Developments of Porphyrin Derivatives As Photosensitizers for Photodynamic Therapy

Photodynamic therapy (PDT) is accepted as one of the promising treatments for cancers. In PDT, three individually nontoxic components (photosensitizer, light, and molecular oxygen) are combined only in tumor tissue to produce reactive oxygen species (ROS), particularly singlet oxygen. Thus the patient can improve the quality of life by PDT different from conventional therapies, such as radiotherapy, surgery or chemotherapy. To develop PDT, improvements of the photosensitizing drug are required. Mainly, there are two methods to improve photosensitizers. The first is improvement of photodynamic activity. The second method is to reduce side effects. Tetraphenylporphyrin (TPP) is one of the most fundamental photosensitizers for PDT and thus we have tried to improve its activity and also tried to suppress its side effects.

First, we have tried to improve the activity. Factors controlling the activity involve accumulation efficiency to tumors, cellular uptake efficiency, light absorption efficiency in the red to near-IR region, and quantum yield of singlet oxygen sensitization. We substituted silyl groups to water-soluble TPP derivatives, because silicon is considered to have potential for improving pharmacological and/or photochemical efficiencies. Quantum yield of singlet oxygen sensitization has evaluated by monitoring near-IR phosphorescence from singlet oxygen sensitized, and found that silylation improve the quantum yield. Cell-culture studies have been carried out to evaluate pharmacological properties. We found that silylation also improve cellular uptake efficiency. We carried out in vivo study by using tumor-bearing mice. Silylation also improve selective accumulation efficiency. As a results of these improvements, in vivo PDT activity was found to be enhanced by silylation significantly [1].

Second, we have tried to suppress the side effects. Although the photosensitizer used for PDT possesses tumor selectivity, its concentration is not negligibly small in normal tissue such as skin. Photosensitizers themselves show no side effects in the dark, but under the sun or room light, the side effect will be induced. Thus patients have to remain in a dark room until almost all the photosensitizers injected are eliminated. These long periods are one of the reasons for hesitation in selecting PDT as a cancer treatment. To suppress the side effects, we introduced ON/OFF switching mechanism to photosensitizers. We selected very simple modification i.e. just introduction of amino group(s) to phenyl moiety of TPP derivative to switch photosensitization efficiency by acidity. In the neutral condition, the photosensitization efficiency was low (OFF state) because of photo-induced electron transfer quenching from the aromatic amine moiety to porphyrin moiety. In the acidic condition, the photosensitization efficiency recovered (ON state) by the protonation of amino group. This system is expected to be as a pH-activatable photosensitizer.

[1] H. Horiuchi et al., Chem. Eur. J., (2014), 20, 6054.