Electroporation to optimize boron targeting for Boron Neutron Capture Therapy (BNCT): a study of boron biodistribution with boric acid in the hamster cheek pouch oral cancer model.

MARCELA A. GARABALINO; OLAIZ NAHUEL; IARA S. SANTA CRUZ; PAULA S. RAMOS; AGUSTINA M. PORTU; GISELA SAINT MARTIN; MARIA E. ITOIZ; EMILIANO C.C. POZZI; SILVIA THORP; PAULA CUROTTO; ANDREA MONTI HUGHES; VERONICA A. TRIVILLIN; GUILLERMO MARSHALL; AMANDA E. SCHWINT

Taipei

Congreso; 18th international congress on neutron capture therapy; 2018

National Tsing Hua University

The biodistribution of boron carriers in tumor in terms of absolute and relative 10B concentration, retention in tumor, targeting homogeneity and microdistribution conditions the therapeutic efficacy of BNCT. We previously demonstrated the potential of Electroporation (EP) to induce an increase in tumor boron uptake employing sodium decahydrodecaborate (GB-10) ? -a chemically non-selective boron compound- in the hamster cheek pouch oral cancer model. It is of great relevance to optimize the biodistribution of boron compounds authorized for their use in humans, thus bridging the gap between research and clinical application. Within this context, the aim of this study was to evaluate in the hamster cheek pouch oral cancer model if EP can be used as a non-specific drug delivery system to optimize the delivery of the boron compound Boric Acid (BA), improving the therapeutic efficacy of BNCT. Materials and methods: Exophytic tumors (Squamous Cell Carcinoma) were induced in the pouch of 10 Syrian hamsters by topical application of the carcinogen dimethyl-benzanthracene (DMBA) twice a week for 3 months. We performed electroporation experiments in tumors (1000 v/cm, 8 pulses of 100μs) as part of 2 protocols employing BA (50 mg 10B/kg iv) varying the time between EP and the administration of the boron compound: (1) BA (t = 0 min) - Early EP (t =10 min) - sacrifice (t =3 hs); (2) BA (t =0 min) ? Late EP (t =2.5 hs) ? sacrifice (t =3 hs). As a control, the previous biodistribution study with BA (50 mg10B/kg iv, 3-4 hs) without EP performed in the same experimental model was used. Samples of blood, tumor, precancerous tissue and normal pouch tissue, liver, kidney and spleen were processed by sulfuric-nitric acid 1:1 digestion at 100ºC for 1h for ICP-OES boron measurements. In addition, samples were taken and sectioned using a novel procedure to include the Ttumor, the Iinsertion zone and the surrounding Pprecancerous tissue in a single section (TIP section), to study boron microdistribution using the neutron autoradiography technique. Results: We observed a statistically significant increase (p< 0.0001) in boron uptake in tumors corresponding to the protocol BA + Early EP (47 ppm) versus control BA without EP (36 ppm), whereas for the BA + Late EP protocol boron tumor uptake (35 ppm) was similar to the control BA without EP (36 ppm). Both EP protocols, Early and Late, caused a statistically significant increase (p< 0.0001) in blood boron concentration compared to the control BA without EP, from 15 ppm (control) to 52 ppm (BA + Early EP) and 31 ppm (BA + Late EP). No changes in the boron concentration values were observed in precancerous tissue and normal pouch tissue in Early and Late EP vs only BA only protocols, . with Measured values were within the range of 30-40 ppm and 28 -38 ppm for precancerous and normal tissue, respectively. The boron concentration ratios Tumor/Precancerous tissue and Tumor/Normal tissue of the EP protocols were similar to the control without EP, in the range of 1.1 to 1.3. Conversely, the Tumor/Blood boron concentration ratio showed a decrease in tumor selectivity for both the EP protocols versus control without EP. Conclusion: Biodistribution studies showed that Early EP induced an increase in mean gross boron concentration in tumor and would contribute to BA-BNCT-induced tumor response. Ongoing neutron autoradiography studies seek to determine if potential enhanced therapeutic efficacy would be partially due to EP induced changes in 10B microdistribution. Radiobiological studies in experimental oral cancer are necessary to assess the potential therapeutic efficacy and radiotoxicity of BA+EP/BNCT and the role of high boron concentration values in blood.