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

该提案旨在开发两类新的光敏剂，方英酮和crocones，用于肿瘤的光动力治疗（PDT）。前期工作表明，该化合物具有较长的波长吸收（> ~ 700nm）、良好的三态产率、较强的光毒性和较小的暗毒性。该项目涉及各种衍生物的合成及其光物理和光化学性质的表征（吸收和荧光光谱、三重态和单线态氧产率、光产物）。然后将选定的化合物附着在两种类型的递送系统上，以特异性靶向肿瘤细胞，即(i)叶酸-血清白蛋白偶联物和（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，用于受体介导的摄取。负载输送系统将被广泛地描述。光敏剂在黑暗和照射下的细胞毒性将在各种恶性（叶酸受体携带）肿瘤细胞系和非恶性比较中进行研究，包括有和没有传递系统。将使用流式细胞术分析（FACS）在正常和恶性细胞的共培养中研究细胞摄取。确定（照片）遗传毒性和机制研究将补充将新药作为未来体内试验候选药物的努力。

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.