| Photodynamic therapy (PDT) requires three components for cytotoxicity: a photosensitizer, light, and oxygen. To selectively destroy cancer, a photosensitizer needs to be accumulated in tumor and to be locally activated by light to elicit a series of photochemical reactions. PhotofrinRTM is the only approved photosensitizer for clinical use. To avoid prolonged skin phototoxicity and bladder contracture, the feasibility of intravesical (i.b.) administration of Photofrin for whole bladder PDT was investigated in an orthotopic rat bladder tumor model. Second-generation photosensitizers with short elimination half-life or better tumor selectivity were examined for their photoefficiency and toxicity.; To establish an orthotopic rat bladder tumor model, tumor cells from the rat transitional cell carcinoma cell line AY-27, were instilled into rat bladders. Tumor growth was assessed by magnetic resonance imaging. Tumor take was close to 100%, the majority of tumors were superficial by 16 days. Rats bearing bladder tumors were treated with i.b. or i.v. Photofrin or 5-aminolevulinic acid (ALA). The biodistribution times for ALA were 2, 4, or 6 h, and for Photofrin, 4 h. The porphyrin fluorescence intensities, representative of photosensitizer levels within tumor, bladder wall and abdominal muscle were semi-quantitated by confocal microscopy. While both i.v. and i.b. drug administrations reached comparable tumor photosensitization, porphyrin fluorescence was detected only within tumor and urothelium after bladder instillation, sparing the bladder muscle.; Studies of whole bladder PDT of superficial bladder cancers demonstrated that i.b. instillation of Photofrin was as effective as i.v. injection, but with much less toxicity to the bladder and other organs. ALA-mediated PDT exerted similar tumor destruction to Photofrin after i.b. instillation. Interstitial PDT with multiple optical fibers in tumor broadens the application of PDT from superficial to solid tumors. Small, subcutaneous rat prostate and bladder tumors could be completely eliminated after ALA injection and 3000 J irradiation. Intraspheroid distribution, clonogenic assays, and photobleaching studies suggest that hypocrellins are promising second generation photosensitizers.; The orthotopic rat bladder tumor model is an ideal model system for pre-clinical evaluation of new treatments for bladder cancer. Intravesical instillation is an effective and safe route of drug administration for whole bladder PDT. |
