This study assessed the therapeutic efficacy of intraperitoneal photodynamic therapy (PDT) using photosensitizer activation at two different wavelengths, 405 and 664 nm, in a mouse model of peritoneal carcinomatosis.
The dark and light cytotoxicity of chlorin e6-polyvinylpyrrolidone (Phonozen) were measured in vitro under 402 ± 14 and 670 ± 18 nm LED activation in bioluminescent human gastric cancer cells, MKN45-luc. Cell viability was measured at 6 h after irradiation using the PrestoBlue assay. Corresponding in vivo studies were performed in athymic nude mice by intraperitoneal injection of 1 × 106 MKN45-luc cells. PDT was performed 10 d after tumor induction and comprised intraperitoneal injection of Phonozen followed by light irradiation at 3 h, delivered by a diffusing-tip optical fiber placed in the peritoneal cavity and coupled to a 405 or 664 nm diode laser to deliver a total energy of 50 J (20 mice per cohort). Whole-body bioluminescence imaging was used to track the tumor burden after PDT out to 130 days, and 5 mice in each cohort were sacrificed at 4 h post treatment to measure the acute tumor necrosis.
Photosensitizer dose-dependent photocytotoxicity was higher in vitro at 405 than 664 nm. In vivo, PDT reduced the tumor growth rate at both wavelengths, with no statistically significant difference. There was substantial necrosis, and median survival was significantly prolonged at both wavelengths compared with controls (46 and 46 vs. 34 days).
Phonozen-mediated PDT results in significant cytotoxicity in vitro as well as tumor necrosis and prolonged survival in vivo following intraperitoneal light irradiation. Blue light was more photocytotoxic than red in vitro and had marginally higher efficacy in vivo.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Azaïs, H., Rebahi, C., Baydoun, M., Serouart, B., Ziane, L., Moralès, O., Frochot, C., Colombeau, L., Thécua, E., Collinet, P., Delhem, N., & Mordon, S. (2020). A global approach for the development of photodynamic therapy of peritoneal metastases regardless of their origin. Photodiagnosis and Photodynamic Therapy, 30, 101683.
Kusamura, S., Baratti, D., Zaffaroni, N., Villa, R., Laterza, B., Balestra, M. R., & Deraco, M. (2010). Pathophysiology and biology of peritoneal carcinomatosis. World Journal of Gastrointestinal Oncology, 2(1), 12–18.
Furuse, K., Fukuoka, M., Kato, H., Horai, T., Kubota, K., Kodama, N., Kusunoki, Y., Takifuji, N., Okunaka, T., Konaka, C., et al. (1993). A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan lung cancer photodynamic therapy study group. Journal of Clinical Oncology, 11(10), 1852–1857.
Shim, C. S., Cheon, Y. K., Cha, S. W., Bhandari, S., Moon, J. H., Cho, Y. D., Kim, Y. S., Lee, L. S., Lee, M. S., & Kim, B. S. (2005). Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy, 37(5), 425–433.
Lou, P. J., Jäger, H. R., Jones, L., Theodossy, T., Bown, S. G., & Hopper, C. (2004). Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer. British Journal of Cancer, 91(3), 441–446.
Sidoroff, A., & Thaler, P. (2010). Taking treatment decisions in non-melanoma skin cancer–the place for topical photodynamic therapy (PDT). Photodiagnosis and Photodynamic Therapy, 7(1), 24–32.
DeLaney, T. F., Sindelar, W. F., Tochner, Z., Smith, P. D., Friauf, W. S., Thomas, G., Dachowski, L., Cole, J. W., Steinberg, S. M., & Glatstein, E. (1993). Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. International Journal of Radiation Oncology, Biology, Physics, 25(3), 445–457.
Hahn, S. M., Fraker, D. L., Mick, R., Metz, J., Busch, T. M., Smith, D., Zhu, T., Rodriguez, C., Dimofte, A., Spitz, F., Putt, M., Rubin, S. C., Menon, C., Wang, H. W., Shin, D., Yodh, A., & Glatstein, E. (2006). A phase II trial of intraperitoneal photodynamic therapy for patients with peritoneal carcinomatosis and sarcomatosis. Clinical Cancer Research, 12(8), 2517–2525.
