Sono-activatable Photosensitizer for Photodynamic Therapy

Abstract

A carboxy tetraphenylporphyrin derivative formed aggregate by decreasing its pH, and suppressed its fluorescence and sensitization of singlet oxygen. This indicates that ON/OFF switching of the photosensitization can be achieved by aggregation and disaggregation of photosensitizers. To induce disaggregation, ultrasound was applied to the solution of the aggregate of photosensitizers, and disaggregation was confirmed by studying the fluorescence of the photosensitizer and phosphorescence of singlet oxygen sensitized. Thus this system works as a sono-activatable photosensitizer for photodynamic therapy.Photodynamic therapy (PDT) is known as a promising cancer treatment. PDT is expected to show lower side effects than conventional major treatments for cancer such as surgery, chemotherapy, and radiotherapy. PDT is based on light irradiation and injection of photosensitizer which are preferentially taken up and/or retained by tumors. To develop PDT, improvements of photosensitizer are indispensable. Mainly, there are two methods to improve photosensitizers. The first is improvement of activity. Factors controlling the activity of a photosensitizer 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 Φ ¦ . Many studies have been devoted to improve these factors.14 We have also improved photosensitizers by introducing silyl groups into tetraphenylporphyrin derivatives and clarified that silylation improves Φ ¦ , 57 cellular uptake efficiency, 6,7 and selective accumulation efficiency to tumors, 7 simultaneously. As a result of these improvements, we confirmed the enhancement of in vivo PDT activity by using tumorbearing mice. 7 The second method is to reduce side effects. Photosensitizers themselves show no side effects in the dark. During treatment, the tumor is irradiated with intense light as a trigger to kill cancer cells. However, patients are also exposed to this trigger in daily life (room light and/or sunlight). Although the photosensitizer used for PDT possesses tumor selectivity, its concentration is not negligibly small in normal tissue such as skin. Thus patients have to remain in a dark room until almost all the photosensitizers injected are eliminated. The period for staying in the dark room is usually one week for NPe6, and one month for Photofrinμ. These long periods are one of the reasons for hesitation in selecting PDT as a cancer treatment. There are two strategies to reduce this side effect. The first is to reduce concentration of photosensitizer in normal tissue, i.e., improvement of tumor selectivity. Various kinds of drug delivery systems have been developed not only for photosensitizers but also for anticancer agents. Silylation of porphyrin derivatives is also a method to improve tumor selectivity. 7 The second strategy is to introduce an ON/OFF switch on the photosensitizer. This activatable photosensitizer should not sensitize singlet oxygen in the normal condition (OF...

pH-Response Optimization of Amino-Substituted Tetraphenylporphyrin Derivatives as pH-Activatable Photosensitizers

“…However, one or more trigger(s) change their chemical properties, leading to the recovery of Φ Δ (ON state). As activation triggers, the binding to DNA, − enzyme, − low pH, − and external stimuli such as ultrasound have attracted much attention.…”