Abstract
Photodynamic therapy (PDT) is a promising antineoplastic modality in the oncology field. We assessed the safety of repeated intravenous administrations of sinoporphyrin, a porphyrin derivative, with and without illumination in rats. Toxicokinetic studies of single and multiple administrations of sinoporphyrin were also carried out. Sprague-Dawley rats were randomly assigned to the dark-toxicity and PDT groups. Animals in the dark toxicity group received an i.v. infusion of sinoporphyrin at 3 doses: 2 mg kg−1, 6 mg kg−1, and 18 mg kg−1. The PDT group included 2 doses of sinoporphyrin (2 mg kg−1 and 18 mg kg−1), and the rats received 60 J of 630 nm laser illumination 24 h after photosensitizer infusion. The treatments were repeated every 7 days for 5 cycles and were followed by a 14-day recovery period. Systematic analyses were conducted at the end of treatment and recovery periods. Blood samples were obtained 5 min, 30 min, 2 h, 8 h, 24 h, 48 h, 72 h, and 96 h after the first and fifth treatments for toxicokinetic studies. Sinoporphyrin-PDT led to the death of one out of 270 rats; the dead animal had been treated with 18 mg kg−1 sinoporphyrin and died at the end of the fifth PDT treatment. Liver injury, the primary toxicity observed in the study, was identified using biochemical tests, necropsy, and histopathology. Elevated white blood cell and neutrophil counts were found in the rats in both the dark toxicity and PDT groups. Skin lesions at the illumination site were obvious in the PDT group. Pigment deposits were detected in multiple organs such as the liver, spleen, lymph nodes, and ovaries in the 6 mg kg−1 and 18 mg kg−1 groups. No other abnormalities were observed. The toxicokinetic parameters of single and multiple sinoporphyrin administrations were calculated and compared. Repeated sinoporphyrin administrations both alone and in combination with laser illumination were tolerable, and all toxicities were transient. The no observed adverse effect level (NOAEL) for repeated sinoporphyrin administration and sinoporphyrin-PDT was 6 mg kg−1 and 2 mg kg−1, respectively. Further studies are warranted.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Notes and references
L. Dalla Via and S. Marciani Magno, Photochemotherapy in the treatment of cancer, Curr. Med. Chem., 2001, 812, 1405–1418.
B. J. Qumseya, W. David and H. C. Wolfsen, Photodynamic Therapy for Barrett’s Esophagus and Esophageal Carcinoma, Clin. Endosc., 2013, 461, 30–37.
G. Shafirstein, A. Battoo and K. Harris, et al., Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions, Ann. Am. Thorac. Soc., 2016, 132, 265–275.
T. Zoepf, Photodynamic therapy of cholangiocarcinoma, HPB, 2008, 103, 161–163.
M. Biel, Advances in photodynamic therapy for the treatment of head and neck cancers, Lasers Surg. Med., 2006, 385, 349–355.
L. R. Braathen, R. M. Szeimies and N. Basset-Seguin, et al., Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005, J. Am. Acad. Dermatol., 2007, 561, 125–143.
J. Akimoto, Photodynamic Therapy for Malignant Brain Tumors, Neurol. Med. Chir., 2016, 564, 151–157.
A. E. O’Connor, W. M. Gallagher and A. T. Byrne, Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy, Photochem. Photobiol., 2009, 85, 1053–1074.
M. J. Garland, C. M. Cassidy and D. Woolfson, et al., Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments, Future Med. Chem., 2009, 14, 667–691.
S. K. Pushpan, S. Venkatraman and V. G. Anand, et al., Porphyrins in photodynamic therapy - a search for ideal photosensitizers, Curr. Med. Chem. Anticancer Agents, 2002, 22, 187–207.
R. Bonnett, Photodynamic therapy in historical perspective, Rev. Contemp. Pharmacother., 1999, 101, 1–17.
E. S. Nyman and P. H. Hynninen, Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy, J. Photochem. Photobiol., B, 2004, 731–2, 1–28.
Q. Fang, Photodynamic therapy for cancer treatment and the new antitumor photosensitizer sinoporphyrin sodium, Chinese J. New Drugs, 2014, 2313, 1540–1545.
Q.-C. Fang and D. Yang, Ether-linked porphyrin dimer salts and their manufacturing method, CN, ZL200910179116.5, 2012-08-29.
L. Wu, X. Wang and Q. Liu, et al., Sinoporphyrin sodium mediated photodynamic therapy inhibits the migration associated with collapse of F-actin filaments cytoskeleton in MDA-MB-231 cells, Photodiagn. Photodyn. Ther., 2016, 13, 58–65.
J. Hu, X. Wang and Q. Liu, et al., Antitumor effect of sinoporphyrin sodium-mediated photodynamic therapy on human esophageal cancer Eca-109 cells, Photochem. Photobiol., 2014, 906, 1404–1412.
J. Zhihuan, S. Rui and L. Chao, et al., Inhibitory effects of DVDMS-2-based-photodynamic therapy on the growth of tumor in vitro and in vivo, Teratog., Carcinog., Mutagen., 2013, 253, 163–167.
X. Wang, J. Hu, P. Wang, et al., Analysis of the in vivo and in vitro effects of photodynamic therapy on breast cancer by using a sensitizer, sinoporphyrin sodium, Theranostics, 2015, 57, 772–786.
T. Yano, M. Muto and K. Minashi, et al., Photodynamic therapy as salvage treatment for local failure after chemoradiotherapy in patients with esophageal squamous cell carcinoma: a phase II study, Int. J. Cancer, 2012, 1315, 1228–1234.
