PHOTODYNAMIC ANTITUMOR AGENTS - BETA-METHOXYETHYL GROUPS GIVE ACCESS TO FUNCTIONALIZED PORPHYCENES AND ENHANCE CELLULAR UPTAKE AND ACTIVITY

Porphycene photosensitizers bearing two or four methoxyethyl side chai ns were synthesized in nine steps from commercially available starting materials. Ether cleavage led to (hydroxyethyl)- and (bromoethyl)porp hycenes that were converted to vinyl and benzo derivatives. Five of th e side chain-functionalized porphycenes were biologically studied in c omparison with two tetra-n-propylporphycenes. Porphycenes were incorpo rated in small unilamellar liposomes and incubated with cultivated SSK 2 murine fibrosarcoma cells. Cellular uptake and phototoxicity 24 h af ter 5 J/cm(2) laser light treatment were determined. The porphycenes t ested were between 17 and 220 times more photodynamically active than the currently clinically used sensitizer Photofrin, although extinctio n coefficients of the porphycenes' irradiated bands are only approxima tely 10-fold higher. The LD(50) concentration for SSK2 cells in the in cubation medium was as low as (8.5 +/- 2.8) x 10(-9) M for tetrakis(me thoxyethyl)porphycene. Two methoxy or hydroxy groups enhanced cellular uptake, three or four methoxy groups both enhanced and accelerated ce llular uptake of tetraalkylporphycenes. Half-life times of the uptake processes varied between (0.14 +/- 0.04) and (14 +/- 4) h and cellular saturation levels between (1.2 +/- 0.2) and (26 +/- 3) pmol/10(5) cel ls. When individual uptake rates were accounted for, all porphycenes h ad a similar ''cellular'' phototoxicity, pointing toward a common mech anism of action. Evidence is presented for the assumption that cell me mbranes are the primary targets of the tested porphycenes and that mem brane solubility may play a critical role in their photodynamic effici ency. The results show that nonionic polar side chain functionalities can strongly enhance cellular uptake and antitumor activity of lipophi lic porphyrinoids and thus that the known lipophilicity/activity relat ionship can be reversed for very hydrophobic sensitizers.