Phototriggerable 2′,7-Caged Paclitaxel

Three different variants of photoactivatable caged paclitaxel (PTX) have been synthesized and their bioactivity was characterized in in vitro assays and in living cells. The caged PTXs contain the photoremovable chromophore 4,5-dimethoxy-2-nitrobenzyloxycarbonyl (Nvoc) attached to position C7, C2' and to both of these positions via a carbonate bond. Single caged PTXs remained biologically active even at low dosages. Double caging was necessary in order to fully inhibit its activity and to obtain a phototriggerable PTX that can be applied successfully at commonly used concentrations. Irradiation of solutions containing the double caged PTX allowed dose-dependent delivery of functional PTX. Light-triggered stabilization of microtubule assemblies in vitro and in vivo by controlled light exposure of tubulin solutions or cell cultures containing caged PTX was demonstrated. Short light exposure under a fluorescence microscope allowed controlled delivery of free PTX during imaging.

本研究合成了三种不同的光活化笼状紫杉醇（photoactivatable caged paclitaxel，简称PTX）变体，并通过体外实验与活细胞实验对其生物活性开展了系统表征。该类笼状紫杉醇通过碳酸酯键，将光可移除生色团4,5-二甲氧基-2-硝基苄氧羰基（Nvoc）分别连接于C7、C2'位点，或同时修饰于两个位点。单笼化紫杉醇即便在低剂量条件下仍可保留生物活性；若要完全抑制其活性，则需采用双笼化修饰策略，以此获得可光触发激活的紫杉醇衍生物，且该产物可在常规使用浓度下顺利应用。对含双笼化紫杉醇的溶液进行辐照，可实现活性紫杉醇的剂量依赖性释放。本研究证实，通过对微管蛋白溶液或含笼状紫杉醇的细胞培养物进行可控光照射，可在体外与体内实现微管组装的光触发稳定作用。在荧光显微镜下进行短时间光照射，即可在成像过程中可控释放游离紫杉醇。