Conditions of tailored Electroporation (EP) to improve boron targeting for Boron Neutron Capture Therapy (BNCT) in an oral cancer model

GARABALINO MA; CUROTTO, P.; MARSHALL, G; OLAIZ, NAHUEL; THORP, S.; TRIVILLIN, V.; POZZI, E.C.; MONTI HUGHES, A.; SCHWINT, A.E.

Norfolk

Congreso; 2nd World Congress on Electroporation and Pulsed Electric Fields in Biology, Medicine, and Food & Environmental Technologies; 2017

Introduction: BNCT is based on the selective incorporation of 10B carriers in tumor followed by neutron irradiation. 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. These phenomena are directly related with different permeabilization mechanisms which are presently under discussion. It hasbeen proven that pulsed electric fields (PEF), greatly enhance cell membrane permeabilization. Aim: Optimize the parameters of electroporation (EP) in the Hamster Cheek Pouch Oral Cancer Model (HCPOCM) to improve the delivery of the boron compounds p-Borophenylalanine (BPA) and sodium decahydrodecaborate (GB-10) and thus enhance the therapeutic response to BNCT. Materials and methods: Exophytic tumors (Squamous Cell Carcinoma) were induced in the pouch of hamsters by topical application of dimethyl-benzanthracene (DMBA) and classified according to the initial tumor volume (v) as small (v< 10 mm3) or medium and large (v> 10 mm3). We performed electroporation experiments in tumors (1000 V/cm, 8 pulses of 100 μs) with two differentplate electrodes. The first plate electrode, employed for the small tumors, was 3x3 mm in dimension; the voltage maintained between the two parallel metal plates was 200 V for a distance of 2 mm and 300 V for a distance of 3 mm. The second plate electrode, employed for the medium/large tumors, was 10x10 mm in dimension; the voltage maintained between two parallel metal plates was 400 V for a distance of 4 mm and 500 V for a distance of 5 mm. Employing BPA or GB-10, varying the time between EP and the administration of the boron compound, the following tests were performed: 1. BPA (t=0 min) ? EP (t=10 min) -irradiation (t=3 h); 2. BPA (t=0 min) ? EP (t=2:50 h) - irradiation (t=3 h); 3. GB-10 (t=0 min) ? EP (2:50 h) - irradiation (t=3 h); 4. GB-10 (t=0 min) - EP (t=10 min) -irradiation (t=3 h); 5. Control EP only. Neutron irradiations to deliver 1.9 x1012 n.cm-2 were performed at the thermal facility of the RA-3 Nuclear Reactor. The animals were followed during 1 month to assess clinical signs, tumor response and mucositis in dose-limiting precancerous tissue. Results: Based on tumorresponse, we calculated an index of effective EP that optimizes effective tumor response: 0.012-0.055 S/cm. We found a maximum EP efficiency for each type of electrode used and for each tumor volume. Conclusion: We established adequate conditions of EP in the HCPOCM and provided evidence that EP could be a tool to improve the therapeutic efficacy of BNCT in vivo.