model was developed, and boric acid (BA) was used as the boron drug for BNCT. The pharmacokinetics of BA, following intravenous injection, were evaluated to determine the optimal time window for neutron irradiation. OS-bearing rats were irradiated by an epithermal neutron beam at Tsing Hua Open-Pool Reactor (THOR). The therapeutic efficacy of and tissue response after BNCT were evaluated by radiographic and histopathological observations. RESULTS: OS-bearing rats were irradiated by neutrons in the first hour following the intravenous injection of BA. The prescription-absorbed doses in the tumor regions were 5.8 and 11.0 Gy. BNCT reduced the body weight of the tumor-bearing rats, but they recovered after a few days. The BA-mediated BNCT effectively controlled the orthotopic OS tumor, reduced osteolysis, and induced bone healing. Autoradiography and histological analysis confirmed that the BA retention region is consistent with the calcification region in OS tissue. CONCLUSION: BA is specifically retained in OS, and the BA-mediated BNCT can significantly reduce the tumor burden and osteolysis in OS-bearing rats.

Evaluation of the Key Advantages between Two Modalities of Boronophenylalanine Administration for Clinical Boron Neutron Capture Therapy Using an Animal Model.

In clinical boron neutron capture therapy (BNCT), boronophenylalanine (BPA) administrations through one-step infusion (OSI) and two-step infusion (TSI) are the most widely used. This study compared the advantages of OSI and TSI using a human oral squamous cell carcinoma-bearing animal model. OSI was administered at a high-dose rate of 20 mg/kg/min for 20 min (total dose: 400 mg/kg) as the first step infusion. TSI was a prolonged infusion at a low-dose rate of 1.67 mg/kg/min for 15, 30, 45, and 60 min (total dose: 25, 50, 75, and 100 mg/kg) following the first step infusion. The sigmoid Emax model was used to evaluate the boron accumulation effect in the tumor. The advantages of TSI were observed to be greater than those of OSI. The observed advantages of TSI were as follows: a stable level of boron concentration in blood; tumor to blood boron ratio (T/B); tumor to muscle boron ratio (T/M); and skin to blood boron ratio (S/B). The boron accumulation effect in tumors increased to 68.98%. Thus, effective boron concentration in these tumor cells was achieved to enhance the lethal damage in BNCT treatment. Boron concentration in the blood was equal to that in the skin. Therefore, the equivalent dose was accurately estimated for the skin.

Analysis of DNA Damage Responses After Boric Acid-mediated Boron Neutron Capture Therapy in Hepatocellular Carcinoma.

BACKGROUND: Boron neutron capture therapy (BNCT) selectively kills tumor cells while sparing adjacent normal cells. Boric acid (BA)-mediated BNCT showed therapeutic efficacy in treating hepatocellular carcinoma (HCC) in vivo. However, DNA damage and corresponding responses induced by BA-mediated BNCT remained unclear. This study aimed to investigate whether BA-mediated BNCT induced DNA double-strand breaks (DSBs) and to explore DNA damage responses in vitro. MATERIALS AND METHODS: Huh7 Human HCC cells were treated with BA and irradiated with neutrons during BA-BNCT. Cell survival and DNA DSBs were examined by clonogenic assay and expression of phosphorylated H2A histone family member X (γH2AX), respectively. The DNA damage response was explored by determining the expression levels of DNA repair- and apoptosis-associated proteins and conducting a cell-cycle analysis. RESULTS: DNA DSBs induced by BA-mediated BNCT were primarily repaired through the homologous recombination pathway. BA-mediated BNCT induced G2/M arrest and apoptosis in HCC. CONCLUSION: Our findings may enable the identification of radiosensitizers or adjuvant drugs for potentiating the therapeutic effectiveness of BA-mediated BNCT for HCC.

Clinical trials for treating recurrent head and neck cancer with boron neutron capture therapy using the Tsing-Hua Open Pool Reactor.

Head and neck (HN) cancer is an endemic disease in Taiwan, China. Locally recurrent HN cancer after full-dose irradiation poses a therapeutic challenge, and boron neutron capture therapy (BNCT) may be a solution that could provide durable local control with tolerable toxicity. The Tsing-Hua Open Pool Reactor (THOR) at National Tsing-Hua University in Hsin-Chu, provides a high-quality epithermal neutron source for basic and clinical BNCT research. Our first clinical trial, entitled "A phase I/II trial of boron neutron capture therapy for recurrent head and neck cancer at THOR", was carried out between 2010 and 2013. A total of 17 patients with 23 recurrent HN tumors who had received high-dose photon irradiation were enrolled in the study. The fructose complex of L-boronophenylalanine was used as a boron carrier, and a two-fraction BNCT treatment regimen at 28-day intervals was used for each patient. Toxicity was acceptable, and although the response rate was high (12/17), re-recurrence within or near the radiation site was common. To obtain better local control, another clinical trial entitled "A phase I/II trial of boron neutron capture therapy combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for locally recurrent HN cancer" was initiated in 2014. The first administration of BNCT was performed according to our previous protocol, and IG-IMRT was initiated 28 days after BNCT. As of May 2017, seven patients have been treated with this combination. The treatment-related toxicity was similar to that previously observed with two BNCT applications. Three patients had a complete response, but locoregional recurrence was the major cause of failure despite initially good responses. Future clinical trials combining BNCT with other local or systemic treatments will be carried out for recurrent HN cancer patients at THOR.

