A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo-photodynamic therapy
A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo-photodynamic therapy
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用于协同化学光动力疗法的肿瘤靶向 Ganetespib-锌酞菁结合物
DOI：
10.1016/j.ejmech.2018.03.077
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发表时间：
2018-05-10
影响因子：
6.7
通讯作者：
Zhao, Chunshun
中科院分区：
文献类型：
--
作者：
Huang, Liangfeng;Wei, Gaofei;Zhao, Chunshun
光动力学疗法（PDT）的治疗效果受到光敏剂（PS）选择性的限制。本研究开发了一种新型的肿瘤靶向药物-PS偶联物（Gan-ZnPc），该偶联物结合了锌酞菁（ZnPc）和Ganetespib。酞菁锌是一种很有前途的光敏剂。Ganetespib是一种热休克蛋白90（Hsp 90）抑制剂，具有优先的肿瘤选择性，并与ZnPc结合作为肿瘤靶向配体。多功能小分子缀合物Gan-ZnPc可以与细胞外Hsp 90结合，然后选择性地内化到肿瘤细胞中，随后在照射后产生丰富的细胞内活性氧（ROS）。此外，Gan-ZnPc可通过抑制Hsp 90而抑制细胞增殖并诱导细胞凋亡。在此，Gan-ZnPc结合Hsp 90的抑制和细胞毒性ROS的产生，以协同的方式实现肿瘤选择性、集中的PDT和化疗，这在体外和体内产生高效的抗肿瘤活性。(C)2018 Elsevier Masson SAS。All rights reserved.
Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo. (C) 2018 Elsevier Masson SAS. All rights reserved.