Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology , Tianjin University , 300072 Tianjin , PR China.
Department of Nuclear Medicine , Tianjin Medical University General Hospital , 300052 Tianjin , PR China.
Mol Pharm. 2018 Aug 6;15(8):3318-3331. doi: 10.1021/acs.molpharmaceut.8b00351. Epub 2018 Jul 18.
Photodynamic therapy (PDT) is commonly restricted by inefficient tumor selectivity during clinical study. Hence, a mitochondria-targeting multifunctional nanocarrier "theranosome (TNS)" was developed for near-infrared fluorescent (NIRF) imaging and photoacoustic (PA) imaging. What's more, the TNS can also enhance PDT efficacy. In this work, chlorin e6 (Ce6) undertakes reactive oxygen generation and fluorescence emission. Ce6 was quenched when being encapsulated into TNS together with IR780 iodide. When exposed under 808 nm NIR light, IR780 from the TNS can be photobleached; thus, the phototoxicity of Ce6 can be activated. The IR780 induced hyperthermia damaged tumor cells to perform photothermal therapy (PTT) effect. Then lysosomes disruption under PTT facilitated PDT effect induced by Ce6 through enhanced cytoplasmic delivery. Moreover, in vitro subcellular uptake experiments showed that triphenylphosphonium (TPP) group attached to the IR780/Ce6 TNS (ICT) could promote mitochondria targeting capacity. It can lead to PDT induced oxidizing damage to the mitochondria by mitochondrial membrane potential decreasing and cell apoptosis eventually. In in vivo antitumor studies, the TPP/IR780/Ce6 TNS (TICT) substantially repressed tumor growth in nude mice. Besides, we did not find any obvious side effects to normal tissues and organs. The results suggested the TICT conjugate provided a dual NIRF/PA tumor imaging modalities with spatial resolution and superior imaging contrast. This study offered an improved phototherapy for potential theranostic application.
光动力疗法（PDT）在临床研究中通常受到肿瘤选择性低的限制。因此，开发了一种靶向线粒体的多功能纳米载体“theranosome（TNS）”，用于近红外荧光（NIRF）成像和光声（PA）成像。更重要的是，TNS 还可以增强 PDT 疗效。在这项工作中，叶绿素 e6（Ce6）承担了产生活性氧和荧光发射的作用。Ce6 被包裹在 TNS 中与 IR780 碘化物一起时被猝灭。当暴露在 808nm 近红外光下时，TNS 中的 IR780 可以被光漂白，从而激活 Ce6 的光毒性。IR780 诱导的热疗破坏肿瘤细胞以发挥光热治疗（PTT）效应。然后，PTT 下的溶酶体破裂通过增强细胞质传递促进由 Ce6 引起的 PDT 效应。此外，体外亚细胞摄取实验表明，连接到 IR780/Ce6 TNS（ICT）上的三苯基膦（TPP）基团可以促进线粒体靶向能力。它可以通过降低线粒体膜电位和细胞凋亡最终导致由线粒体 PDT 诱导的氧化损伤。在体内抗肿瘤研究中，TPP/IR780/Ce6 TNS（TICT）在裸鼠中显著抑制肿瘤生长。此外，我们没有发现对正常组织和器官有任何明显的副作用。结果表明，TICT 缀合物提供了具有空间分辨率和优异成像对比度的双近红外荧光/PA 肿瘤成像模式。这项研究为潜在的治疗应用提供了一种改进的光疗方法。
