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Hyperbranched Polyglycerol Loaded with (Zinc-)Porphyrins: Photosensitizer Release Under Reductive and Acidic Conditions for Improved Photodynamic Therapy
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-12-12 00:00:00 , DOI: 10.1021/acs.biomac.7b01485 Michael H. Staegemann 1, 2 , Susanna Gräfe 2 , Burkhard Gitter 2 , Katharina Achazi 1 , Elisa Quaas 1 , Rainer Haag 1 , Arno Wiehe 1, 2
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-12-12 00:00:00 , DOI: 10.1021/acs.biomac.7b01485 Michael H. Staegemann 1, 2 , Susanna Gräfe 2 , Burkhard Gitter 2 , Katharina Achazi 1 , Elisa Quaas 1 , Rainer Haag 1 , Arno Wiehe 1, 2
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An adaptable approach toward cleavable nanoparticle carrier systems for photodynamic therapy (PDT) is presented, comprising a biocompatible carrier loaded with multiple photosensitizer (PS) molecules related to the clinically employed PS Temoporfin, two linkers cleavable under different triggers and glyco-targeting with mannose. A synthetic pathway to stimuli responsive hyperbranched polyglycerol (hPG) porphyrin conjugates via the copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) or the strain-promoted alkyne–azide cycloaddition (SPAAC) has been developed. The PS 10,15,20-tris(3-hydroxyphenyl)-5-(2,3,4,5,6-pentafluorophenyl)porphyrin was functionalized with disulfide containing cystamine and acid-labile benzacetal linkers. Conjugates with reductively and pH labile linkers were thus obtained. Cleavage of the active PS agents from the polymer carrier is shown in several different release studies. The uptake of the conjugates into the cells is demonstrated via confocal laser scanning microscopy (CLSM) and flow cytometry. Finally, the antitumor and antibacterial phototoxicity of selected conjugates has been assessed in four different tumor cell lines and in cultures of the bacterium Staphylococcus aureus. The conjugates exhibited phototoxicity in several tumor cell lines in which conjugates with reductively cleavable linkers were more efficient compared to conjugates with acid-cleavable linkers. For S. aureus, strong phototoxicity was observed for a combination of the reductively cleavable and the pH labile linker and likewise for the cleavable conjugate with mannose targeting groups. The results thus suggest that the conjugates have potential for antitumor as well as antibacterial PDT.
中文翻译：
含（锌）卟啉的超支化聚甘油：在还原和酸性条件下释放光敏剂，以改善光动力疗法
提出了一种适用于光动力疗法（PDT）的可裂解纳米颗粒载体系统的适应性方法，该方法包括生物相容性载体，该载体负载了与临床使用的PS Temoporfin有关的多个光敏剂（PS）分子，两个在不同触发条件下可裂解的连接子以及以甘露糖为靶标的糖。已经开发了通过铜（I）催化的1,3-偶极环加成（CuAAC）或应变促进的炔-叠氮化物环加成（SPAAC）来刺激响应性超支化聚甘油（hPG）卟啉缀合物的合成途径。PS 10,15,20-三（3-羟基苯基）-5-（2,3,4,5,6-五氟苯基）卟啉用含有胱胺和酸不稳定的苯乙缩醛连接基的二硫键官能化。由此获得具有还原性和pH不稳定的接头的缀合物。在几种不同的释放研究中显示了从聚合物载体上裂解活性PS剂。通过共聚焦激光扫描显微镜（CLSM）和流式细胞仪证明了缀合物被吸收到细胞中。最后，已在四种不同的肿瘤细胞系和细菌培养物中评估了所选结合物的抗肿瘤和抗菌光毒性。金黄色葡萄球菌。缀合物在几种肿瘤细胞系中表现出光毒性，其中与具有酸可裂解的接头的缀合物相比，具有可还原性裂解的接头的缀合物更有效。对于金黄色葡萄球菌，对于可还原裂解的和pH不稳定的接头的组合，以及对于具有甘露糖靶向基团的可裂解的缀合物，均观察到强烈的光毒性。因此结果表明，缀合物具有抗肿瘤和抗菌PDT的潜力。
更新日期：2017-12-12
中文翻译：
含（锌）卟啉的超支化聚甘油：在还原和酸性条件下释放光敏剂，以改善光动力疗法
提出了一种适用于光动力疗法（PDT）的可裂解纳米颗粒载体系统的适应性方法，该方法包括生物相容性载体，该载体负载了与临床使用的PS Temoporfin有关的多个光敏剂（PS）分子，两个在不同触发条件下可裂解的连接子以及以甘露糖为靶标的糖。已经开发了通过铜（I）催化的1,3-偶极环加成（CuAAC）或应变促进的炔-叠氮化物环加成（SPAAC）来刺激响应性超支化聚甘油（hPG）卟啉缀合物的合成途径。PS 10,15,20-三（3-羟基苯基）-5-（2,3,4,5,6-五氟苯基）卟啉用含有胱胺和酸不稳定的苯乙缩醛连接基的二硫键官能化。由此获得具有还原性和pH不稳定的接头的缀合物。在几种不同的释放研究中显示了从聚合物载体上裂解活性PS剂。通过共聚焦激光扫描显微镜（CLSM）和流式细胞仪证明了缀合物被吸收到细胞中。最后，已在四种不同的肿瘤细胞系和细菌培养物中评估了所选结合物的抗肿瘤和抗菌光毒性。金黄色葡萄球菌。缀合物在几种肿瘤细胞系中表现出光毒性，其中与具有酸可裂解的接头的缀合物相比，具有可还原性裂解的接头的缀合物更有效。对于金黄色葡萄球菌，对于可还原裂解的和pH不稳定的接头的组合，以及对于具有甘露糖靶向基团的可裂解的缀合物，均观察到强烈的光毒性。因此结果表明，缀合物具有抗肿瘤和抗菌PDT的潜力。
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