Herein, we report the synthesis of a new prodrug system consisting of regioselectively addressable functionalized templates bearing multiple pheophorbide A moieties for use in photodynamic therapy. These coupling reactions were achieved using copper-free “click” chemistry, namely a strain-promoted azide–alkyne cycloaddition. This new design was used to obtain well-defined quenched photosensitizer prodrugs with perfect knowledge of the number and position of loaded photosensitizers, providing structures bearing up to six photosentitizers and two PEG chains. These conjugates are ideally quenched in their native state regarding their fluorescence emission (up to 155 ± 28 times less fluorescent for an hexasubstituted conjugate than a monosubstituted non-quenched reference compound) or singlet oxygen production (decreased 8.7-fold in the best case) when excited. After 2 h of proteolytic activation, the fluorescence emission of a tetrasubstituted conjugate was increased 17-fold compared with the initial fluorescence emission.

中文翻译：

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环肽光敏剂前药作为脱镁脱镁叶绿酸A的蛋白水解触发药物递送系统：第一部分–自淬灭前药†

在本文中，我们报告了一种新的前药系统的合成，该系统由用于光动力学治疗的带有多个脱镁叶绿酸A部分的区域选择性可寻址功能化模板组成。这些偶联反应是通过无铜“点击”化学反应完成的，即应变促进的叠氮化物-炔烃环加成反应。这种新设计用于获得定义明确的淬灭型光敏剂前药，并且对所装载的光敏剂的数量和位置具有完备的知识，可提供最多包含六个光敏剂和两个PEG链的结构。这些缀合物在其荧光发射方面理想地以其天然状态淬灭（六取代的缀合物的荧光比单取代的非猝灭参比化合物少高达155±28倍）或单线态氧产生（降低8）。兴奋时最好的情况是7倍）。蛋白水解激活2小时后，四取代缀合物的荧光发射与初始荧光发射相比增加了17倍。