New photodynamic therapy with next-generation photosensitizers

Abstract

Photodynamic therapy (PDT) is a non-invasive antitumor treatment that uses the combination of a photosensitizer, tissue oxygen, and visible light irradiation to produce cytotoxic reactive oxygen species, predominantly singlet oxygen. Currently, first-generation PDT using porfimer sodium with an excimer dye laser, and second-generation PDT using talaporfin sodium PDT with a semiconductor laser are approved by health insurance for use in Japan. However, the cancer cell specificity and selectivity of these treatments are inadequate. Cancer cells consume higher levels of glucose than normal cells and this phenomenon is known as the Warburg effect. Thus, we developed a third-generation PDT, based on the Warburg effect, by synthesizing a novel photosensitizer, sugar-conjugated chlorin, with increased cancer cell-selective accumulation. Glucose-conjugated chlorin (G-chlorin) PDT showed significantly stronger antitumor effects than second-generation talaporfin PDT. We also found that PDT with G-chlorin induced immunogenic cell death which is characterized by the secretion, release, or surface exposure of damage-associated molecular patterns (DAMPs), including calreticulin (CRT) and the high-mobility group box 1 (HMGB1) protein. Mannose-conjugated chlorin (M-chlorin) PDT which targets the mannose receptors on the surface of cancer cells and tumor-associated macrophages (TAMs) in cancer tissue stroma also showed very strong antitumor effects. These novel PDTs using glucose or M-chlorins stand as new candidates for very effective, next-generation PDTs.

Keywords: Photodynamic therapy (PDT); Warburg effect; chlorin; photosensitizer; tumor-associated macrophage (TAM).

Figure 1

A case of local recurrence of esophageal cancer after chemo-radio therapy cured by the use of talaporfin sodium PDT with a diode laser. PDT, photodynamic therapy; CRT, chemo-radio therapy.

Figure 2

Sugar-conjugated chlorins. (A) G-chlorin is a newly developed PDT photosensitizer that shows very strong antitumor effects. We synthesized a newly developed photosensitizer, G-chlorin, which is composed of chlorin conjugated with four molecules of glucose. By Warburg’s effect, cancer cell may uptake G-chlorin via glucose transporters, GLUT 1, 3 and 4. The lower table shows the PDT effects by talaporfin and G-chlorin against gastric cancer cells and colon cancer cells. As shown here, G-chlorin PDT showed very strong antitumor effects, being 20–50 times more cytotoxic than talaporfin PDT [IC 50: half maximal (50%) inhibitory concentration]; (B) the structure of M-chlorin and maltotriose-conjugated chlorin. We synthesized M-chlorin, which is composed of chlorin conjugated with 4 molecules of D-mannose (left). M-chlorin can target the TAMs as well as cancer cells. We also synthesized maltotriose-conjugated chlorin, which is composed of chlorin conjugated with four molecules of maltotriose (right). Maltotriose-conjugated chlorin has a hydrophilic nature. G-chlorin, glucose-conjugated chlorin; PDT, photodynamic therapy; M-chlorin, mannose-conjugated chlorin; TAMs, tumor-associated macrophages.

Figure 3

The roles of TAMs which exist in the stroma of cancer tissue (18). TAMs, tumor-associated macrophages.