Wierrani, F., Fiedler, D., Grin, W., Henry, M., Krammer, B., & Grunberger, W. (1997). Intraoperative Meso-Tetrahydroxyphenylchlorin-based photodynamic therapy in metastatic gynecologic cancer tissue: initial results. Journal of Gynecologic Surgery, 13(23), 23–30.
Harlow, S. P., Rodriguez-Bigas, M., Mang, T., & Petrelli, N. J. (1995). Intraoperative photodynamic therapy as an adjunct to surgery for recurrent rectal cancer. Annals of Surgical Oncology, 2(3), 228–232.
Allardice, J. T., Abulafi, A. M., Grahn, M. F., & Williams, N. S. (1994). Adjuvant intraoperative photodynamic therapy for colorectal carcinoma: a clinical study. Surgical Oncology, 3(1), 1–10.
Herrera-Ornelas L Fau-Petrelli, N. J., Petrelli Nj Fau-Mittelman, A., Mittelman A Fau-Dougherty, T. J., Dougherty Tj Fau-Boyle, D. G., & Boyle, D. G. (1986). Photodynamic therapy in patients with colorectal cancer. Cancer, 1(0008-543X (Print)), 677–684.
Canter, R. J., Mick, R., Kesmodel, S. B., Raz, D. J., Spitz, F. R., Metz, J. M., Glatstein, E. J., Hahn, S. M., & Fraker, D. L. (2003). Intraperitoneal photodynamic therapy causes a capillary-leak syndrome. Annals of Surgical Oncology, 10(5), 514–524.
Betrouni, N., Munck, C., Bensoltana, W., Baert, G., Dewalle-Vignion, A. S., Scherpereel, A., & Mordon, S. (2017). Real-time light dosimetry for intra-cavity photodynamic therapy: application for pleural mesothelioma treatment. Photodiagnosis and Photodynamic Therapy, 18, 155–161.
Lilge, L., Molpus, K., Hasan, T., & Wilson, B. C. (1998). Light dosimetry for intraperitoneal photodynamic therapy in a murine xenograft model of human epithelial ovarian carcinoma. Photochemistry and Photobiology, 68(3), 281–288.
Zhong, W., Celli, J. P., Rizvi, I., Mai, Z., Spring, B. Q., Yun, S. H., & Hasan, T. (2009). In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring. British Journal of Cancer, 101(12), 2015–2022.
Kato, A., Kataoka, H., Yano, S., Hayashi, K., Hayashi, N., Tanaka, M., Naitoh, I., Ban, T., Miyabe, K., Kondo, H., Yoshida, M., Fujita, Y., Hori, Y., Natsume, M., Murakami, T., Narumi, A., Nomoto, A., Naiki-Ito, A., Takahashi, S., & Joh, T. (2017). Maltotriose conjugation to a chlorin derivative enhances the antitumor effects of photodynamic therapy in peritoneal dissemination of pancreatic cancer. Molecular Cancer Therapeutics, 16(6), 1124–1132.
Mroz, P., Xia, Y., Asanuma, D., Konopko, A., Zhiyentayev, T., Huang, Y. Y., Sharma, S. K., Dai, T., Khan, U. J., Wharton, T., & Hamblin, M. R. (2011). Intraperitoneal photodynamic therapy mediated by a fullerene in a mouse model of abdominal dissemination of colon adenocarcinoma. Nanomedicine : Nanotechnology, Biology and Medicine, 7(6), 965–974.
Kishi, K., Yano, M., Inoue, M., Miyashiro, I., Motoori, M., Tanaka, K., Goto, K., Eguchi, H., Noura, S., Yamada, T., Ohue, M., Ohigashi, H., & Ishikawa, O. (2010). Talaporfin-mediated photodynamic therapy for peritoneal metastasis of gastric cancer in an in vivo mouse model: drug distribution and efficacy studies. International Journal of Oncology, 36(2), 313–320.
Thapa Magar TB, Shrestha R, Gurung P, Lim J, Kim Y-W. (2022). Improved pilot-plant-scale synthesis of chlorin e6 and its efficacy as a photosensitizer for photodynamic therapy and photoacoustic contrast agent. Processes, 10, 1–14.
Efendiev, K. T., Alekseeva, P. M., Shiryaev, A. A., Skobeltsin, A. S., Solonina, I. L., Fatyanova, A. S., Reshetov, I. V., & Loschenov, V. B. (2022). Preliminary low-dose photodynamic exposure to skin cancer with chlorin e6 photosensitizer. Photodiagnosis and Photodynamic Therapy, 38, 102894.
