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 (isoBOSINC) is a representative of a group of naphthalocyanine derivatives with spectral and photophysical properties that make them attractive candidates for photodynamic therapy (PDT). Tissue distributions were studied in tumor-bearing rats as a function of delivery system and time following administration. The tumor model was an N-(4-[5-nitro-2-furyl]-2-thiazolyl) formamide (FANFT)-induced urothelial cell carcinoma transplanted into one hind leg of male Fischer 344 rats; isoBOSINC was delivered 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% (Cremophor EL + propylene glycol) in saline (Cremophor). The isoBOSINC was isolated from several tissues and organs, as well as tumors and peritumoral muscles and skin. Quantitation was by a high-performance liquid chromatographic technique with detection that utilizes the native fluorescence of the naphthalocyanine derivative. Independent of the delivery system, the dye was retained in tumors at higher concentrations than in normal tissues, except for spleen and liver. The isoBOSINC retention in tumors was high and was vehicle dependent. For Tween, the maximal ratio of dye in tumor versus peritumoral muscle occurred 12 h after injection; for Cremophor, the maximal ratio occurred later, 336 h postinjection. When the drug was delivered in Tween, isoBOSINC in serum 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 tissues at later times with Cremophor as the vehicle. An interesting exception 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 after Cremophor delivery. Levels of dye were very low or not detectable in the brain. Optimal parameters for PDT of tumors with this novel photosensitizer are clearly time- and vehicle-dependent, and future PDT studies will need to incorporate these modulators.
Zuk
M M
MM
Research Department, St. Vincent Medical Center, Toledo, OH 43608-2691, USA.
Rihter
B D
BD
Kenney
M E
ME
Rodgers
M A
MA
Kreimer-Birnbaum
M
M
D000818:Animals; D016503:Drug Delivery Systems; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017646:Organosilicon Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D001749:Urinary Bladder Neoplasms / Q000473:pathology
D008665:Metalloporphyrins; D017646:Organosilicon Compounds; D017319:Photosensitizing Agents; C072758:bis(di-isobutyloctadecylsiloxy)silicon 2,3-naphthalocyanine