The biological activities of 5,15-diaryl-10,20-dihalogeno porphyrins for photodynamic therapy

Abstract

Purpose: Esophageal cancer is the most common gastrointestinal tumor and is difficult to be eradicated with conventional treatment. Porphyrin-based photosensitizers (PSs) mediated photodynamic therapy (PDT) could kill tumor cells with less damage to normal cells. As the most widely used porphyrin-based photosensitizer in clinics, Photofrin II has excellent anti-tumor effect. However, it has some disadvantages such as weak absorption at near infrared region, the complexity of components and prolonged skin photosensitivity. Here series novel 5,15-diaryl-10,20-dihalogeno porphyrin derivatives were afforded and evaluated to develop more effective and safer photosensitizers for tumor therapy.

Methods: The photophysical properties and singlet oxygen generation rates of 5,15-diaryl-10,20-dihalogeno porphyrins (I_1-6, II_1-4) were tested. The cytotoxicity of I_1-6 and II_1-4 were measured by MTT assay. The pathway of cell death was studied by flow cytometry. In vivo photodynamic efficacy of I₃ and II_2-4 in Eca-109 tumor-bearing BABL/c nude mice were measured and histopathological analysis were examined.

Results: 5,15-Diaryl-10,20-dihalogeno porphyrins I_1-6 and II_1-4 were synthesized. The longest absorption wavelength of these halogenated porphyrins (λ_max = 660 nm) displayed a red shift around 30 nm compared to the unhalogenated porphyrins PS₁ (λ_max = 630 nm). The singlet oxygen generation rates of I_1-6 and II_1-4 were significantly higher than PS₁ and HMME. All PSs mediated PDT showed obvious cytotoxic effect against Eca-109 cells compared to HMME in vitro and in vivo. Among these PSs, II₄ exhibited appropriate absorption in the phototherapeutic window, higher ¹O₂ generation rate (k = 0.0061 s^-1), the strongest phototoxicity (IC₅₀ = 0.4 μM), lower dark toxicity, high generation of intracellular ROS in Eca-109 cells and excellent photodynamic anti-tumor efficacy in vivo. Besides, cell necrosis was induced by compound II₄ mediated PDT.

Conclusion: All new compounds have obvious photodynamic anti-esophageal cancer effects. Among them, the photosensitizer II₄ showed excellent efficacy in vitro and in vivo, which has the potential to become a photodynamic anti-tumor drug.

Keywords: Anti-tumor; Halogenated porphyrin; Photodynamic therapy; Photosensitizer.