Yu, Z., Xiao, Z., Shuai, X., & Tian, J. (2020). Local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively prevents osteosarcoma recurrence. Journal of Materials Chemistry B, 8(30), 6418–6428.
Shen, Y., Li, M., Sun, F., Zhang, Y., Qu, C., Zhou, M., Shen, F., & Xu, L. (2020). Low-dose photodynamic therapy-induced increase in the metastatic potential of pancreatic tumor cells and its blockade by simvastatin. Journal of Photochemistry and Photobiology B, Biology, 207, 111889.
He, Z., Jiang, H., Zhang, X., Zhang, H., Cui, Z., Sun, L., Li, H., Qian, J., Ma, J., & Huang, J. (2020). Nano-delivery vehicle based on chlorin E6, photodynamic therapy, doxorubicin chemotherapy provides targeted treatment of HER-2 negative, ανβ3-positive breast cancer. Pharmacological Research, 160, 105184.
Lee, L. S., Thong, P. S., Olivo, M., Chin, W. W., Ramaswamy, B., Kho, K. W., Lim, P. L., & Lau, W. K. (2010). Chlorin e6-polyvinylpyrrolidone mediated photodynamic therapy–A potential bladder sparing option for high risk non-muscle invasive bladder cancer. Photodiagnosis and Photodynamic Therapy, 7(4), 213–220.
Piatrouskaya, N. A., Kharuzhyk, S. A., Vozmitel, M. A., Mazurenko, A. N., & Istomin, Y. P. (2010). Experimental study of antiangiogenic and photodynamic therapies combination for treatment of peritoneal carcinomatosis: preliminary results. Experimental Oncology, 32(2), 100–103.
Shrestha R, Mallik SK, Lim J, Gurung P, Magar TBT, Kim YW (2023) Efficient synthesis of chlorin e6 and its potential photodynamic immunotherapy in mouse melanoma by the abscopal effect. International Journal of Molecular Sciences. 24, 3901.
Bauer, T. W., Hahn, S. M., Spitz, F. R., Kachur, A., Glatstein, E., & Fraker, D. L. (2001). Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis. Annals of Surgical Oncology, 8(3), 254–259.
Sindelar, W. F., DeLaney, T. F., Tochner, Z., Thomas, G. F., Dachoswki, L. J., Smith, P. D., Friauf, W. S., Cole, J. W., & Glatstein, E. (1991). Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study. Archives of Surgery, 126(3), 318–324.
Bisland, S. K., Lilge, L., Lin, A., Rusnov, R., & Wilson, B. C. (2004). Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors. Photochemistry and Photobiology, 80, 22–30.
Shrestha, R., Lee, H. J., Lim, J., Gurung, P., Thapa Magar, T. B., Kim, Y.-T., Lee, K., Bae, S., & Kim, Y.-W. (2022). Effect of photodynamic therapy with chlorin e6 on canine tumors. Life, 12, 2102.
De Clercq, K., Xie, F., De Wever, O., Descamps, B., Hoorens, A., Vermeulen, A., Ceelen, W., & Vervaet, C. (2019). Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer. Scientific Reports, 9(1), 14881.
Derrien, A., Gouard, S., Maurel, C., Gaugler, M. H., Bruchertseifer, F., Morgenstern, A., Faivre-Chauvet, A., Classe, J. M., & Chérel, M. (2015). Therapeutic efficacy of alpha-RIT using a (213)Bi-Anti-hCD138 antibody in a mouse model of ovarian peritoneal carcinomatosis. Frontiers in Medicine, 2, 88.
Yakovlev, D. V., Farrakhova, D. S., Shiryaev, A. A., Efendiev, K. T., Loschenov, M. V., Amirkhanova, L. M., Kornev, D. O., Levkin, V. V., Reshetov, I. V., & Loschenov, V. B. (2020). New approaches to diagnostics and treatment of cholangiocellular cancer based on photonics methods. Front Optoelectron, 13(4), 352–359.
Shiryaev, A. A., Musaev, G. K., Levkin, V. V., Reshetov, I. V., Loshchenov, M. V., Alekseeva, P. M., Volkov, V. V., Linkov, K. G., Makarov, V. I., Shchekoturov, I. O., Borodkin, A. V., & Loschenov, V. B. (2019). Combined treatment of nonresectable cholangiocarcinoma complicated by obstructive jaundice. Photodiagnosis and Photodynamic Therapy, 26, 218–223.
