GSH-Activatable NIR Nanoplatform with Mitochondria Targeting for Enhancing Tumor-Specific Therapy
GSH-Activatable NIR Nanoplatform with Mitochondria Targeting for Enhancing Tumor-Specific Therapy
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具有线粒体靶向功能的 GSH 可激活近红外纳米平台可增强肿瘤特异性治疗
DOI：
10.1021/acsami.9b15996
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发表时间：
2019
影响因子：
9.5
通讯作者：
Weian Zhang
中科院分区：
文献类型：
--
作者：
Guoliang Yang;Chao Chen;Yucheng Zhu;Zhiyong Liu;Yudong Xue;Sheng Zhong;Chaochao Wang;Yun Gao;Weian Zhang
开发对肿瘤特异性信号敏感的智能光敏剂，以最小的副作用和增强的抗肿瘤功效是肿瘤光疗法的巨大挑战。在此，我们构建了一个纳米平台与谷胱甘肽（GSH）激活和靶向的前光敏剂包封由超灵敏的pH响应聚合物实现成像引导的肿瘤特异性光动力学治疗（PDT）。GSH-可活化的前光敏剂，二花青（DCy 7），已经合成，其中两个花青部分通过二硫键共价缀合，并且疏水DCy 7进一步用两亲性pH响应性二嵌段共聚物POEGMA-b-PDPA封装以形成P @ DCy 7纳米颗粒。在被癌细胞内吞后，P @ DCy 7纳米颗粒首先在内体处解离，然后DCy 7被释放到细胞质中，随后被高浓度的GSH激活，最后靶向线粒体用于细胞器靶向PDT。此外，细胞内抗氧化剂GSH在激活过程中被消耗，这有利于有效的PDT。这些P@DCy7纳米颗粒在体外显示出对肿瘤细胞（HepG 2或4 T1细胞）超过正常细胞（BEAS-2B细胞）的选择性光毒性，并且在荷瘤小鼠中进一步证实了它们的GSH可活化增强的PDT功效。因此，P@DCy7纳米颗粒允许准确和高效的PDT，副作用最小，为细胞器靶向的精确PDT提供了有吸引力的纳米平台。
Developing smart photosensitizers that are sensitive to tumor-specific signals for minimal side effects and enhanced antitumor efficacy is a tremendous challenge for tumor phototherapies. Herein, we construct a nanoplatform with glutathione (GSH)-activatable and mitochondria-targeted pro-photosensitizer encapsulated by ultrasensitive pH-responsive polymer for achieving imaging-guided tumor-specific photodynamic therapy (PDT). The GSH-activatable pro-photosensitizer, di-cyanine (DCy7), has been synthesized where two cyanine moieties are covalently conjugated by a disulfide bond, and the hydrophobic DCy7 is further encapsulated with an amphiphilic pH-responsive diblock copolymer POEGMA-b-PDPA to form P@DCy7 nanoparticles. Upon endocytosis by cancer cells, P@DCy7 nanoparticles dissociate at endosome first and then DCy7 is released to cytoplasm and subsequently activated by the high concentration of GSH, finally targets mitochondria for organelle-targeted PDT. Moreover, intracellular antioxidant GSH is consumed during the activation procedure that is beneficial to efficient PDT. These P@DCy7 nanoparticles display selective phototoxicity against tumor cells (HepG2 or 4T1 cells) over normal cells (BEAS-2B cells) in vitro, and their GSH-activatable enhanced PDT efficacy is further confirmed in tumor-bearing mice. Thus, P@DCy7 nanoparticles allow for accurate and highly efficient PDT with minimal side effects, providing an attractive nanoplatform for organelle-targeted precise PDT.