Feinweber Daniela, Verwanger Thomas, Brüggemann Oliver, Teasdale Ian, Krammer Barbara
Division of Molecular Tumor Biology, Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, 5020 Salzburg, Austria.
Photochem Photobiol Sci. 2014 Nov;13(11):1607-20. doi: 10.1039/c4pp00251b.
Two series of water soluble novel conjugates of the photosensitizer hypericin were prepared and evaluated for their use as agents for photodynamic therapy, with covalently and non-covalently loaded hypericin on functionalised, hydrolytically degradable inorganic-organic hybrid polyphosphazenes. The conjugates showed excellent aqueous solubility and similar fluorescence spectra to pristine hypericin. Detailed in vitro investigations revealed that the substances were non-toxic in the dark over a wide concentration range, but displayed phototoxicity upon irradiation. Cell uptake studies showed rapid uptake with localization of hypericin observed in endoplasmic reticulum, Golgi complex and particularly in the lysosomes. Furthermore, a DNA fragmentation assay revealed that the photosensitizer conjugates are efficient inducers of apoptosis with some tumor cell selectivity caused by faster and enhanced accumulation in A431 than in HaCaT cells, and thus a moderately higher phototoxicity of A431 compared to HaCaT cells. These novel photosensitizer conjugates hence represent viable hydrolytically degradable alternatives for the advanced delivery of hypericin.
制备了两系列水溶性新型金丝桃素共轭物，并评估了它们作为光动力治疗剂的用途，其中金丝桃素通过共价和非共价方式负载在功能化的、可水解降解的无机-有机杂化聚磷腈上。这些共轭物表现出优异的水溶性，并且荧光光谱与原始金丝桃素相似。详细的体外研究表明，这些物质在较宽的浓度范围内黑暗条件下无毒，但在光照时具有光毒性。细胞摄取研究表明摄取迅速，在内质网、高尔基体尤其是溶酶体中观察到金丝桃素的定位。此外，DNA片段化分析表明，这些光敏剂共轭物是有效的凋亡诱导剂，对某些肿瘤细胞具有选择性，这是由于在A431细胞中比在HaCaT细胞中积累更快且更多，因此与HaCaT细胞相比，A431细胞具有适度更高的光毒性。因此，这些新型光敏剂共轭物代表了用于金丝桃素高级递送的可行的可水解降解替代物。
