Mitochondrial photodamage in photodynamic therapy (PDT) has been reported to play an integral role in the induction of apoptosis. Hence, the photodynamic activity of photosensitizers can be improved by delivering them to the mitochondria of cancer cells. Epithelial cancer cells have higher plasma and mitochondria membrane potentials compared to normal cells, consequently delocalized lipophilic cations (DLCs) tend to accumulate more in them than in normal cells. This provides a strategy to selectively target cancer cells. Two conjugates: TPP-Rh (a porphyrin- rhodamine B conjugate) and TPP-AO (a porphyrin-acridine orange conjugate), each possessing a single delocalized lipophilic cation were synthesized as mitochondria targeting photosensitizers. The conjugates were synthesized by conjugating a monohydroxy porphyrin (TPP-OH) to rhodamine B (Rh B) and acridine orange base (AO) respectively via a saturated hydrocarbon linker. To evaluate the efficiency of the conjugates as photosensitizers for PDT, the photophysical properties and the in vitro photodynamic activities of the conjugates were studied in comparison to those of TPP-OH. Although fluorescence energy transfer was observed in the conjugates, they were capable of generating singlet oxygen at rates comparable to TPP-OH. Biologically, whereas the two conjugates showed high phototoxicities (TPP-AO IC50 = 3.28; TPP-Rh IC50 = 3.95), upon irradiation with a water-filtered halogen light source (3 mW/cm2 for 1 hour, 10.8 J/cm2), no significant phototoxicity was observed in cells treated with up to 20 \#956;M of TPP-OH. This was most probably due to the much greater cellular uptake of the conjugates compared to that of TPP-OH (all conjugates showed at least an 8 fold greater uptake than TPP-OH). Furthermore, whereas TPP-OH was accumulated in the lysosomes, the conjugates seemed to accumulate more in the mitochondria. Thus, conjugating TPP-OH to Rh B and AO respectively did improve its cellular uptake and in vitro photodynamic activity.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 633.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO