The photodynamic response of two rodent tumour models to four zinc (II)-substituted phthalocyanines

Abstract

Summary Four novel zinc (I1)-substituted phthalocyanines, varying in charge and hydrophobicity, were evaluated in vivo as new photosensitizers for photodynamic therapy. Two rat tumours with differing vascularity were used: a mammary carcinoma (LMC,) and a fibrosarcoma (LSBD1), with vascular components six times higher in the latter (10.8% ± 1.5) than in the former (1.8% ± 1.4). Each sensitizer was assessed for tumour response relative to normal tissue damage, and optimum doses were selected for further study, ranging from 0.5 to 20 mg kg-'. Interstitial illumination of the tumours was carried out using a 200-gm-core optical fibre with a 0.5 cm length of diffusing tip, at either 680 or 692 nm, depending on the sensitizer. Light doses of between 200 and 600 J were delivered at a rate of 100 mW from the 0.5-cm diffusing section of the fibre. Maximum mean growth delays ranged from 9 to 13.5 days depending on sensitizer and type of tumour, with the most potent photosensitizer appearing to be the cationic compound. Histopathological changes were investigated after treatment to determine the mechanism by which tumour necrosis was effected. The tumours had the appearance of an infarct and, under the conditions used, the observed damage was shown to be mainly due to ischaemic processes, although some direct tumour cell damage could not be ruled out.Keywords: photodynamic therapy; zinc phthalocyanines; rodent tumours; ischaemia Photodynamic therapy (PDT) is a method of cancer treatment that has been clinically applied to the eradication or palliation of tumours at various sites, including bladder (Benson, 1985), brain (Kaye et al, 1987), lung (Okunaka et al, 1991), chest wall (Sperduto et al, 1991), skin (Caimduff et al, 1994) and oesophagus (Moghissi et al, 1995). The only photosensitizer so far approved for general use is Photofrin, which is a complex mixture of porphyrin monomers and oligomers. However, this drug also has relatively low light absorption in the red region of the spectrum, where light penetration in tissue is greatest, and also induces a prolonged skin photosensitivity (Richter et al, 1991).To overcome the problems associated with the limited depth of light penetration, chemical purity and stability, low absorption coefficient and skin photosensitivity, possible alternatives to the haematoporphyrin photosensitizers have been investigated. One such group is the phthalocyanines, which are synthetic porphyrin analogues. A number of phthalocyanine compounds have been tested in vitro (Chan et al, 1991;Boyle et al, 1993) and in vivo (Barr et al, 1991;Boyle et al, 1992) and show sufficient potential for clinical use to merit further investigation. They demonstrate strong absorbance in the red region of the spectrum and the potential for a greater PDT effect is enhanced by the increased tissue penetration by light of longer wavelength. They also appear to induce a smaller degree of skin photosensitivity than haematoporhyrin derivative (HPD) under experimental conditions (Roberts et al, 1989) and the compounds st...

Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

“…The pattern of tumour growth delay over the time course was similar for both a 652 nm diode laser ( Figure 3) and a 652 nm Copper Vapour pumped dye laser (data not shown) with no significant difference between the two sources. After most treatments, there was an immediate increase in tumour diameter that regressed after approximately 24 h. This oedema is a shortlived inflammatory response due more to the insertion of the fibre than PDT and has also been observed with other photosensitisers in this model (Cruse-Sawyer et al, 1998).…”

31P magnetic resonance spectroscopy as a predictor of efficacy in photodynamic therapy using differently charged zinc phthalocyanines

“…To date there have been few studies of neutral photosensitizers, in part because of problems with water-solubility. Similar results were found for comparison of the same or similar sensitizers in a transplanted fibrosarcoma in the rat (Cruse-Sawyer et al, 1998). Both this study and the recent study referred to above (Cruse-Sawyer et al, 1998) have suggested that the cationic phthalocyanine is the most effective in PDT.…”

“…Similar results were found for comparison of the same or similar sensitizers in a transplanted fibrosarcoma in the rat (Cruse-Sawyer et al, 1998). Both this study and the recent study referred to above (Cruse-Sawyer et al, 1998) have suggested that the cationic phthalocyanine is the most effective in PDT. It was not possible to determine octanol:water partition coefficients because, for each sensitizer, almost all of the sensitizer was found in the aqueous layer.…”

“…We have developed a series of novel photosensitizers based on zinc(II) phthalocyanine, rendered water-soluble by appropriate substitution at the periphery of the molecule (Cruse-Sawyer et al, 1998). Three such sensitizers are of particular interest in mechanistic terms, since they contain negatively charged, positively charged and neutral peripheral groups respectively (Figure 1).…”

Decreased Efficiency of Trypsinization of Cells Following Photodynamic Therapy: Evaluation of a Role for Tissue Transglutaminase¶

“…The response of cells to photodynamic therapy (PDT) † appears to depend on a number of factors, one of which is the ¶Posted on the website on 22 sensitizer used. Following the development of Photofrin , numerous so-called second generation sensitizers have been developed which have shown good activity in vitro and in vivo (1)(2)(3). Charge and hydrophobicity appear to be the main factors governing cellular localization (1), with localization being the major determinant of cell death (2,4).…”