State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Biomaterials. 2019 Aug;213:119219. doi: 10.1016/j.biomaterials.2019.05.030. Epub 2019 May 18.
Mitochondria-targeted photodynamic therapy (PDT) has emerged as one of the most efficient antitumor strategies. However, the therapeutic outcome of mitochondria-targeted PDT nanocarriers has been hampered by its poor capability of endosome escape and always-ON mode which induces normal tissue damage. To tackle these limitations, herein a novel pH-activatable nanoparticle is developed with dual-stage targeting capacity of early endosome and mitochondria for exponential activation of fluorescent signals and photodynamic efficacy. This nanoparticle is composed of pH-responsive mPEG-b-PDPA-Cy7.5 fluorescent copolymer and mitochondria-targeted photosensitizer (TPPa). The TPPa-encapsulated nanoparticles (M-TPPa) exhibit 111- and 151-fold enhancement in fluorescent signal and singlet oxygen generation (SOG) on encounting acidic pH environment, respectively. The M-TPPa can be quickly endocytosed by cancer cells and immediately dissociate at acidic early endosome to activate fluorescent signals and photoactivity. Subsequently, the activated TPPa quickly translocates from early endosome to mitochondria. Under laser irradiation, singlet oxygen could be generated in mitochondria, inducing intrinsic apoptosis in human HO8910 ovarian cancer cells. M-TPPa also exhibits high tumor imaging contrast and remarkable inhibition on tumor progression without obvious toxicity in HO8910-tumor bearing mice. Therefore, the rationally designed nanoparticles, with precise dual-targeting of distinct organelles and theranostic signal amplification, provides a promising strategy for efficient cancer treatment.
线粒体靶向光动力疗法（PDT）已成为最有效的抗肿瘤策略之一。然而，线粒体靶向 PDT 纳米载体的治疗效果受到其内在的内涵体逃逸能力差和持续开启模式的限制，这会导致正常组织损伤。为了解决这些限制，本文开发了一种具有早期内涵体和线粒体双重靶向能力的新型 pH 激活纳米颗粒，用于荧光信号和光动力疗效的指数激活。该纳米颗粒由 pH 响应的 mPEG-b-PDPA-Cy7.5 荧光共聚物和线粒体靶向光敏剂（TPPa）组成。TPPa 包封的纳米颗粒（M-TPPa）在遇到酸性 pH 环境时，荧光信号和单线态氧生成（SOG）分别增强了 111 倍和 151 倍。M-TPPa 可以被癌细胞快速内吞，并在酸性早期内涵体中立即解离以激活荧光信号和光活性。随后，激活的 TPPa 迅速从早期内涵体转运到线粒体。在激光照射下，线粒体中可以产生单线态氧，诱导人 HO8910 卵巢癌细胞发生内在凋亡。M-TPPa 还在荷瘤小鼠中表现出高肿瘤成像对比度和对肿瘤进展的显著抑制作用，而没有明显的毒性。因此，这种合理设计的纳米颗粒具有针对不同细胞器的精确双重靶向和治疗信号放大的特性，为高效癌症治疗提供了一种有前途的策略。
