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A folate-targeted photosensitizer to improve specificity of intraperitoneal photodynamic therapy of ovarian peritoneal metastasis
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Abstracts / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375
edge-response profile of the system from which we extract optical property contrast and resolution. We demonstrate that our visible-light SFDI system is capable of recovering s and a within ∼10–15% accuracy. Finally, we performed in vivo measurements to find the optical property maps over a ∼25 cm2 field-of-view for potential application in intraoperative photodynamic therapy (PDT) dosimetry. http://dx.doi.org/10.1016/j.pdpdt.2015.07.032 Use of a novel 3D-tumoroid experimental model to assess cytotoxicity mediated by Photochemical Internalisation of saporin in 4T1 breast cancer cells Derick Adigbli, Alejandra Martinez De Pinillos Bayona, Josephine Woodhams, Alexander MacRobert, Marilena Loizidou Division of Surgery & Interventional Sciences, UCL, UK Introduction: The increasing drive to reduce the use of animals for in vivo experimentation has led to the development of novel tumour models. The 3D-tumoroid model is one such solution that may have an important role in enabling more representative experimentation to investigate the efficacy of Photochemical Internalisation (PCI) as tool to enhance selective cytotoxicity in cancer therapeutics. The model is based on a new plastic compression technique for preparing collagen scaffolds. Aim: To determine if disulfonated tetraphenylporphine (TPPS2a) based PCI of saporin (SAP) could enhance cytotoxicity in a 3D tumoroid model. Methodology: 4T1 breast cancer cells were imbedded in a collagen matrix and placed under plastic compression to form 3D tumoroid scaffolds. PCI was performed following 8 days of incubation to enable tumoroid development. Cytotoxicity was assessed 7 days later using AlamarBlue® . Results: PCI resulted in 51% and 61% (p < 0.01) increased cytotoxicity compared to (SAP) or PDT (TPPS2a) alone. Conclusion: The results indicate that the 3D tumoroid model can be used as a tool to assess PCI mediated cytotoxicity in cancer therapeutics. The ability to assess treatment response in 3D cancer models will play an increasing role in initiating translation of basic scientific concepts into therapeutic solutions. http://dx.doi.org/10.1016/j.pdpdt.2015.07.033 Macrophage mediated PCI enhanced gene-directed enzyme prodrug therapy Henry Hirschberg, Kristian Berg, Young J. Kwon, Steen Madsen Beckman Laser Institute, University of California, Irvine, USA The ability of monocytes/macrophages (Mo/Ma) to target tumors allows their utilization as vectors to deliver several types of anti-cancer payloads. Cells as opposed to nanoparticles have the ability to target and infiltrate the tumor interstitium by an active process, obtaining access despite stromal barriers and the elevated interstitial pressure present in most tumors. Although Mo/Ma can readily be loaded with metallic NP they have proven difficult to transfect, limiting their usefulness as gene delivery vehicles. To increase the transfection efficiency of the prodrug activating gene, E. coli cytosine deaminase (CD), an approach combining
photochemical internalization, together with specially designed core/shell NPs as gene carrier was used. Expression of this gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-FC, to the toxic metabolite, 5-fluorouracil (5-FU). 5-FC can readily cross the blood–brain barrier (BBB). In addition the bystander effect, where activated drug is exported from the transfected cancer cells into the tumor microenvironment, plays an important role by inhibiting growth of adjacent tumor cells. The introduction of subpopulations of CD transfected Ma into glioma tumor spheroids inhibited the growth of the spheroids in the presence but not the absence of 5-FC. http://dx.doi.org/10.1016/j.pdpdt.2015.07.034 A folate-targeted photosensitizer to improve specificity of intraperitoneal photodynamic therapy of ovarian peritoneal metastasis Henri Azaïs 1,2 , Céline Frochot 3 , Nacim Betrouni 1 , Pierre Collinet 1,2 , Serge Mordon 1 1 INSERM, U1189 – ONCO-THAI, University of Lille, 59000 Lille, France 2 Department of Gynecology, University of Lille, 59000 Lille, France 3 Laboratoire Réactions et Génie des Procédés, UMR 7274 CNRS – University of Lorraine, France
New generation photosensitizer targeted by folate is specific for epithelial ovarian cancer (EOC) and may allow the development of efficient and safe intraperitoneal photodynamic therapy to improve microscopic cytoreduction after macroscopic complete surgery for EOC. Introduction: Prognosis of ovarian cancer remains poor. Current treatment is the association of complete cytoreductive surgery and platinum-based chemotherapy. The absence of peritoneal residual disease after surgery is a key to improve prognosis. 60% of patients treated by optimal treatment will develop peritoneal recurrence. Folate receptor ␣ (FR␣) shows promising prospects in targeting ovarian cancerous cells with good specificity. Aims and objectives: We hypothesize that using tetraphenylporphyrin as a photosensitizer (PS) targeted by folate allows performing effective intraperitoneal PDT (iPDT) with a sufficient specificity to increase procedure tolerance. Our objective is to assess the specificity of this PS. Material and methods: In vivo experiments were done on a preclinical model of ovarian peritoneal carcinomatosis (female Fisher 344 rats). The expression of FR␣ by several organs has been correlated with the PS uptake in these organs measured by fluorescence and tissue quantification, four hours after the intraperitoneal injection. Results: FR␣ is expressed by tumoral lesions, ovaries and in a lesser extent by liver. PS fluorescence has been observed in those organs by confocal microscopy. Tissue quantification shows a good specificity (tumour-to-tissue ratio: 9.6). Conclusion: New generation of targeted PS exhibits a specificity that could allow performing iPDT at the end of complete cytoreductive surgery. http://dx.doi.org/10.1016/j.pdpdt.2015.07.035
