Double-targeting using a TrkC ligand conjugated to dipyrrometheneboron difluoride (BODIPY) based photodynamic therapy (PDT) agent.
Double-targeting using a TrkC ligand conjugated to dipyrrometheneboron difluoride (BODIPY) based photodynamic therapy (PDT) agent.
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DOI：
10.1021/jm4012142
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发表时间：
2013-10-10
影响因子：
7.3
通讯作者：
Burgess K
中科院分区：
文献类型：
--
作者：
Kamkaew A;Burgess K
分子1（IY-IY-PDT）被设计为含有靶向TrkC受体的片段（IY-IY）和充当光动力疗法（PDT）的药剂的光敏剂。分子1对经工程化以稳定表达TrkC（NIH 3 T3-TrkC）或天然表达高水平TrkC（SY 5 Y神经母细胞瘤系）的细胞具有亚微摩尔光细胞毒性。对照实验显示1在黑暗中没有细胞毒性，并且对不表达TrkC的细胞（NIH 3 T3-WT）具有显著更小的光细胞毒性。以类似试剂2（YI-YI-PDT）为特征的其他对照显示，1对TrkC+细胞的光细胞毒性显著高于2，所述类似试剂2与1相同且是异构体，不同之处在于靶向区域是乱序的（YI-YI基序，参见正文）。在用荧光剂1（IY-IY-PDT）处理后对活的TrkC+细胞进行成像，证明1渗透到TrkC+细胞中并定位在溶酶体中。该观察结果间接表明试剂1通过TrkC受体进入细胞。与此一致，1的剂量依赖性PDT效应可以被天然TrkC配体神经营养因子NT 3竞争性降低。
A molecule 1 (IY-IY-PDT) was designed to contain a fragment (IY-IY) that targets the TrkC receptor, and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule 1 had sub-micromolar photocytotoxicities to cells that were either engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SY5Y neuroblastoma lines). Control experiments showed 1 is not cytotoxic in the dark, and has significantly less photocytotoxicity towards cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent 2 (YI-YI-PDT) which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text) showed 1 is considerably more photocytotoxic than 2 on TrkC+ cells. Imaging live TrkC+ cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC+ cells and localizes in the lysosomes. This observation indirectly indicates agent 1 enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3.
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