Polymeric photosensitizer prodrugs for photodynamic therapy
Polymeric photosensitizer prodrugs for photodynamic therapy
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DOI：
10.1111/j.1751-1097.2007.00090.x
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发表时间：
2007-07-01
影响因子：
3.3
通讯作者：
Lange, Norbert
中科院分区：
文献类型：
--
作者：
Campo, Marino A.;Gabriel, Doris;Lange, Norbert
基于病理组织内聚合物光敏剂前药（PPP）的选择性酶介导的活化的靶向策略已经导致具有检测和治疗癌症的双重能力的药剂的开发。在此，描述了这些前药的简单模型系统的详细研究。我们通过直接将光敏剂（PS）脱镁叶绿酸a经由N-异丙基酰胺键连接到聚（L）-赖氨酸来制备“第一代”PPP，并且观察到通过增加聚合物链上的PS的数量，PS单元之间的能量转移得到改善，从而导致更好的猝灭效率。通过胰蛋白酶消化的PPP主链的片段化引起显著的荧光增加，并且在光照射时更有效地产生活性氧。使用T-24膀胱癌细胞系的体外试验和使用小鼠肠的离体实验说明了这些PPP在酶激活后发荧光和诱导光毒性的显著和选择性能力。这项工作阐明了基本的物理化学参数，如水溶性和淬灭/活化行为，所需的未来制定更适应性的“第二代”PPP，其中PS是拴在一个蛋白水解稳定的聚合物骨架通过酶特异性肽接头。这种聚合物结构提供了很大的灵活性，可以定制PPP，以靶向任何已知过表达特定酶的病理组织。
A targeting strategy based on the selective enzyme-mediated activation of polymeric photosensitizer prodrugs (PPP) within pathological tissue has led to the development of agents with the dual ability to detect and treat cancer. Herein, a detailed study of a simple model system for these prodrugs is described. We prepared "first-generation" PPP by directly tethering the photosensitizer (PS) pheophorbide a to poly-(L)-lysine via epsilon amide links and observed that by increasing the number of PS on a polymer chain, energy transfer between PS units improved leading to better quenching efficiency. Fragmentation of the PPP backbone by trypsin digestion gave rise to a pronounced fluorescence increase and to more efficient generation of reactive oxygen species upon light irradiation. In vitro tests using the T-24 bladder carcinoma cell line and ex vivo experiments using mouse intestines illustrated the remarkable and selective ability of these PPP to fluoresce and induce phototoxicity upon enzymatic activation. This work elucidated the basic physicochemical parameters, such as water solubility and quenching/activation behavior, required for the future elaboration of more adaptable "second-generation" PPP, in which the PS is tethered to a proteolytically stable polymer backbone via enzyme-specific peptide linkers. This polymer architecture offers great flexibility to tailor make the PPP to target any pathological tissue known to over-express a specific enzyme.