Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

Abstract

Summary Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 ( 10 B) in the oral mucosa to the biological effectiveness of the 10 B(n,α) 7 Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10 B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10 B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10 B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10 B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10 B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10 B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10 B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10 B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiationinduced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10 B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT.

Deterministic Parsing Model of the Compound Biological Effectiveness (<i>CBE</i>) Factor for Intracellular <sup>10</sup>Boron Distribution in Boron Neutron Capture Therapy

“…It is evident that the CBE factors for BPA, calculated using Equation 7are the almost same values with those obtained in previous animal experiments [10]- [13] and well expressed without distinction of tissues and tumor. Considered overall, the CBE factor is given as a function of boron concentration ratio, N th /N max .…”

“…As for the CBE factor and boron concentration data set of BPA previously obtained in biological test for normal tumor, skin lung, liver [10] [11], heart [12] and oral mucosal tissues [13] [14], we can classify these data into two main groups, tumor and normal tissue and no relationship between N B-max and CBE factor was not found in normal tissue group (Table 1, Figure 1).…”

“…The CBE factor = [(X-ray ED 50 ) − (thermal beam component of ED 50 × RBE]/ 10 B(p, α) 7 Li component of ED 50 . Recently, the CBE factors concerning to tumor, skin lung, liver [10] [11], heart [12] and oral mucosal tissues [13] were reported and prospect of actually using BNCT for the patients has been developing under the right circumstances. However, there is no theoretical unified explanation of the CBE factors for normal tissues and tumor, despite the fact that significance of high precision of the CBE factor evaluation is requested for the patients.…”

Comparison of the pharmacokinetics between L-BPA and L-FBPA using the same administration dose and protocol: a validation study for the theranostic approach using [18F]-L-FBPA positron emission tomography in boron neutron capture therapy

“…First, our measurement methods by ICP-AES could not evaluate the microdistribution of boron atoms in tissue components. GM Morris and colleagues showed the different microdistribution patterns of boron atoms in murine tongue mucosa following the administration of L-BPA or BSH [24]. BNCT is based on the neutron capture reaction resulting in two particles ( 4 He and 7 Li) whose range is limited to the diameter of a single cell (5–9 μm).…”

Determination of the Compound Biological Effectiveness (CBE) Factors Based on the <i>ISHIYAMA-IMAHORI</i> Deterministic Parsing Model with the Dynamic PET Technique

“…The CBE factors concerning to tumor, skin lung, liver [10]- [12] and oral mucosal tissues [13] are reported and prospect of actually using BNCT for the patients has been developing under the right circumstances. However, there is no theoretical unified explanation of the CBE factors for normal tissues and tumor, despite the fact that significance of high precision of the CBE factor evaluation is requested for the patients.…”