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Design of novel sensitizers and investigation of tumor targeting carrier systems for their applications in photodynamic therapy

新型敏化剂的设计及肿瘤靶向载体系统在光动力治疗中的应用研究

基本信息

批准号：
119930158
负责人：
Professor Dr. Bernd Epe
金额：
--
依托单位：
DWI - Leibniz-Institut für Interaktive Materialien e.V.
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/119930158?language=en
关键词：
Design novel sensitizers investigation tumor

项目摘要

The proposal aims at developing two new classes of photosensitizers, squaraines and croconaines, for application in the photodynamic therapy (PDT) of tumors. Preparatory work has demonstrated that the compounds have long wavelength absorption (>700 nm), good triplet yields, strong phototoxicity and little dark toxicity. The project involves the synthesis of various derivatives and the characterization of their photophysical and photochemical properties (absorption and fluorescence spectra, triplet and singlet oxygen yields, photoproducts). Selected compounds will then be attached to two types of delivery systems for the specific targeting of tumor cells, namely (i) folate-serum albumin conjugates and (ii) nanoparticles (block copolymer micelles) carrying a corona of oligonucleotides, to which folate is bound in the terminal position for receptor-mediated uptake. The loaded delivery systems will be characterized extensively. The cytotoxicity of the photosensitzers in the dark and under irradiation will be studied in various malignant (folate-receptor carrying) tumor cell lines and non-malignant comparisons, both with and without the delivery systems. Cellular uptake will be studied in co-cultures of normal and malignant cells using flow cytometric analysis (FACS). Determinations of (photo)genotoxicity and mechanistic studies will complement the efforts to establish the new drugs as candidates for future in vivo tests.

该提案旨在开发两种新的光敏剂，方酸碱和克可酸碱，用于肿瘤的光动力治疗（PDT）。前期工作表明，该类化合物具有长波长吸收（>700 nm）、良好的三重态产率、强的光毒性和小的暗毒性。该项目涉及各种衍生物的合成及其生物物理和光化学性质的表征（吸收和荧光光谱、三线态和单线态氧产率、光产物）。然后将选定的化合物连接到两种类型的递送系统，用于特异性靶向肿瘤细胞，即（i）叶酸-血清白蛋白缀合物和（ii）携带寡核苷酸冠的纳米颗粒（嵌段共聚物胶束），叶酸在末端位置结合到所述寡核苷酸冠以用于受体介导的摄取。将对装载的输送系统进行广泛表征。将在各种恶性（携带叶酸受体）肿瘤细胞系和非恶性比较中研究光敏剂在黑暗和辐照下的细胞毒性，包括使用和不使用递送系统。将使用流式细胞术分析（FACS）在正常和恶性细胞的共培养物中研究细胞摄取。（光）遗传毒性和机制研究的测定将补充建立新药作为未来体内试验候选药物的努力。