Tatsuya Kato1, Cheng S Jin2, Hideki Ujiie3, Daiyoon Lee3, Kosuke Fujino3, Hironobu Wada3, Hsin-Pei Hu3, Robert A Weersink4, Juan Chen5, Mitsuhito Kaji6, Kichizo Kaga7, Yoshiro Matsui7, Brian C Wilson8, Gang Zheng9, Kazuhiro Yasufuku10. 1. Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada; Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 2. Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada; Institute of Biomaterial and Biomedical Engineering, University of Toronto, Canada; Guided Therapeutics, Princess Margaret Cancer Centre and TECHNA Institute, University Health Network, Canada. 3. Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada. 4. Guided Therapeutics, Princess Margaret Cancer Centre and TECHNA Institute, University Health Network, Canada. 5. Department of Medical Biophysics, University of Toronto, Canada. 6. Department of Thoracic Surgery, Sapporo Minami-sanjo Hospital, Sapporo, Hokkaido, Japan. 7. Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 8. Guided Therapeutics, Princess Margaret Cancer Centre and TECHNA Institute, University Health Network, Canada; Department of Medical Biophysics, University of Toronto, Canada. 9. Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada; Institute of Biomaterial and Biomedical Engineering, University of Toronto, Canada; Guided Therapeutics, Princess Margaret Cancer Centre and TECHNA Institute, University Health Network, Canada; Department of Medical Biophysics, University of Toronto, Canada; Division of Experimental Therapeutics, Respiratory & Critical Care, Princess Margaret Cancer Centre, Canada. 10. Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Biomaterial and Biomedical Engineering, University of Toronto, Canada; Guided Therapeutics, Princess Margaret Cancer Centre and TECHNA Institute, University Health Network, Canada; Division of Experimental Therapeutics, Respiratory & Critical Care, Princess Margaret Cancer Centre, Canada. Electronic address: kazuhiro.yasufuku@uhn.ca.
Abstract
OBJECTIVE: Despite modest improvements, the prognosis of lung cancer patients has still remained poor and new treatment are urgently needed. Photodynamic therapy (PDT), the use of light-activated compounds (photosensitizers) is a treatment option but its use has been restricted to central airway lesions. Here, we report the use of novel porphyrin-lipid nanoparticles (porphysomes) targeted to folate receptor 1 (FOLR1) to enhance the efficacy and specificity of PDT that may translate into a minimally-invasive intervention for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. MATERIALS AND METHODS: The frequency of FOLR1 expression in primary lung cancer and metastatic lymph nodes was first analyzed by human tissue samples from surgery and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA). Confocal fluorescence microscopy was then used to confirm the cellular uptake and fluorescence activation in lung cancer cells, and the photocytotoxicity was evaluated using a cell viability assay. In vivo fluorescence activation and quantification of uptake were investigated in mouse lung orthotopic tumor models, followed by the evaluation of in vivo PDT efficacy. RESULTS: FOLR1 was highly expressed in metastatic lymph node samples from patients with advanced lung cancer and was mainly expressed in lung adenocarcinomas in primary lung cancer. Expression of FOLR1 in lung cancer cell lines corresponded with the intracellular uptake of folate-porphysomes in vitro. When irradiated with a 671nm laser at a dose of 10J/cm2, folate-porphysomes showed marked therapeutic efficacy compared with untargeted porphysomes (28% vs. 83% and 24% vs. 99% cell viability in A549 and SBC5 lung cancer cells, respectively). Systemically-administered folate-porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast. Folate-porphysomes mediated PDT successfully inhibited tumor cell proliferation and activated tumor cell apoptosis. CONCLUSION: Folate-porphysome based PDT shows promise in selectively ablating lung cancer based on FOLR1 expression in these preclinical models.
OBJECTIVE: Despite modest improvements, the prognosis of lung cancerpatients has still remained poor and new treatment are urgently needed. Photodynamic therapy (PDT), the use of light-activated compounds (photosensitizers) is a treatment option but its use has been restricted to central airway lesions. Here, we report the use of novel porphyrin-lipid nanoparticles (porphysomes) targeted to folate receptor 1 (FOLR1) to enhance the efficacy and specificity of PDT that may translate into a minimally-invasive intervention for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. MATERIALS AND METHODS: The frequency of FOLR1 expression in primary lung cancer and metastatic lymph nodes was first analyzed by human tissue samples from surgery and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA). Confocal fluorescence microscopy was then used to confirm the cellular uptake and fluorescence activation in lung cancer cells, and the photocytotoxicity was evaluated using a cell viability assay. In vivo fluorescence activation and quantification of uptake were investigated in mouse lung orthotopic tumor models, followed by the evaluation of in vivo PDT efficacy. RESULTS:FOLR1 was highly expressed in metastatic lymph node samples from patients with advanced lung cancer and was mainly expressed in lung adenocarcinomas in primary lung cancer. Expression of FOLR1 in lung cancer cell lines corresponded with the intracellular uptake of folate-porphysomes in vitro. When irradiated with a 671nm laser at a dose of 10J/cm2, folate-porphysomes showed marked therapeutic efficacy compared with untargeted porphysomes (28% vs. 83% and 24% vs. 99% cell viability in A549 and SBC5 lung cancer cells, respectively). Systemically-administered folate-porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast. Folate-porphysomes mediated PDT successfully inhibited tumor cell proliferation and activated tumor cell apoptosis. CONCLUSION:Folate-porphysome based PDT shows promise in selectively ablating lung cancer based on FOLR1 expression in these preclinical models.
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