Abstracts / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375
edge-response profile of the system from which we extract optical property contrast and resolution. We demonstrate that our visible-light SFDI system is capable of recovering s and a within ∼10–15% accuracy. Finally, we performed in vivo measurements to find the optical property maps over a ∼25 cm2 field-of-view for potential application in intraoperative photodynamic therapy (PDT) dosimetry. http://dx.doi.org/10.1016/j.pdpdt.2015.07.032 Use of a novel 3D-tumoroid experimental model to assess cytotoxicity mediated by Photochemical Internalisation of saporin in 4T1 breast cancer cells Derick Adigbli, Alejandra Martinez De Pinillos Bayona, Josephine Woodhams, Alexander MacRobert, Marilena Loizidou Division of Surgery & Interventional Sciences, UCL, UK Introduction: The increasing drive to reduce the use of animals for in vivo experimentation has led to the development of novel tumour models. The 3D-tumoroid model is one such solution that may have an important role in enabling more representative experimentation to investigate the efficacy of Photochemical Internalisation (PCI) as tool to enhance selective cytotoxicity in cancer therapeutics. The model is based on a new plastic compression technique for preparing collagen scaffolds. Aim: To determine if disulfonated tetraphenylporphine (TPPS2a) based PCI of saporin (SAP) could enhance cytotoxicity in a 3D tumoroid model. Methodology: 4T1 breast cancer cells were imbedded in a collagen matrix and placed under plastic compression to form 3D tumoroid scaffolds. PCI was performed following 8 days of incubation to enable tumoroid development. Cytotoxicity was assessed 7 days later using AlamarBlue® . Results: PCI resulted in 51% and 61% (p < 0.01) increased cytotoxicity compared to (SAP) or PDT (TPPS2a) alone. Conclusion: The results indicate that the 3D tumoroid model can be used as a tool to assess PCI mediated cytotoxicity in cancer therapeutics. The ability to assess treatment response in 3D cancer models will play an increasing role in initiating translation of basic scientific concepts into therapeutic solutions. http://dx.doi.org/10.1016/j.pdpdt.2015.07.033 Macrophage mediated PCI enhanced gene-directed enzyme prodrug therapy Henry Hirschberg, Kristian Berg, Young J. Kwon, Steen Madsen Beckman Laser Institute, University of California, Irvine, USA The ability of monocytes/macrophages (Mo/Ma) to target tumors allows their utilization as vectors to deliver several types of anti-cancer payloads. Cells as opposed to nanoparticles have the ability to target and infiltrate the tumor interstitium by an active process, obtaining access despite stromal barriers and the elevated interstitial pressure present in most tumors. Although Mo/Ma can readily be loaded with metallic NP they have proven difficult to transfect, limiting their usefulness as gene delivery vehicles. To increase the transfection efficiency of the prodrug activating gene, E. coli cytosine deaminase (CD), an approach combining
photochemical internalization, together with specially designed core/shell NPs as gene carrier was used. Expression of this gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-FC, to the toxic metabolite, 5-fluorouracil (5-FU). 5-FC can readily cross the blood–brain barrier (BBB). In addition the bystander effect, where activated drug is exported from the transfected cancer cells into the tumor microenvironment, plays an important role by inhibiting growth of adjacent tumor cells. The introduction of subpopulations of CD transfected Ma into glioma tumor spheroids inhibited the growth of the spheroids in the presence but not the absence of 5-FC. http://dx.doi.org/10.1016/j.pdpdt.2015.07.034 A folate-targeted photosensitizer to improve specificity of intraperitoneal photodynamic therapy of ovarian peritoneal metastasis Henri Azaïs 1,2 , Céline Frochot 3 , Nacim Betrouni 1 , Pierre Collinet 1,2 , Serge Mordon 1 1 INSERM, U1189 – ONCO-THAI, University of Lille, 59000 Lille, France 2 Department of Gynecology, University of Lille, 59000 Lille, France 3 Laboratoire Réactions et Génie des Procédés, UMR 7274 CNRS – University of Lorraine, France
New generation photosensitizer targeted by folate is specific for epithelial ovarian cancer (EOC) and may allow the development of efficient and safe intraperitoneal photodynamic therapy to improve microscopic cytoreduction after macroscopic complete surgery for EOC. Introduction: Prognosis of ovarian cancer remains poor. Current treatment is the association of complete cytoreductive surgery and platinum-based chemotherapy. The absence of peritoneal residual disease after surgery is a key to improve prognosis. 60% of patients treated by optimal treatment will develop peritoneal recurrence. Folate receptor ␣ (FR␣) shows promising prospects in targeting ovarian cancerous cells with good specificity. Aims and objectives: We hypothesize that using tetraphenylporphyrin as a photosensitizer (PS) targeted by folate allows performing effective intraperitoneal PDT (iPDT) with a sufficient specificity to increase procedure tolerance. Our objective is to assess the specificity of this PS. Material and methods: In vivo experiments were done on a preclinical model of ovarian peritoneal carcinomatosis (female Fisher 344 rats). The expression of FR␣ by several organs has been correlated with the PS uptake in these organs measured by fluorescence and tissue quantification, four hours after the intraperitoneal injection. Results: FR␣ is expressed by tumoral lesions, ovaries and in a lesser extent by liver. PS fluorescence has been observed in those organs by confocal microscopy. Tissue quantification shows a good specificity (tumour-to-tissue ratio: 9.6). Conclusion: New generation of targeted PS exhibits a specificity that could allow performing iPDT at the end of complete cytoreductive surgery. http://dx.doi.org/10.1016/j.pdpdt.2015.07.035