Phthalocyanine Derivatives Possessing 2‑(Morpholin-4-yl)ethoxy Groups As Potential Agents for Photodynamic Therapy

Three 2-(morpholin-4-yl)­ethoxy
substituted phthalocyanines were
synthesized and characterized. Phthalocyanine derivatives revealed
moderate to high quantum yields of singlet oxygen production depending
on the solvent applied (e.g., in DMF ranging from 0.25 to 0.53). Their
photosensitizing potential for photodynamic therapy was investigated
in an in vitro model using cancer cell lines. Biological test results
were found particularly encouraging for the zinc­(II) phthalocyanine
derivative possessing two 2-(morpholin-4-yl)­ethoxy substituents in
nonperipheral positions. Cells irradiated for 20 min at 2 mW/cm2 revealed the lowest IC50 value at 0.25 μM
for prostate cell line (PC3), whereas 1.47 μM was observed for
human malignant melanoma (A375) cells. The cytotoxic activity in nonirradiated
cells of novel phthalocyanine was found to be very low. Moreover,
the cellular uptake, localization, cell cycle, apoptosis through an
ELISA assay, and immunochemistry method were investigated in LNCaP
cells. Our results showed that the tested photosensitizer possesses
very interesting biological activity, depending on experimental conditions.

本研究合成并表征了3种经2-(吗啉-4-基)乙氧基（2-(morpholin-4-yl)ethoxy）修饰的酞菁（phthalocyanine）衍生物。该类酞菁衍生物的单线态氧生成量子产率处于中等至较高水平，具体数值取决于所用溶剂：例如在N,N-二甲基甲酰胺（DMF）中，该值范围为0.25~0.53。本研究采用癌细胞系构建体外模型，评估了这类酞菁衍生物用于光动力治疗（photodynamic therapy）的光敏潜力。生物学测试结果显示，带有两个2-(吗啉-4-基)乙氧基取代基且取代位点为非周边位置（nonperipheral positions）的锌(II)酞菁（zinc(II) phthalocyanine）衍生物，其表现尤为优异。在功率密度2 mW/cm²下照射20分钟后，该衍生物对前列腺癌细胞系（PC3）的半最大效应浓度（IC50）最低，仅为0.25 μM；而对人恶性黑色素瘤细胞（A375）的IC50为1.47 μM。未经照射的细胞中，该新型酞菁衍生物的细胞毒活性（cytotoxic activity）极低。此外，本研究在LNCaP细胞中开展了多项实验，包括细胞摄取（cellular uptake）、亚细胞定位、细胞周期（cell cycle）分析、通过酶联免疫吸附测定（ELISA）检测细胞凋亡（apoptosis），以及免疫化学方法研究。本研究结果表明，所测试的光敏剂（photosensitizer）具备极具研究价值的生物学活性，其活性表现取决于具体的实验条件。