EFFECT OF DELIVERY SYSTEM ON THE PHARMACOKINETICS AND TISSUE DISTRIBUTION OF BIS(DI-ISOBUTYL OCTADECYLSILOXY)SILICON 2,3-NAPHTHALOCYANINE (ISOBOSINC), A PHOTOSENSITIZER FOR TUMOR-THERAPY

Bis(di-isobutyl octadecylsiloxy)silicon 2,3-naphthalocyanine (isoBOSIN C) is a representative of a group of naphthalocyanine derivatives with spectral and photophysical properties that make them attractive candi dates for photodynamic therapy (PDT). Tissue distributions were studie d in tumor-bearing rats as a function of delivery system and time foll owing administration. The tumor model was an N-(4-[5-nitro-2-furyl]-2- thiazolyl) formamide (FANFT)-induced urothelial cell carcinoma transpl anted into one hind leg of male Fischer 344 rats; isoBOSINC was delive red to the rats by intravenous injection of 0.50 mg/kg of body weight as a suspension either in 10% Tween 80 in saline (Tween) or 10% (Cremo phor (R) EL + propylene glycol) in saline (Cremophor). The isoBOSINC w as isolated from several tissues and organs, as well as tumors and per itumoral muscles and skin. Quantitation was by a high-performance liqu id chromatographic technique with detection that utilizes the native f luorescence of the naphthalocyanine derivative, Independent of the del ivery system, the dye was retained in tumors at higher concentrations than in normal tissues, except for spleen and liver. The isoBOSINC ret ention in tumors was high and was vehicle dependent. For Tween, the ma ximal ratio of dye in tumor versus peritumoral muscle occurred 12 h af ter injection; for Cremophor, the maximal ratio occurred later, 336 h postinjection. When the drug was delivered in Tween, isoBOSINC in seru m showed two compartment kinetics: half-lives of about 2 and 11 h were found for the distribution and the elimination phases, respectively. When Cremophor was the vehicle, the elimination half-life was about 20 h, and one compartment kinetics was observed. The latter findings may explain the generally higher levels of the dye attained by the tissue s at later times with Cremophor as the vehicle. An interesting excepti on was that after 7 and 14 days postinjection in Tween, the levels of dye found in testes were six- to seven-fold higher than those found af ter Cremophor delivery. Levels of dye were very low or not detectable in the brain. Optimal parameters for PDT of tumors with this novel pho tosensitizer are clearly time- and vehicle-dependent, and future PDT s tudies will need to incorporate these modulators.