An Intracellular Self-Assembly-Driven Uninterrupted ROS Generator Augments 5-Aminolevulinic-Acid-Based Tumor Therapy.
【作者】Shi, Jinjin; Nie, Weimin; Zhao, Xiu; Yang, Xinyuan; Cheng, Hui; Zhou, Tonghai; Zhang, Yun; Zhang, Kaixiang; Liu, Junjie
【作者单位】School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China
【年，卷(期)：页码】2022, 35: 2201049
【关键词】Uninterrupted free radical generator; Intracellular self-assembly; 5-aminolevulinic acid; Peroxidase mimics; Mitochondria/nuclei damage
【摘要】Free radical therapy based on 5-aminolevulinic acid (ALA, a precursor of the photosensitizer protoporphyrin IX (PpIX)) has been approved by the US Food and Drug Administration for clinical tumor treatment. However, PpIX can be quickly converted into photoinactive heme, leading to unexpectedly paused production of free radicals and severely hindering its therapeutic benefits. Here, inspired by the natural biotransformation of ALA (ALA-PpIX-heme), an uninterrupted reactive oxygen species generator (URG) that converts useless heme to peroxidase mimics via intracellular self-assembly is developed. The URG is prepared by enwrapping ALA-loaded polyamide-amine dendrimers in red blood cell membrane vesicles with a further surface modification of G-quadruplex-structured AS1411. The URGs realize “1O2−•OH” uninterrupted generation through “recycling waste” in two steps: i) PpIX generates 1O2 under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H2O2 conversion into •OH. Interestingly, the specific generation of 1O2 in mitochondria and •OH in nuclei further augments the free-radical-induced damage. It is demonstrated that URG can continuously produce free radicals for 6 h postirradiation, and shows 3.3-times more than that of the nonassembly group, achieving nearly 80% regression of tumors in vivo.