School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou, Henan Province, 450001, China.
Adv Mater. 2022 Jul;34(30):e2201049. doi: 10.1002/adma.202201049. Epub 2022 Jun 20.
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 " O -•OH" uninterrupted generation through "recycling waste" in two steps: i) PpIX generates O under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H O conversion into •OH. Interestingly, the specific generation of O 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.
基于 5-氨基酮戊酸（ALA，一种原卟啉 IX（PpIX）的光敏剂前体）的自由基疗法已被美国食品和药物管理局批准用于临床肿瘤治疗。然而，PpIX 可以迅速转化为非光活性的血红素，导致自由基的产生意外暂停，严重阻碍了其治疗效果。在这里，受 ALA（ALA-PpIX-血红素）的自然生物转化的启发，开发了一种不间断的活性氧物种发生器（URG），它通过细胞内自组装将无用的血红素转化为过氧化物酶模拟物。URG 通过用 G-四链体结构 AS1411 进一步表面修饰将负载 ALA 的聚酰胺-胺树枝状大分子包裹在红细胞膜囊泡中制备。URGs 通过两步“回收废物”实现“ O -•OH”的不间断生成：i）激光照射下 PpIX 生成 O ；ii）与 AS1411 自组装的非光活性代谢物血红素催化 H O 转化为•OH。有趣的是，线粒体中 O 的特异性生成和核中•OH 的特异性生成进一步增强了自由基诱导的损伤。结果表明，URG 可以在辐照后持续 6 小时产生自由基，比非组装组多产生 3.3 倍，在体内实现近 80%的肿瘤消退。
