Original article Photodynamic effects of isosteric water-soluble phthalocyanines on human nasopharynx KB carcinoma cells Julieta Marino a, 1 , María C. García Vior b, 1 , Lelia E. Dicelio c , Leonor P. Roguin a , Josefina Awruch b, * a Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956,1113 Buenos Aires, Argentina b Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956,1113 Buenos Aires, Argentina c INQUIMAE, Departamento de Química Inorgánica, Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Buenos Aires, Argentina article info Article history: Received 13 January 2010 Received in revised form 7 May 2010 Accepted 2 June 2010 Available online 16 June 2010 Keywords: Photodynamic therapy Phthalocyanines Singlet oxygen Apoptosis Lysosomes KB cells abstract The photodynamic activity of water-soluble cationic zinc(II) phthalocyanines using human nasopharynx carcinoma (KB cells) was investigated. A sulfur-linked cationic dye, named: 2,9(10),16(17),23(24)-tetrakis [(2-trimethylammonium)ethylsulfanyl]phthalocyaninatozinc(II) tetraioidide (13) is the most active of four sensitizer assays and shows a singlet oxygen quantum yield of 0.58 and a higher bathochromic shift of 10 nm for the Q-band as compared with the oxygen-linked cationic aliphatic phthalocyanine: 2,9 (10),16(17),23(24)-tetrakis[(2-trimethylammonium)ethoxy]phthalocyaninatozinc(II) tetraioidide (11) and the best photo-stability in water in comparison with their tetra-a-substituted counterparts 1,8(11),15 (18),22(25)-tetrakis[(2-trimethylammonium)ethoxy]phthalocyaninatozinc(II) tetraioidide (12) and 1,8 (11),15(18),22(25)-tetrakis[(2-trimethylammonium)ethylsulfanyl]phthalocyaninatozinc(II) tetraioidide (14). Phthalocyanine 13, partially localized in lysosomes, led to cell photoinactivation in a concentration- and light dose-dependent manner. After photodynamic treatment, compound 13 induced an apoptotic response e as indicated by morphological cell changes e an increase in the activity of caspase-3 and the cleavage of poly-ADP-ribose-polymerase substrate (PARP). Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Photodynamic therapy (PDT) is emerging as a promising method for the treatment of a variety of oncological, dermatolog- ical, cardiovascular and ophthalmic diseases [1e5]. PDT combines the intravenous or topical administration of a photosensitizer which preferentially localizes within the tumor, followed by illumination of the target tissue thus resulting in the formation of reactive oxygen species, believed to be responsible for the cascade of cellular and molecular events that finally lead to selective tumor destruction [1]. Phthalocyanines have been found to have applications as phototoxic drugs for PDT [4,6e8]. In addition to their well-known chemical stability, phthalocyanines possess characteristic absorp- tion spectra [9], with a Soret band at approximately 350 nm and a usually narrow but very strong Q-band around 675 nm, with a molar absorption coefficient in the range of 10 5 M 1 cm 1 . Zinc, aluminum, and silicon phthalocyanines that have been found to be useful photosensitizers for PDT, are efficient generators of singlet oxygen, the cytotoxic species capable of destroying malignant cells [10e14]. The silicon phthalocyanine Pc 4 is in various stages of clinical evaluation for cutaneous and subcuta- neous lesions from diverse solid tumor origins [15]. The uptake and efficacy of photosensitizers such as phthalocy- anines, porphyrins, and core-modified porphyrins are directly related to the number of hydrophilic groups [8,10] that the dye carries on its structure. Thus, in the aluminum sulfonate phthalo- cyanine series, those with two groups attached to the macrocycle show greater uptake and phototoxicity than phthalocyanines with three sulfonate groups which in turn show greater uptake and efficacy than phthalocyanines with four sulfonate groups. In BALB/c mice bearing EMT-6 tumors, aluminum sulfonate phthalocyanine substituted with two sulfonate groups is 10 times more phototoxic than aluminum phthalocyanine carrying four sulfonate groups [14]. Great efforts have been made to study the structureeactivity relationship between the site [16,17] and kind of substitution [18] and the photodynamic activity. However, to our knowledge, studies directed to establish the structureeactivity relationship between isosteric phthalocyanines are quite uncommon. * Corresponding author. Tel.: þ54 11 4964 8252; fax: þ54 11 4508 3645. E-mail address: jawruch@ffyb.uba.ar (J. Awruch). 1 Both authors contributed equally to this work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.06.002 European Journal of Medicinal Chemistry 45 (2010) 4129e4139