Electroporation enhances tumor control induced by GB-10-BNCT in the hamster cheek pouch oral cancer model

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

Conferencia; 17th International Congress on Neutron Capture Therapy.; 2016

Introduction:A critical aspect of the therapeutic efficacy of BNCTis the biodistribution of 10B in tumor and in the dose limiting normaland precancerous tissues in the target volume. Given that electroporation (EP)can act as a non-specific system to administer anti-tumoral agents, the aim ofthe present study was to evaluate if EP could improve the targeting of 10Bin BNCT mediated by the boron compound GB-10, thus increasing tumor response in vivo in the hamster cheek pouch oralcancer model (HCPOCM). In addition, we evaluated the effect of EPpost-administration of GB-10 on the mean gross boron concentration of 10Bin tumor, precancerous tissue and normal tissue in an attempt to understand themechanisms involved. Materials and methods: Tumor bearing hamster cheekpouches (cancerized with DMBA) weretreated with: 1) GB-10-BNCT without EP(n=33 tumors) and 2) GB-10-BNCT+EP (10 min. post-administration of GB-10) (n=46tumors). Irradiations were carried out 3 hours post-administration of GB-10 inthe thermal facility of the RA-3 Reactor in the Centro Atómico Ezeiza with aneutron fluence of 1.9 x 1012 n/cm2. Tumor response and degree of mucositis in precancerous tissuesurrounding tumors were evaluated 7, 14, 21 and 28 days post-irradiation. Fisher´s exact test was used to assess thestatistical significance of the difference in tumor response between protocols(statistical significance was set at p<0.05). In additional groups we performed biodistributionstudies of 10B with 1) GB-10 without EP (n=20 tumors) and 2) GB-10+EP (n=13 tumors).Tissue samples were taken 3 hs post-administration of GB-10 and processed tomeasure [10B] byICP-MS. Statistical analysis of the biodistribution data was performed using unpaired t test (p<0.05). Experimentalstudies in animals were conducted in accordance with the GCULA (NIH, 1996). Results:We observed astatistically significant increase (p< 0.0001) incomplete remission of tumors in protocol GB-10-BNCT+EP (46%) vs protocol GB-10-BNCT without EP (6%). Likewise, overalltumor control (complete remission + partial remission) increased significantly(p< 0.0001) in protocol GB-10-BNCT+EP (92%) vs protocol GB-10-BNCTwithout EP (48%). For both protocols toxicity (mucositis) in precanceroustissue was reversible and slight/moderate. Biodistribution studies showed thatmean gross 10B concentration in tumor in the case of GB-10+EP (18.5±6.5 ppm 10B) was significantly higher (p<0.01) thanin the case of GB-10 without EP (9.2±2.6ppm 10B). Similarly, Tumor/Normal Tissue and Tumor/Blood [10B]ratios were significantly (p< 0.01) higher for GB-10+EP versus GB-10 (2.3±0.8vs 0.7±0.2and 1.3±0.4vs 0.5±0.2, respectively).Conclusion: Electroporationincreases the therapeutic efficacy of GB-10-BNCT in vivo in the HCPOCM without inducing severe mucositis in thedose-limiting precancerous tissue. Biodistribution studies suggest thatEP-induced increase in mean gross boron concentration in tumor and in Tumor/NormalTissue and Tumor/Blood ratios would contribute to GB-10-BNCT-induced tumorresponse. Ongoing neutron autoradiography studies seek to determine if enhancedtherapeutic efficacy would be partially due to EP induced changes in 10Bmicrodistribution in tissue as we previously described in aberrant tumor bloodvessel normalization studies in the same model.