Novel porphyrin conjugates with a potent photodynamic antitumor effect: differential efficacy of mono- and bis-beta-cyclodextrin derivatives in vitro and in vivo.
In the present study we investigated the photosensitizing properties of two novel mono- and bis-cyclodextrin tetrakis (pentafluorophenyl) porphyrin derivatives in several tumor cell lines and in BALB/c mice bearing subcutaneously transplanted syngeneic mouse mammary carcinoma 4T1. Both studied sensitizers were localized mainly in lysosomes and were found to induce cell death by triggering apoptosis in human leukemic cells HL-60. In 4T1 and other cell lines both apoptotic and necrotic modes of cell death occurred depending on drug and light doses. Mono-cyclodextrin porphyrin derivative P(beta-CD)1 exhibited stronger in vitro phototoxic effect than bis-cyclodextrin derivative P(beta-CD)2. However, in vivo P(beta-CD)2 displayed faster tumor uptake with maximal accumulation 6 h after application, leading to complete and prolonged elimination of subcutaneous tumors within 3 days after irradiation (100 J cm(-2)). In contrast, P(beta-CD)1 uptake was slower (48 h) and the reduction of tumor mass was only transient, reaching the maximum at the 12 h interval when a favorable tumor-to-skin ratio appeared. Thus, P(beta-CD)2 represents a new photosensitizing drug displaying fast and selective tumor uptake, strong antitumor activity and fast elimination from the body.
Kralova
Jarmila
J
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic. kralova@img.cas.cz
Synytsya
Alla
A
Pouckova
Pavla
P
Koc
Michal
M
Dvorak
Michal
M
Kral
Vladimir
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D017484:Dermatitis, Phototoxic / Q000188:drug therapy; D006801:Humans; D008247:Lysosomes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D047392:beta-Cyclodextrins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; D047392:beta-Cyclodextrins