An Intracellular Self-Assembly-Driven Uninterrupted ROS Generator Augments 5-Aminolevulinic-Acid-Based Tumor Therapy
An Intracellular Self-Assembly-Driven Uninterrupted ROS Generator Augments 5-Aminolevulinic-Acid-Based Tumor Therapy
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DOI：
10.1002/adma.202201049
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发表时间：
2022-06-20
影响因子：
29.4
通讯作者：
Liu, Junjie
中科院分区：
文献类型：
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作者：
Shi, Jinjin;Nie, Weimin;Liu, Junjie
基于5-氨基乙酰丙酸(ALA，光敏剂原卟啉IX(PPIX)的前体)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可以迅速转化为光不活跃的血红素，导致自由基的产生意外停止，并严重阻碍其治疗效果。在这里，受丙氨酸(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生成器(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是通过将负载ALA的聚酰胺-胺树状大分子包裹在红细胞膜微囊中，并进一步对G-四链结构的AS1411进行表面修饰而制备的。URGs通过两个步骤：i)PpIX在激光照射下产生O-1(2)；ii)与AS1411自组装光非活性代谢产物血红素，催化H_2O_2转化为中心点OH，从而实现了“O-1(2)-中心点OH”的不间断产生。有趣的是，线粒体中O-1(2)的特异性生成和细胞核中中心点OH的生成进一步增强了自由基诱导的损伤。结果表明，URG在照射后6h内可持续产生自由基，是未组装组的3.3倍，体内肿瘤消退率接近80%。
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-1(2)-center dot OH" uninterrupted generation through "recycling waste" in two steps: i) PpIX generates O-1(2) under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H2O2 conversion into center dot OH. Interestingly, the specific generation of O-1(2) in mitochondria and center dot 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.