Liposomal meso-tetrakis-phenylporphyrin (TPP) was tested for photodynamic therapy (PDT) of human amelanotic melanomas implanted in nude mice. After intratumoural TPP application (15 mg.kg -1 ) followed by PDT lamp irradiation (600 -700 nm, 635 nm peak), tumours retained their original volume up to the 23rd day post-PDT, whereas volumes increased 6 times in controls. PDT with intravenously (i. Key words: photodynamic therapy; meso-tetrakis-phenylporphyrin; meso-tetrakis-sulfonatophenylporphyrin; nude mice; liposomal drug delivery; human amelanotic melanoma A substantial difference was found in photodynamic therapy (PDT) of tumours between the effects of hydrophobic vs. hydrophilic photosensitizers. Although exceptions exist, hydrophilic photosensitizers frequently destroy the tumour bed microvasculature, which results in vascular stasis, anoxia and tumour necrosis, 1-3 whereas the hydrophobic photosensitizers can penetrate deeply into cells and might cause better disintegration of their membranes and organelles, thus directly killing the tumour cells. 2 Hydrophobic porphyrins, once administered to patients, are tightly bound by serum low-density lipoproteins, 4 -6 which are preferentially internalized by receptor-mediated endocytosis in the hyperprolife-rating cells. 7,8 Hydrophobic photosensitizers could be advantageous even for topical PDT, since they keep their direct cell-killing effect. Liposome-mediated delivery might increase the efficacy of PDT. It also overcomes problems caused by the water insolubility of hydrophobic compounds. In particular, the small unilamellar vesicles are significantly taken up by skin and intestine. 9 Hence, liposomal preparations of photosensitizers have been studied quite frequently and were developed commercially. 6,10 -21 We tried to develop a liposomal form of a hydrophobic photosensitizer for both topical and intravenous application. The compound of our choice was meso-tetrakisphenylporphy-rin (TPP), the nonsulfonated derivative of meso-tetrakis-sulfonatophenylporphyrin, TPPS 4 . 23 TPPS 4 has been abandoned in human medicine for some years due to the reported neurotoxicity after intraperitoneal application. 24 Later, these problems were solved by a better purification of the product. For example, Jirsa et al. 25 have synthesized pure TPPS 4 that did not delay motor nerve conduction velocity in rats or rabbits even in high doses. 26 Recently, we have also shown that hydrophobic TPP (nonsulfonated TPPS 4 ) in lipid environment is also the efficient singlet oxygen producer. 27 Even being shielded by lipid headgroups, TPP in a membrane interacts with the native oxygen solubilized in the surrounding aqueous space. Moreover, we have demonstrated the reducing decay rate of triplet-states of TPP in the membrane system, which can be due to an irreversible interaction of the singlet oxygen formed in the previous reaction cycle with the membrane lipids. 27 All these results demonstrated on the physicochemical basis a possible potential of the liposomal form of TPP to destroy the me...
Photodynamic therapy (PDT) has entered an era of clinical acceptance; however, for its wider use, including drug formulations for topical applications, it must have a rapid effect and be free of skinphotosensitization effects. Preclinical studies of two prototype formulations exhibiting successful therapeutic rates based on translucent gels containing liposomes with hydrophobic photosensitizers are presented. Experimental PDT of human tumors implanted in nude mice with liposomal gels containing meso-tetrakisphenylporphyrin (TPP) or hydroxy-aluminum phthalocyanine (PC) caused significant dystrophy of human basal cell carcinoma, amelanotic melanoma, breast carcinoma, and colorectal carcinoma. Whereas the drug-to-light time interval for TPP was 12 h, much less than that of most commercially available approved photosensitizers, 10 min was sufficient to disintegrate the effects of the PC liposomal gel. Liposomes containing hydrophobic photosensitizers were prepared either by extrusion through 100-nm filters or using a microfluidizer. Histology of tumors in remission showed existence of overall necrosis and the presence of only small islets of tumorous cells in incomplete remission. Fibrinoid necrosis of the tumors was a visible sign of the therapeutic effect. TPP and PC from the gel were distributed by circulation to the organs and tissues in a different and more favorable pattern than by intravenous injection. We conclude that hydrophobic photosensitizers are preferable and more efficient for PDT (Ježek et al., Int J Cancer 103:693-702, 2003) and their liposomal gel formulations are predicted to be optimum preparations enabling wide ranging use of topical PDT for numerous cancer indications, initially for nonmelanoma skin cancer. Drug Dev Res 68: [235][236][237][238][239][240][241][242][243][244][245][246][247][248][249][250][251][252] 2007 r 2007 Wiley-Liss, Inc.
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