Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Nanoscale Horiz. 2020 May 1;5(5):886-894. doi: 10.1039/d0nh00034e. Epub 2020 Mar 27.
Photodynamic therapy (PDT) leads to tumor hypoxia which could be utilized for the activation of hypoxia-activated prodrugs (HAPs). However, conventional photosensitizer-loaded nanoformulations suffer from an aggregation-caused quenching (ACQ) effect, which limits the efficiency of PDT and synergistic therapy. Herein, prodrug-nanoparticles (NPs) are prepared by the self-assembly of heterodimeric prodrugs composed of pyropheophorbide a (PPa), hypoxia-activated prodrug PR104A, and a thioether or thioketal linkage. In addition, a novel dual-modality drug release pattern is proposed on the basis of the structural states of prodrug-NPs. Under light irradiation, PR104A is released via photoinduced electron transfer (PET) due to the aggregation state of prodrugs. With the disassembly of prodrug-NPs, the ACQ effect is relieved, and PPa produces singlet oxygen which further promotes the reactive oxygen species (ROS)-sensitive release of PR104A. Such prodrug-NPs turn the disadvantage of the ACQ effect to facilitate drug release, demonstrating high-efficiency synergy in combination with PDT and hypoxia-activated therapy.
光动力疗法（PDT）会导致肿瘤缺氧，这可以被用于激活缺氧激活前药（HAPs）。然而，传统的载光敏剂的纳米制剂受到聚集导致的猝灭（ACQ）效应的限制，这限制了 PDT 和协同治疗的效率。在此，通过由组成的杂二聚体前药的自组装来制备前药纳米颗粒（NPs），所述杂二聚体前药由焦脱镁叶绿酸 a（PPa）、缺氧激活前药 PR104A 和硫醚或硫缩酮键组成。此外，基于前药-NPs 的结构状态提出了一种新的双重模式药物释放模式。在光照射下，由于前药的聚集状态，通过光诱导电子转移（PET）释放 PR104A。随着前药-NPs 的解体，ACQ 效应得到缓解，PPa 产生单线态氧，这进一步促进了 PR104A 的 ROS 敏感释放。这种前药-NPs 将 ACQ 效应的劣势转化为促进药物释放的优势，在与 PDT 和缺氧激活治疗相结合时表现出高效协同作用。
