Laville Isabelle, Pigaglio Sophie, Blais Jean-Claude, Doz François, Loock Bernard, Maillard Philippe, Grierson David S, Blais Jocelyne
BIOMOCETI, UMR CNRS 7033/Université Pierre et Marie Curie, 4 place Jussieu, F-75252 Paris Cedex 05, France.
J Med Chem. 2006 Apr 20;49(8):2558-67. doi: 10.1021/jm0580151.
Photodynamic therapy (PDT) is emerging as a new strategy for the conservative treatment of hereditary retinoblastoma. The glycoconjugated porphyrins TPP(p-Deg-O-alpha-GalOH)(3), TPP(p-Deg-O-beta-GalOH)(3), TPP(p-Deg-O-alpha-ManOH)(3), and their S-analogues were synthesized to obtain efficient photosensitizers with some retinoblastoma cell affinity. In these systems, a sugar motif and porphyrin core were linked by a diethylene glycol spacer (Deg). Cellular uptake, localization, and photoactivity have been examined in human retinoblastoma cells (Y79). After preincubation with corresponding glycosylated albumin, the uptake of TPP(p-Deg-O-beta-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) was 40-45% inhibited, indicating a possible cell-sugar-receptor saturation. High photoactivity was observed for the two alpha-galacto/manno porphyrins 8 and 10 (LD(50) = 0.05 and 0.35 muM, respectively) at 514 nm and low fluence (1 J/cm(2)). Analysis by MALDI-TOF mass spectrometry only indicated a small metabolic cleavage of the O-glycoconjugates and a good stability of the S-glycoside porphyrins. On the basis of these in vitro data, TPP(p-Deg-O-alpha-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) were selected for in vivo studies.
光动力疗法（PDT）正在成为遗传性视网膜母细胞瘤保守治疗的一种新策略。合成了糖缀合卟啉TPP(p-Deg-O-α-GalOH)(3)、TPP(p-Deg-O-β-GalOH)(3)、TPP(p-Deg-O-α-ManOH)(3)及其S-类似物，以获得对某些视网膜母细胞瘤细胞具有亲和力的高效光敏剂。在这些体系中，糖基序和卟啉核心通过二甘醇间隔基（Deg）相连。已在人视网膜母细胞瘤细胞（Y79）中检测了细胞摄取、定位和光活性。在用相应的糖基化白蛋白预孵育后，TPP(p-Deg-O-β-GalOH)(3)和TPP(p-Deg-O-α-ManOH)(3)的摄取受到40-45%的抑制，表明可能存在细胞-糖-受体饱和。在514nm和低通量（1J/cm²）下，观察到两种α-半乳糖/甘露糖卟啉8和10具有高光活性（LD(50)分别为0.05和0.35μM）。基质辅助激光解吸电离飞行时间质谱分析仅表明O-糖缀合物有少量代谢裂解，而S-糖苷卟啉具有良好的稳定性。基于这些体外数据，选择TPP(p-Deg-O-α-GalOH)(3)和TPP(p-Deg-O-α-ManOH)(3)进行体内研究。