Application of gamma irradiation in ginseng for both photodegradation of pesticide pentachloronitrobenzene and microbial decontamination.

This study investigates the feasibility of using gamma irradiation for photodegradation of a common residual fungicide, pentachloronitrobenzene (PCNB), in ginseng, and for microbial decontamination. American ginseng, Panax quinquefolius, was subjected to gamma irradiation. PCNB residues were analyzed by gas chromatography with electron capture detection and mass spectrometry. Eighty percent of PCNB (100 ppm) in a methanol aqueous solution was degraded by 5 kGy irradiation, and the primary degradation product was pentachloroaniline. Furthermore, contaminated PCNB (3.7 ppm) in ginseng were reduced to 0.2 ppm after 20 kGy irradiation. The IC(50) for treatment of Sclerotium rolfsii with 20 kGy irradiated PCNB was about 2.7 times higher than that for treatment with unirradiated PCNB. The survival rate of mouse fibroblast L929 cells treated with 20 kGy irradiated PCNB was about 12.9% higher than that of L929 cells treated with unirradiated PCNB. Additionally, after 20 kGy irradiation, less than 5% reduction of contents of ginsenoside Rb1 and Re were observed, and amounts of ginsenosides Rc, Rd, and Rg1 were not reduced significantly. The minimal gamma dose for microbial decontamination was 10 kGy. Therefore, gamma irradiation can be used for both PCNB photodegradation and microbial decontamination of ginseng without obvious loses of ginsenoside contents.

Synthesis and in vitro evaluation of the phenylboric acid derivative entrapped lipiodol in boron neutron capture therapy for hepatoma.

BACKGROUND: Hepatoma, a common cancer in Taiwan, responds poorly to conventional therapies. Boron neutron capture therapy (BNCT) may provide a promising approach for hepatoma therapy. In this study, a pharmaceutical composition, phenylboric acid derivative entrapped lipiodol (PBAD-lipiodol), was synthesized and characterized. In vitro study was used for evaluation of PBAD-lipiodol for the BNCT of hepatoma. MATERIALS AND METHODS: alpha Track observation was used to identify the boron compound in the TLC plate and to evidence the uniform distribution of boron in the PBAD-lipiodol. Inductively coupled plasma-atomic emission spectroscopy and neutron activation analysis were used to determine the concentrations of boron and lipiodol, respectively. Human hepatoma HepG2 cells were used for in vitro experiments. A Nomarski optical microscope was used to investigate the uptake of PBAD-lipiodol globules in individual hepatoma cells. RESULTS: PBAD-lipiodol was stable in human serum. The boron source, PBAD, was uniformly distributed in PBAD-lipiodol. Many of the PBAD-lipiodol globules were internalized and retained in HepG2 cells, and the boron concentration of HepG2 cells reached 269 ppm after 72 hours of PBAD-lipiodol treatment. CONCLUSION: In vitro studies revealed that PBAD-lipiodol could deliver a therapeutically effective amount of PBAD as a boron source for the BNCT of hepatoma. PBAD-lipiodol is a potential new boron drug for the BNCT of hepatoma.

Boron-lipiodol: a potential new drug for the treatment of liver tumors.

BACKGROUND: Boron neutron capture therapy (BNCT) is a form of radiation therapy and has been proposed for the treatment of some malignancies with encouraging results. However, none of them has ever been applied to liver malignancy. The purpose of this study was to evaluate the potential of boron-lipiodol (B-lipiodol) for the treatment of VX2 liver tumor via BNCT. MATERIALS AND METHODS: Twelve New Zealand rabbits were randomly separated into two groups: lipiodol and boron-lipiodol groups. The rabbits were anesthetized, a midline incision was made and the left lobe of the liver was injected with 0.1 ml of VX2 tumor cells. After the tumor reached 2-3 cm in diameter, the rabbits were anesthetized and 0.5 ml of boron-lipiodol was injected into the hepatic artery via an angiocatheter. Liver function tests and renal function tests were performed before, at 12 hours, 24 hours, 48 hours and 7 days after injection of drugs in both groups. The concentration of boron in various tissues was determined on the 7th day after injection. RESULTS: Liver function was abnormal at 12 hours after injection, and then gradually returned to normal at 7 days, indicative of acute temporary hepatic damage. As for the renal function, no significant change was noted in either group. The boron level was 49.7 ppm in tumor and 6.31 ppm in the healthy liver 7 days after injection of B-lipiodol. The ratio of boron concentrations between the tumor and the normal liver tissue was 7.87. As for blood and other organs including spleen, heart and kidney, the concentration of boron was low. In the lipiodol group, the boron concentrations in tumor and various organs were low. CONCLUSION: The high concentration of boron after intra-arterial injection of B-lipiodol can be used for neutron capture therapy. B-lipiodol has potential for the treatment of liver malignancy.