Tissue localization of photosensitizers and the mechanism of photodynamic tissue destruction.

Abstract

This paper outlines our present knowledge of photosensitizer tissue distribution, derived from preclinical animal studies, and relates it to the observed biological response to photodynamic therapy (PDT). Emphasis is placed on porphyrins (haematoporphyrin derivative (HpD), Photofrin II) and phthalocyanines (aluminum phthalocyanine sulphonate AlPcS). In mice, both groups of sensitizers show multiphasic plasma clearance kinetics with an initial rapid decline followed by further slow reduction. Residual amounts of Photofrin II are detectable 75 days after injection. Drug elimination occurs through urine and faeces, but faecal elimination predominates for Photofrin II. Circulating sensitizer greatly influences the mouse ear-swelling response, but not the foot response. Tumours and normal skin can be destroyed by vascular damage, if illumination occurs at times of maximal plasma sensitizer concentration, with no detectable sensitizer accumulation in tumour cells. Organ retention for both photosensitizer groups is similar and persistent. Organs rich in reticuloendothelial elements (liver, kidney, spleen) accumulate and retain the highest levels, skin and muscle the lowest, while normal brain tissue excludes sensitizer. The adrenal and pancreatic glands, as well as urinary bladder, also retain high amounts of Photofrin II. Tumour/skin ratios of 1 to 3:1 and 2 to 7:1 have been reported for porphyrins and sulphonated phthalocyanines respectively. Tissue destruction upon light exposure is not always correlated with photosensitizer levels, as is exemplified by liver and pancreas. Stromal sensitizer localization usually predominates in tumour and normal tissue, and often determines tumour response. Certain compounds, such as monosulphonated tetraphenylporphyrin and AlPcS, may favour parenchymal localization. The formed blood elements remain free of photosensitizer, while mast cells and macrophages accumulate especially large amounts and, upon illumination, release an array of vasoactive inflammatory and immune mediators.