School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People's Republic of China.
Nanotechnology. 2018 Jun 22;29(25):255101. doi: 10.1088/1361-6528/aabbdb. Epub 2018 Apr 5.
The efficacy of nanoparticulate photodynamic therapy is often compromised by the short life time and limited diffusion radius of singlet oxygen as well as uncontrolled intracellular distribution of photosensitizer. It was hypothesized that rapid photosensitizer release upon nanoparticle internalization and its preferred accumulation in mitochondria would address the above problems. Hence, the aim of this study was to engineer a multifunctional micellar nanosystem featured with singlet oxygen-responsive cargo release and mitochondria-targeting. An imidazole-bearing amphiphilic copolymer was employed as the micelle building block to encapsulate triphenylphosphonium-pyropheophorbide a (TPP-PPa) conjugate or PPa. Upon laser irradiation, the singlet oxygen produced by TPP-PPa/PPa oxidized the imidazole moiety to produce hydrophilic urea, leading to micelle disassembly and rapid cargo release. The co-localization analysis showed that the TPP moiety significantly enhanced the photosensitizer uptake by mitochondria, improved mitochondria depolarization upon irradiation, and hence boosted the cytotoxicity in 4T1 cells. The targeting strategy also dramatically reduced the intracellular ATP concentration as a consequence of mitochondria injury. The mitochondria damage was accompanied with the activation of the apoptosis signals (caspase 3 and caspase 9), whose level was directly correlated to the apoptosis extent. The current work provides a facile and robust means to enhance the efficacy of photodynamic therapy.
纳米颗粒光动力疗法的疗效常常受到单线态氧的短寿命和有限扩散半径以及光敏剂的不可控细胞内分布的限制。据推测，纳米颗粒内化时迅速释放光敏剂及其在线粒体中的优先积累将解决上述问题。因此，本研究的目的是设计一种具有单线态氧响应的货物释放和靶向线粒体的多功能胶束纳米系统。一种含咪唑的两亲性共聚物被用作胶束构建块来封装三苯基膦-原卟啉 a（TPP-PPa）缀合物或 PPa。在激光照射下，TPP-PPa/PPa 产生的单线态氧氧化咪唑部分生成亲水性脲，导致胶束解体和快速释放货物。共定位分析表明，TPP 部分显著增强了光敏剂对线粒体的摄取，照射时增加线粒体去极化，从而提高 4T1 细胞的细胞毒性。靶向策略还由于线粒体损伤而显著降低细胞内 ATP 浓度。线粒体损伤伴随着凋亡信号（caspase 3 和 caspase 9）的激活，其水平与凋亡程度直接相关。本工作为提高光动力疗法的疗效提供了一种简便而有效的方法。
