Evaluation of the third generation photosensitiser SC102 in two animal models

SC102, a poly(ethylene glycol) (PEG-2000) derivative of the second generati on photosensitiser temoporfin (Foscan), was evaluated for photodynamic acti vity utilising two standard animal models: the rabbit, inoculated with the cottontail rabbit papilloma virus (CRPV) and the healthy canine larynx. Opt imal drug dose and drug-light interval (DLI) were determined in a series of pharmacokinetic experiments using SC102 administered intravenously at dose s of 3 and 30 mg/kg in our standard CRPV rabbit model. Plasma pharmacokinet ics in the rabbit showed an elimination half-life of 121+/-20 h. Peak tumou r concentration occurred at 144 h for the 3 mg/kg group and at 240 h for th e 30 mg/kg group. The disposition ratio of SC102 between tumour to healthy tissue, at peak tumour levels, was approximately 4 to 1 for both dose level s. Skin tolerance to increasing 652 nm wavelength fluences was excellent. E ven in those rabbits given a 30 mg/kg SC102 dose, no significant damage to the skin was observed, even when a fluence of 160 J/cm(2) was applied at th e optimal drug-light interval of 10 days. Tumour efficacy of SC102 PDT was evaluated in rabbits previously inoculated , with CRPV. One time photoactivation of a single 30 mg/kg dose of SC102 at a DLT of 10 days using a fluence of 100 J/cm(2) achieved a complete tumour clearance rate of 35%. Two-time photoactivation on days 6 and 10 after sin gle administration of the same dose in a separate group of rabbits, using a fluence of 75 J/cm(2) on both occasions, yielded an improved cure rate of 58%. Evaluation of normal tissue tolerance to SC102 PDT was also investigated in the healthy dog larynx model 10 days after an intravenous dose of 30 mg/kg SC102. A fluence of 200 J was determined to be the maximum tolerated dose at which time there was a 4:1 ratio of SC102 between laryngeal mucosa and m uscle. The photophysical and pharmacokinetic profiles of SC102 show signifi cant differences from those of Foscan from which it is derived. In these pr eliminary in vivo experiments we have demonstrated the outstanding toleranc e of normal tissues to SC102 PDT using high fluences. We have also shown tu mour efficacy with light doses readily achievable in the clinical setting. Disposition of SC102 in the skin is low and photosensitivity risk may disap pear within the drug-light interval. Based on these conclusions we believe SC102 PDT may have potential utility as an adjunct to surgical resection of tumours necessitating wide field exposure of normal tissue to activating l ight.