Li YiCong, Hu DanRong, Pan Meng, Qu Ying, Chu BingYang, Liao JinFeng, Zhou XiaoHan, Liu QingYa, Cheng Shuang, Chen Yu, Wei Quan, Qian ZhiYong
Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, Key Laboratory of Rehabilitation Medicine in Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center, Chengdu, Sichuan, 610041, PR China.
Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China.
Biomaterials. 2022 Sep;288:121700. doi: 10.1016/j.biomaterials.2022.121700. Epub 2022 Aug 17.
Currently, activatable photodynamic therapy (PDT) that is precisely regulated by endogenous or exogenous stimuli to selectively produce cytotoxic reactive oxygen species at the tumor site is urgently in demand. Herein, we fabricated a dual-activatable PDT nanosystem regulated by the redox tumor microenvironment and near-infrared (NIR) light-induced photothermal therapy (PTT). In this study, photosensitizer chlorin e6 (Ce6) was conjugated to hyaluronic acid (HA) via a diselenide bond to form an amphiphilic polymer (HSeC) for loading PTT agent IR780 to produce HSeC/IR nanoparticles (NPs). The photoactivity of Ce6 for PDT was "double-locked" by the aggregation-caused quenching (ACQ) effect and the fluorescence resonance energy transfer (FRET) from Ce6 to IR780 during blood circulation. After selective accumulation into tumors, HSeC/IR NPs were subsequently dissociated due to the "double-key", which included diselenide bond dissociation under high redox conditions and IR780 degradation upon NIR laser irradiation, resulting in recovering Ce6. In vitro studies indicated that Ce6 photoactivity in HSeC/IR NPs was significantly suppressed when compared with free Ce6 or in HSeC NPs. Moreover, BALB/c mice treated with HSeC/IR NPs displayed distinctly alleviated skin damage during PDT. Synergetic cascaded PTT-PDT with superior tumor suppression was observed in SCC7 tumor-bearing mice. Therefore, the study findings could provide a promising treatment strategy for PTT-facilitated PDT with high antitumor efficacies and reduced skin phototoxicity levels.
目前，迫切需要一种可激活的光动力疗法（PDT），该疗法能由内源性或外源性刺激精确调控，以在肿瘤部位选择性地产生活细胞毒性的活性氧。在此，我们构建了一种由氧化还原肿瘤微环境和近红外（NIR）光诱导的光热疗法（PTT）调控的双激活PDT纳米系统。在本研究中，光敏剂二氢卟吩e6（Ce6）通过二硒键与透明质酸（HA）偶联，形成两亲性聚合物（HSeC），用于负载PTT试剂IR780以制备HSeC/IR纳米颗粒（NPs）。在血液循环过程中，Ce6对PDT的光活性通过聚集诱导猝灭（ACQ）效应以及从Ce6到IR780的荧光共振能量转移（FRET）被“双重锁定”。在选择性积聚到肿瘤中后，HSeC/IR NPs随后由于“双键”而解离，其中包括在高氧化还原条件下二硒键的解离以及近红外激光照射后IR780的降解，从而使Ce6恢复。体外研究表明，与游离Ce6或HSeC NPs中的Ce6相比，HSeC/IR NPs中Ce6的光活性受到显著抑制。此外，用HSeC/IR NPs处理的BALB/c小鼠在PDT过程中皮肤损伤明显减轻。在荷SCC7肿瘤的小鼠中观察到具有优异肿瘤抑制效果的协同级联PTT-PDT。因此，该研究结果可为具有高抗肿瘤疗效和降低皮肤光毒性水平的PTT促进的PDT提供一种有前景的治疗策略。
