Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release.
Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release.
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DOI：
10.1021/bc9005656
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发表时间：
2010-05-19
影响因子：
4.7
通讯作者：
Ojima, Iwao
中科院分区：
文献类型：
--
作者：
Chen, Shuyi;Zhao, Xianrui;Chen, Jingyi;Chen, Jin;Kuznetsova, Larisa;Wong, Stanislaus S.;Ojima, Iwao
基于肿瘤特异性维生素受体介导的内吞作用，开发了一种有效的基于机制的肿瘤靶向给药系统。肿瘤靶向药物递送系统是肿瘤靶向分子（生物素：维生素H或维生素B-7）、基于机制的自分解连接体和作为细胞毒性剂的第二代紫杉烷（SB-T-1214）的缀合物。该缀合物（1）被设计为（i）对肿瘤细胞表面上过表达的维生素受体具有特异性，（ii）通过受体介导的内吞作用有效内化，随后通过谷胱甘肽触发的接头自分解而平稳释放药物。为了监控和验证假设的事件序列，即，受体介导的缀合物的内吞作用、药物释放和药物与靶蛋白（微管）的结合，设计并合成了三种荧光/荧光分子探针（2、3和4）。通过使用过表达生物素受体的L1210 FR白血病细胞的共聚焦荧光显微镜（CFM）和流式细胞术，明确证实了这些过程的实际发生。携带与荧光素连接的紫杉烷的分子探针4也用于检查细胞特异性（即，基于受体的细胞靶向的功效），L1210 FR（生物素受体过表达）、L1210（生物素受体未过表达）和WI 38（正常人肺成纤维细胞，生物素受体阴性）。如所预期的，分子探针4仅对L1210 FR表现出高特异性。为了确认探针4的细胞特异性药物递送和抗癌活性之间的直接相关性，还检查了其对这三种细胞系的细胞毒性。结果清楚地表明，两种方法之间有很好的相关性。以相同的方式，证实了缀合物1（没有荧光素附着到紫杉烷上）针对相同的三种细胞系的优异的细胞特异性细胞毒性。这种基于机制的肿瘤靶向给药系统将得到广泛的应用。
An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface, (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate, drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3 and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed) and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications.
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影响因子：
7.3
作者：
Ojima, I;Slater, JC;Bernacki, RJ
通讯作者：
Bernacki, RJ
影响因子：
15
作者：
Chen, Jingyi;Chen, Shuyi;Zhao, Xianrui;Kuznetsova, Larisa V.;Wong, Stanislaus S.;Ojima, Iwao
通讯作者：
Ojima, Iwao
影响因子：
15
作者：
Hong, R;Han, G;Rotello, VM
通讯作者：
Rotello, VM
影响因子：
11.2
作者：
Chu, Ted C.;Marks, John W., III;Levy, Matthew
通讯作者：
Levy, Matthew
DOI：
10.1073/pnas.0601755103
发表时间：
2006-04-18
影响因子：
11.1
作者：
Farokhzad, OC;Cheng, JJ;Langer, R
通讯作者：
Langer, R