Tatarchuk, T., Dunaevskaya, V., Tzerkovsky, D., & Zakharenko, N. (2020). Photodynamic therapy in treatment of patients with premalignant vulvar diseases. First experience of the method application in UKRAINE. Georgian Medical News, 309, 12–17.
Istomin, Y. P., Lapzevich, T. P., Chalau, V. N., Shliakhtsin, S. V., & Trukhachova, T. V. (2010). Photodynamic therapy of cervical intraepithelial neoplasia grades II and III with Photolon. Photodiagnosis and Photodynamic Therapy, 7(3), 144–151.
Sheleg, S. V., Zhavrid, E. A., Khodina, T. V., Kochubeev, G. A., Istomin, Y. P., Chalov, V. N., & Zhuravkin, I. N. (2004). Photodynamic therapy with chlorin e(6) for skin metastases of melanoma. Photodermatology, Photoimmunology & Photomedicine, 20(1), 21–26.
Choi, J. H., Oh, D., Lee, J. H., Park, J. H., Kim, K. P., Lee, S. S., Lee, Y. J., Lim, Y. S., Song, T. J., Lee, S. S., Seo, D. W., Lee, S. K., Kim, M. H., & Park, D. H. (2015). Initial human experience of endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter. Endoscopy, 47(11), 1035–1038.
Kalia, A., & Jain, V. (1989). Effects of some divalent metal ions on the aging phenomenon of hematoporphyrin and photofrin II. Indian Journal of Biochemistry & Biophysics, 26(4), 213–218.
Hendren, S. K., Hahn, S. M., Spitz, F. R., Bauer, T. W., Rubin, S. C., Zhu, T., Glatstein, E., & Fraker, D. L. (2001). Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Annals of Surgical Oncology, 8(1), 65–71.
Davies, N., & Wilson, B. C. (2007). Interstitial in vivo ALA-PpIX mediated metronomic photodynamic therapy (mPDT) using the CNS-1 astrocytoma with bioluminescence monitoring. Photodiagnosis and Photodynamic Therapy, 4(3), 202–212.
Cavin, S., Gkasti, A., Faget, J., Hao, Y., Letovanec, I., Reichenbach, M., Gonzalez, M., Krueger, T., Dyson, P. J., Meylan, E., & Perentes, J. Y. (2020). Low-dose photodynamic therapy promotes a cytotoxic immunological response in a murine model of pleural mesothelioma. European Journal of Cardio-Thoracic Surgery, 58(4), 783–791.
Shi, X. F., Jin, W. D., Gao, H., Yin, H. J., Li, Y. X., Huang, H., Ma, H., & Dong, H. J. (2018). A suppository kit for metronomic photodynamic therapy: the elimination of rectal cancer in situ. Journal of Photochemistry and Photobiology B, Biology, 181, 143–149.
Morrison, S. A., Hill, S. L., Rogers, G. S., & Graham, R. A. (2014). Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer. Journal of Surgical Research, 192(2), 235–241.
Kniebühler, G., Pongratz, T., Betz, C. S., Göke, B., Sroka, R., Stepp, H., & Schirra, J. (2013). Photodynamic therapy for cholangiocarcinoma using low dose mTHPC (Foscan(®)). Photodiagnosis and Photodynamic Therapy, 10(3), 220–228.
We thank DongSung Biopharmaceuticals for generously providing Phonozen. This work was financially supported by a faculty research grant from Yonsei University College of Medicine, Seoul, S. Korea (6-2020-0088). Preliminary studies leading to this work were supported by the Terry Fox Research Institute.
The authors have no financial or non-financial interests directly or indirectly related to the work.
Conflict of interest
This study was supported by a faculty research grant from Yonsei University College of Medicine, Seoul, S. Korea (6-2020-0088). Preliminary studies leading to this work were supported by the Terry Fox Research Institute. The funding sources were not involved in the study design, data collection or analysis, or manuscript preparation or submission.
About this article
Cite this article
Kim, HI., Lee, SH., Shin, SJ. et al. Phonozen-mediated photodynamic therapy comparing two wavelengths in a mouse model of peritoneal carcinomatosis. Photochem Photobiol Sci 22, 2563–2572 (2023). https://doi.org/10.1007/s43630-023-00470-w