TARGETING OF THE TUMOR MICROCIRCULATION BY PHOTODYNAMIC THERAPY WITH A SYNTHETIC PORPHYCENE

-2,7,12,17-tetrakis-(beta-methoxyethyl)-porphycene (ATMPn) is a chemic ally pure substance with fast pharmacokinetics and superior photodynam ic properties in vitro as compared to Photofrin(R). In this study the pharmacokinetics, photodynamic efficacy and tissue localization of ATM Pn were investigated in vivo. Amelanotic melanomas (A-Mel-3) were impl anted in dorsal skin fold chambers fitted to Syrian Golden hamsters. F luorescence kinetics of ATMPn (1.4 mu mol kg(-1) b.w. i.v.; n = 8) wer e monitored by intravital microscopy. Quantitative measurements of flu orescence intensity were carried out by digital image analysis. For tu mor growth studies 1.4 mu mol kg(-1) was injected 24 h (n = 3), 3 h (n = 3), 1 min (n = 6) and 2.8 mu mol kg(-1) 1 min (n = 6) before PDT (L aser (630 nm) or lamp (600-750 nm), 100 mW cm(-2), 100 J cm(-2)). Tumo r volume was measured for 28 d. Solid tumors (n = 3) were excised 1 mi n after injection of ATMPn (2.8 mu mol kg(-1)) and cryostat sections ( 20 mm) were analyzed by confocal laser scanning microscopy (CLSM) for tissue localization of the dye. Maximal fluorescence (mean +/- S.E.) a rose in the tumor (94 +/- 7%) and surrounding host tissue (67 +/- 5%) 30 s post injection followed by a rapid decrease. Hardly any fluoresce nce was detectable 12 h after administration. Only PDT 1 min after inj ection of ATMPn was effective yielding 3/6 complete remissions (2.8 mm ol kg(-1), laser) and 6/6 complete remissions (2.8 mu mol kg(-1), lamp ), respectively. One minute after injection the dye is primarily local ized in the vascular wall of normal and tumor vessels as shown by CLSM . PDT at a time, when the dye is localized primarily in the tumor micr ocirculation, exhibits the best tumor killing effects showing that vas cular targeting is effective in treating solid malignant tumors. ATMPn in liposomes makes administration and light irradiation in one sessio n possible due to its fast pharmacokinetics. Thus, using ATMPn as a ph otosensitizer may provide more flexibility to perform PDT after surgic al exploration and debulking as adjuvant therapy. (C) 1997 Elsevier Sc ience S.A.