Abstract
Zinc(II) phthalocyanine, a hydrophobic photosensitiser, was incorporated in unilamellar liposomes and studied in vivo for fluorescence kinetics and photodynamic activity. An observation chamber mounted in a dorsal skinfold of female WAG/Rij rats was used as a model system. In the chamber, an isogeneic mammary carcinoma was transplanted in the subcutaneous tissue. Phthalocyanine fluorescence was excited at 610 nm with a power density of 0.25 mW cm-2 and was detected above 665 nm through a high-pass filter using a two-stage image intensifier coupled to a charge-coupled device (CCD) camera. Following i.v. administration of 0.14 mg kg-1 of the drug, the fluorescence pharmacokinetics of the dye in vasculature, normal tissue and tumour tissue was determined as a function of time. Tumour fluorescence increased slowly to a maximum about 3 h post injection (p.i.), and remained well above the normal tissue fluorescence till 24 h p.i. Fluorescence in the circulation was always stronger than in the tissues. A treatment light dose at a wavelength of 675 nm was delivered 24 h p.i. One group of six animals received a total light dose of 150 J cm-2 (100 mW cm-2). A second group of six animals received a total light dose of 450 J cm-2 at the same dose rate. Vascular damage resulting from treatment was observed only at the final stages of the irradiation, despite the relatively high levels of fluorescence in the circulation. Immediate post-treatment (re)transplantation of the content of the chamber into the flank always resulted in tumour regrowth, confirming the presence of viable tumour cells following photodynamic therapy (PDT). When the chamber was left intact, the light dose of 450 J cm-2 yielded complete tissue necrosis. The role of the dye-carrier complex in shielding the vascular surrounding from photoproducts was studied in a third group of animals. The presence of peroxides was demonstrated in the serum of these animals after PDT with zinc phthalocyanine in liposomes (ZnPc-lip) using a total light dose of 450 J cm-2. This ex vivo observation supports the previously reported observations in vitro that the carrier complex is able to quench the photoproducts resulting from photoactivation of the photosensitiser which is present in the circulation.
Highlights
Phthalocyanines are being investigated as alternative photosensitisers for photodynamic therapy (PDT) (Ben-Hur & Rosenthal, 1986)
We describe the in vivo fluorescence kinetics of this drug-carrier complex and determine the in vivo effects of subsequent optical irradiation on tumour necrosis using a dorsal skinfold chamber model
The animal model permits observation of the pharmacokinetics of photosensitisers based on fluorescence and the assessment of vascular effects resulting from photodynamic therapy (Star et al, 1986; van Leengoed et al, 1990)
Summary
Female WAG/Rij rats (ITRI-TNO, Rijswijk, The Netherlands) 12-14 weeks of age were used. During a 3 week preparation period the animals were equipped with a skinfold chamber on their backs. The chamber includes a 0.5 mm layer of subcutaneous tissue, wedged between two transparent covers. An isogeneic mammary carcinoma was transplanted into the subcutaneous tissue of the chamber. The animal model permits observation of the pharmacokinetics of photosensitisers based on fluorescence and the assessment of vascular effects resulting from photodynamic therapy (Star et al, 1986; van Leengoed et al, 1990). Hypnorm (Janssen Pharmaceuticals, Beerse, Belgium) was used as a general anaesthetic during all procedures. In accordance with the Dutch law on animal experiments, the protocol was submitted to and approved by the animal experiments committee
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