Response to ALA-PDT in 3D ovarian cancer and in vivo models of peritoneal dissemination.

CÉSPEDES, M; ORLANDO G; CALVO, G; TARUSELLI, A; GOLA G; RAMIREZ J; HASAN, T; SAENZ D; DI VENOSA, G; URTREGER, A; CASAS, A

Barcelona

Congreso; 17th International Congress on Photobiology & 18th Congress of the European Society for Photobiology; 2019

European Society for Photobiology and International Union of Photobiology

RESPONSE TO ALA-PDT IN 3D OVARIAN CANCER AND IN VIVO MODELS OF PERITONEAL DISSEMINATIONAuthors: Mariela Céspedes1, Gabriel Orlando1, Gustavo Calvo1, Agustina Taruselli2, Gabriel Gola3, Javier Ramírez3,Tayyaba Hasan4, Daniel Sáenz1, Gabriela Di Venosa1, Alejandro Urtreger2, Adriana Casas1Presenting Author: Adriana Casas1) Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) CONICET-Htal de Clínicas José de San Martín - Universityof Buenos Aires, Argentina 2) Area Investigación Instituto de Oncología ?A. H. Roffo?, University of Buenos Aires, Argentina3) UMYMFOR (CONICET - Facultad de Ciencias Exactas y Naturales). University of Buenos aires, Argentina 4) WellmanCenter, Harvard Medical School, Massachusetts General Hospital Boston, USAALA-PDT is an effective therapy mainly for dermatologic cancer, although its uses have been extended in the lastyears. PDT with benzoporphyrin derivatives has been employed in the treatment of ovarian cancer [1]. In addition,Photodiagnosis with ALA for intraoperative detection of peritoneal metastases of ovarian cancer has been proposed[2].When ALA is administered systemically, tumor selective production of Protoporphyrin IX is observed. One approachto broaden clinical ALA-PDT uses is the design of derivatives of ALA with the aim of improving bioavailability andselectivity.Three-dimensional culture models (spheroids) have proven to be a realistic scenario to test response to ALA-PDT,where physical variables reduce tumor response to treatment. On the other hand, 3D tumorspheres are enriched instem-like cells, which are related to metastasis and resistance. Since ovarian cancer frequently presents peritonealdissemination, the use of 3D models mimicking peritoneal metastasis, constitutes an interesting approach.The aim of this study was to gain insight in the response of ovarian cancer 3D models to PDT employing ALA or newderivatives, and to analyze its selectivity for tumor tissue in vivo.Materials and methods: SKOV-3 and IGROV-1 human ovarian cancer cell lines were employed. SKOV-3 spheroidswere used as metastatic nodules model and IGROV-1 tumorspheres, as tumor stem cells model. Athymic mice N:NIH(S)-Fox1 nu were injected i.p. with SKOV-3 cells to induce peritoneal dissemination. White lamps and a 630 nmlaser (Lumiia, Argentina) were employed as light sources. ALA and ALA derivatives synthesised by multicomponentreactions [3] were employed.IGROV-1 tumorspheres overexpressed NANOG, OCT4 and SOX2 pluripotent genes [4] and exhibited 2-fold increaseof resistance to ALA-PDT as compared to 2D cultures, thus suggesting a role of ovarian stem cells in the resistanceto PDT.The role of the 3D structure on the resistance was studied in spheroid SKOV-3 cultures. They proved to be resistant toALA-PDT employing low power non-coherent light sources. However, they were responsive to the treatment employinga coherent red light source. In addition to increasing light dose, the other approach to revert resistance to PDT wasthe use of more lypophilic ALA compounds, of which the so called 89-ALA was the one which better penetrate thespheroid structure.When 89-ALA was injected into mice with i.p. dissemination of SKOV-3 cells, fluorescence was much more confinedto the tumor spots in comparison to ALA.The use of ALA derivatives improves ALA-PDT performance in ovarian cancer. Our results reinforce the importance ofthe studies of pro-photosensitizer penetration and PDT response in 3D models as a previous step to animal studies.References[1] del Carmen et al. J Natl Cancer Inst. 97:1516-24(2005).[2] Hillemanns et al. Lasers Surg Med. 49:169-176(2017).[3] Gola et al. RSC Adv. 6, 89492-98(2016).[4] Li et al. Chin J Cancer. 32:483-7(2013).