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.