Kiesslich Tobias, Berlanda Juergen, Plaetzer Kristjan, Krammer Barbara, Berr Frieder
Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, 5020, Salzburg, Austria.
Photochem Photobiol Sci. 2007 Jun;6(6):619-27. doi: 10.1039/b617659c. Epub 2007 Feb 26.
Due to the poor prognosis and limited management options for perihilar cholangiocarcinoma (CC) the development of alternatives for treatment is an important topic. Photodynamic therapy (PDT) with porfimer as palliative or neoadjuvant endoscopic treatment of non-resectable perihilar CC has improved quality of life and survival time, but cannot eradicate the primary tumors because of inadequate tumoricidal depth (4 mm only around the tumor stenoses). The use of meta-tetrahydroxyphenyl chlorin (mTHPC) and photoactivation at higher wavelengths (650-660 nm) provides high tumoricidal depth (10 mm) for PDT of pancreatic cancer and should yield similar tumoricidal depth in CC. This study investigates the photodynamic characteristics of mTHPC in solvent-based formulation (Foscan) and in liposomal (water soluble) formulation (Foslip) in an in vitro model system consisting of two biliary cancer cell lines (GBC, gall bladder cancer and BDC, bile duct cancer cells). Dark toxicity, photodynamic efficiency, time-dependent uptake and retention and intracellular localization of Foscan and Foslip were studied. The results prove mTHPC as a potent photosensitizing agent with high phototoxic potential in biliary cancer cells as a concentration of 600 ng ml(-1) and irradiation with 1.5 J cm(-2) (660 +/- 10 nm) is sufficient for about 90% cell killing. Addition of foetal bovine serum (FBS) to the incubation medium and analysis of the uptake and phototoxic properties reveals that both photosensitizer formulations bind to serum protein fractions, i.e. no difference between Foscan and Foslip can be found in the presence of FBS. Laser scanning fluorescence microscopy indicates a similar pattern of perinuclear localization of both sensitizers. This study demonstrates the potential of mTHPC for treatment of bile duct malignancies and provides evidence that Foslip is an equivalent water-soluble formulation of mTHPC that should ease intravenous application and thus clinical use of mTHPC.
由于肝门周围胆管癌（CC）预后较差且治疗选择有限，开发替代治疗方法是一个重要课题。以卟吩姆钠进行光动力疗法（PDT）作为不可切除肝门周围CC的姑息性或新辅助内镜治疗，已改善了生活质量和生存时间，但由于杀瘤深度不足（仅肿瘤狭窄周围4毫米），无法根除原发性肿瘤。使用间-四羟基苯基氯代卟啉（mTHPC）并在更高波长（650 - 660纳米）下进行光激活，可为胰腺癌的PDT提供较高的杀瘤深度（10毫米），并且在CC中应能产生相似的杀瘤深度。本研究在由两种胆管癌细胞系（GBC，胆囊癌细胞和BDC，胆管癌细胞）组成的体外模型系统中，研究了溶剂型制剂（Foscan）和脂质体（水溶性）制剂（Foslip）中mTHPC的光动力特性。研究了Foscan和Foslip的暗毒性、光动力效率、时间依赖性摄取和保留以及细胞内定位。结果证明，mTHPC作为一种有效的光敏剂，在胆管癌细胞中具有高光毒性潜力，因为600纳克/毫升的浓度和1.5焦/平方厘米（660±10纳米）的照射足以杀死约90%的细胞。向孵育培养基中添加胎牛血清（FBS）并分析摄取和光毒性特性表明，两种光敏剂制剂均与血清蛋白组分结合，即在存在FBS的情况下，Foscan和Foslip之间未发现差异。激光扫描荧光显微镜显示两种敏化剂的核周定位模式相似。本研究证明了mTHPC治疗胆管恶性肿瘤的潜力，并提供证据表明Foslip是mTHPC的等效水溶性制剂，应能简化mTHPC的静脉应用及临床使用。
