ELECTROPORACIÓN PARA OPTIMIZAR EL ?TARGETING? DE BORO EN LA TERAPIA POR CAPTURA NEUTRÓNICA EN BORO (BNCT): DESARROLLO E IMPLEMENTACIÓN DE LA TÉCNICA EN UN MODELO DE CÁNCER BUCAL EN HAMSTER

N OLAIZ; GARABALINO M A; POZZI ECC; THORP S; CUROTTO P; ITOIZ M E; AROMANDO R; PORTU A; SAINT MARTIN G; MONTI HUGHES A; TRIVILLIN V A; MARSHALL G; SCHWINT A E

CABA

Congreso; Reunión Anual AATN 2014; 2014

Comisión Nacional de Energía Atómica

p { margin-bottom: 0in; direction: ltr; color: rgb(0, 0, 0); line-height: 200%; text-align: justify; widows: 2; orphans: 2; }p.western { font-family: "Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "Times New Roman",serif; font-size: 12pt; }p.ctl { font-family: "Times New Roman",serif; font-size: 12pt; font-weight: bold; }a:link { color: rgb(0, 0, 255); } BNCT is based on the capture reaction between 10B localized preferentially in tumor, and thermal neutrons, generating short range lethal particles that damage tumor, preserving healthy tissue. 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. 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 optimize the conditions of electroporation (EP) in the hamster cheek pouch oral cancer model and evaluate if EP can be used as a non-specific drug delivery system to optimize the delivery of the boron compounds p-Boro-phenyl-alanine (BPA) and sodium decahydro-decaborate (GB-10), improving the therapeutic efficacy of BNCT. Materials and methods: Exophytic tumors (Squamous Cell Carcinoma) were induced in the pouch of 30 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 9 protocols employing BPA (15.5 mg 10B/kg iv) or GB-10 (50 mg 10B/kg iv), varying the time between EP and the administration of the boron compound: (1) BPA (t=0 min) - EP (t=10 min) - irradiation (t=20 min); (2) BPA (t=0 min) - EP (t=10 min) ? EP (2:50 hs) - irradiation (t=3 hs); (3) BPA (t=0 min) ? EP (2:50 hs) - irradiation (t=3 hs); (4) BPA (t=0 min) ? EP (t=10 min) - irradiation (t=3 hs); (5) GB-10 (t=0 min) ? EP (2:50 hs) - irradiation (t=3 hs); (6) GB-10 (t=0 min) - EP (t=10 min) - irradiation (t=3 hs); (7) Control EP only; (8) EP (t=0 min) - irradiation (t=2:50 hs); (9) Control beam only; (10) Control BPA-BNCT (Molinari et al., 2012); (11) Control GB-10-BNCT (Trivillin et al., 2004). The neutron irradiations were performed at the thermal facility of the RA-3 Nuclear Reactor, 3 hours post-administration of the boron compound, at a thermal neutron fluence of 1.9 x 1012 n/cm2. We evaluated the clinical signs of the animals, tumor response and mucositis in precancerous tissue surrounding the treated tumors 7, 14, 21 and 28 days post-irradiation. Results: A retrospective analysis of the EP conditions revealed that the experiments were performed at 0.0055-0.055 S/cm. The detailed analysis of the tumor response data and the calculation of an index of effective EP revealed the EP window that optimizes effective tumor response: 0.012-0.055 S/cm. Protocols 1, 2 and 3 exhibited a high incidence of severe mucositis (grade 4 and 5) that precluded the evaluation of tumor response. EP showed a therapeutic benefit in the case of protocol 6 in terms of improved tumor control associated to mild-moderate mucositis in precancerous tissue (≤grade 3). Comparing the data of tumor control corresponding to protocol 6 with those corresponding to protocol 11 (GB-10-BNCT reported in Trivillin et al., 2004), we observed an increase in complete remissions in the case of small tumors (<10mm3), 71% vs 42%, and in the case of medium tumors (10-100 mm3), 43% vs 7%. Conclusion: We established the optimum conditions of EP in vivo in the hamster cheek pouch oral cancer model and provided evidence that EP could be a tool to improve the therapeutic efficacy of BNCT in vivo, employing boron compounds approved for their use in humans.