K. Furuse, M. Fukuoka and H. Kato, et al., 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, J. Clin. Oncol., 1993, 1110, 1852–1857.
S. P. Pereira, G. P. Aithal and K. Ragunath, et al., Safety and long term efficacy of porfimer sodium photodynamic therapy in locally advanced biliary tract carcinoma, Photodiagn. Photodyn. Ther., 2012, 94, 287–292.
L. B. Rocha, F. Schaberle and J. M. Dąbrowski, et al., Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents, Int. J. Mol. Sci., 2015, 1612, 29236–29249.
L. Guyon, M. O. Farine and J. C. Lesage, et al., Photodynamic therapy of ovarian cancer peritoneal metastasis with hexaminolevulinate: a toxicity study, Photodiagn. Photodyn. Ther., 2014, 113, 265–274.
R. S. Sellers, D. Morton and B. Michael, et al., Society of Toxicologic Pathology position paper: organ weight recommendations for toxicology studies, Toxicol. Pathol., 2007, 355, 751–755.
C. L. Bregman, R. R. Adler and D. G. Morton, et al., Recommended tissue list for histopathologic examination in repeat-dose toxicity and carcinogenicity studies: a proposal of the Society of Toxicologic Pathology (STP), Toxicol. Pathol., 2003, 312, 252–253.
C. Ruehl-Fehlert, B. Kittel and G. Morawietz, et al., Revised guides for organ sampling and trimming in rats and mice–part 1, Exp. Toxicol. Pathol., 2003, 552–3, 91–106.
J. Min-ge, W. Hai-yan and S. Li-li, et al., Analysis of porphyrin photosensitizers using HPLC method, Acta Pharm. Sin., 2015, 508, 1021–1025.
S. Grimm, D. Mvondo and T. Grune, et al., The outcome of 5-ALA-mediated photodynamic treatment in melanoma cells is influenced by vitamin C and heme oxygenase-1, Biofactors, 2011, 371, 17–24.
A. Józkowicz and J. Dulak, Effects of protoporphyrins on production of nitric oxide and expression of vascular endothelial growth factor in vascular smooth muscle cells and macrophages, Acta Biochim. Pol., 2003, 501, 69–79.
N. G. Abraham and A. Kappas, Heme oxygenase and the cardiovascular-renal system, Free Radicals Biol. Med., 2005, 391, 1–25.
W. Halina, D. Jozef and J. Alicja, Heme Oxygenase-1 in Tumor Biology and Therapy, Curr. Drug Targets, 2010, 1112, 1551–1570.
D. Bressoud, V. Jomini and R. M. Tyrrell, Dark induction of haem oxygenase messenger RNA by haematoporphyrin derivative and zinc phthalocyanine; agents for photodynamic therapy, J. Photochem. Photobiol., B, 1992, 144, 311–318.
M. Miyake, M. Ishii and K. Kawashima, et al., siRNA-mediated knockdown of the heme synthesis and degradation pathways: modulation of treatment effect of 5-aminolevulinic acid-based photodynamic therapy in urothelial cancer cell lines, Photochem. Photobiol., 2009, 854, 1020–1027.
D. Nowis, M. Legat and T. Grzela, et al., Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity, Oncogene, 2006, 2524, 3365–3374.
J. Frank, M. R. Lornejad-Schäfer and H. Schöffl, et al., Inhibition of heme oxygenase-1 increases responsiveness of melanoma cells to ALA-based photodynamic therapy, Int. J. Oncol., 2007, 316, 1539–1545.
W. J. de Vree, M. C. Essers and H. S. de Bruijn, et al., Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo, Cancer Res., 1996, 5613, 2908–2911.
J. Sun, I. Cecic and C. S. Parkins, et al., Neutrophils as inflammatory and immune effectors in photodynamic therapy-treated mouse SCCVII tumours, Photochem. Photobiol. Sci., 2002, 19, 690–695.
P. C. Kousis, B. W. Henderson and P. G. Maier, et al., Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils, Cancer Res., 2007, 6721, 10501–10510.
H. S. de Bruijn, W. Sluiter and A. van der Ploeg-van den Heuvel, et al., Evidence for a bystander role of neutrophils in the response to systemic 5-aminolevulinic acid-based photodynamic therapy, Photodermatol., Photoimmunol. Photomed., 2006, 225, 238–246.
T. M. Busch, Local physiological changes during photodynamic therapy, Lasers Surg. Med., 2006, 385, 494–499.
P. C. Mann, J. Vahle and C. M. Keenan, et al., International harmonization of toxicologic pathology nomenclature: an overview and review of basic principles, Toxicol. Pathol., 2012, 404 Suppl, 7S–13S.
J. R. Bloomer, Liver metabolism of porphyrins and haem, J. Gastroenterol. Hepatol., 1998, 133, 324–329.
N. Lin, C. Li, Z. Wang, et al., A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs, Photochem. Photobiol. Sci., 2015, 144, 815–832.
Author information
Authors and Affiliations
Corresponding author
Additional information
Electronic supplementary information (ESI) available. See DOI: 10.1039/c6pp00276e
Rights and permissions
About this article
Cite this article
Shi, R., Lin, X., Zhang, J. et al. Safety evaluation of repeated intravenous infusion of sinoporphyrin with and without PDT in rats. Photochem Photobiol Sci 15, 1366–1376 (2016). https://doi.org/10.1039/c6pp00276e
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1039/c6pp00276e