{"title":"锰氧化物纳米拉姆丁作为金丝桃素输送和三阴性乳腺癌治疗的内在修饰剂","authors":"","doi":"10.1016/j.ijpharm.2024.124824","DOIUrl":null,"url":null,"abstract":"<div><div>The anti-tumor efficacy of naturally derived photosensitizer-hypericin (Hy) is dampened by hypoxia and over-expressed glutathione in the tumor microenvironment (TME). For rewiring the TME, we encapsulated Hy to an intrinsic modifier-manganese oxide-formed nanorambutan (MnO<sub>x</sub>-Hy NR). In triple-negative breast cancer cells, MnO<sub>x</sub>-Hy NR not only consumed glutathione through Mn<sup>2+</sup> and hypericin release but also facilitated O<sub>2</sub> production to relieve hypoxia, through which the reactive oxygen species (ROS) generation was strengthened by endoplasmic reticulum targeting hypericin. In the meantime, glutathione consumption-induced glutathione peroxidase 4 (GPX4) inactivation and the elevation of lipid hydroperoxide (LPO) level further triggered ferroptosis. Then, the combination of PDT and ferroptosis contributed to a synergic immunogenic cell death (ICD) effect in 4 T1 cells, facilitating the adaptive anti-tumor immune response activation. Thereby, MnO<sub>x</sub>-Hy NR exhibited excellent anti-tumor effects both in primary and distant tumors through the abscopal effect, as well as significant lung metastasis inhibition in the 4 T1 mouse metastatic tumor model.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A manganese-oxide nano-rambutan as the intrinsic modifier for hypericin delivery and triple-negative breast cancer treatment\",\"authors\":\"\",\"doi\":\"10.1016/j.ijpharm.2024.124824\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The anti-tumor efficacy of naturally derived photosensitizer-hypericin (Hy) is dampened by hypoxia and over-expressed glutathione in the tumor microenvironment (TME). For rewiring the TME, we encapsulated Hy to an intrinsic modifier-manganese oxide-formed nanorambutan (MnO<sub>x</sub>-Hy NR). In triple-negative breast cancer cells, MnO<sub>x</sub>-Hy NR not only consumed glutathione through Mn<sup>2+</sup> and hypericin release but also facilitated O<sub>2</sub> production to relieve hypoxia, through which the reactive oxygen species (ROS) generation was strengthened by endoplasmic reticulum targeting hypericin. In the meantime, glutathione consumption-induced glutathione peroxidase 4 (GPX4) inactivation and the elevation of lipid hydroperoxide (LPO) level further triggered ferroptosis. Then, the combination of PDT and ferroptosis contributed to a synergic immunogenic cell death (ICD) effect in 4 T1 cells, facilitating the adaptive anti-tumor immune response activation. Thereby, MnO<sub>x</sub>-Hy NR exhibited excellent anti-tumor effects both in primary and distant tumors through the abscopal effect, as well as significant lung metastasis inhibition in the 4 T1 mouse metastatic tumor model.</div></div>\",\"PeriodicalId\":14187,\"journal\":{\"name\":\"International Journal of Pharmaceutics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Pharmaceutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0378517324010585\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0378517324010585","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
天然光敏剂金丝桃素(Hy)的抗肿瘤功效会受到肿瘤微环境(TME)中缺氧和谷胱甘肽过度表达的影响。为了重新连接肿瘤微环境,我们将 Hy 封装到一种内在修饰剂--氧化锰形成的纳米红豆(MnOx-Hy NR)中。在三阴性乳腺癌细胞中,MnOx-Hy NR不仅通过Mn2+和金丝桃素的释放消耗谷胱甘肽,还促进了氧气的产生以缓解缺氧。与此同时,谷胱甘肽消耗引起的谷胱甘肽过氧化物酶 4(GPX4)失活和脂质过氧化物(LPO)水平升高进一步引发了铁变态反应。然后,PDT 和铁突变的结合有助于在 4 T1 细胞中产生协同免疫性细胞死亡(ICD)效应,促进适应性抗肿瘤免疫反应的激活。因此,MnOx-Hy NR 在原发性肿瘤和远处肿瘤中都表现出了卓越的抗肿瘤效果,并在 4 T1 小鼠转移瘤模型中发挥了显著的肺转移抑制作用。
A manganese-oxide nano-rambutan as the intrinsic modifier for hypericin delivery and triple-negative breast cancer treatment
The anti-tumor efficacy of naturally derived photosensitizer-hypericin (Hy) is dampened by hypoxia and over-expressed glutathione in the tumor microenvironment (TME). For rewiring the TME, we encapsulated Hy to an intrinsic modifier-manganese oxide-formed nanorambutan (MnOx-Hy NR). In triple-negative breast cancer cells, MnOx-Hy NR not only consumed glutathione through Mn2+ and hypericin release but also facilitated O2 production to relieve hypoxia, through which the reactive oxygen species (ROS) generation was strengthened by endoplasmic reticulum targeting hypericin. In the meantime, glutathione consumption-induced glutathione peroxidase 4 (GPX4) inactivation and the elevation of lipid hydroperoxide (LPO) level further triggered ferroptosis. Then, the combination of PDT and ferroptosis contributed to a synergic immunogenic cell death (ICD) effect in 4 T1 cells, facilitating the adaptive anti-tumor immune response activation. Thereby, MnOx-Hy NR exhibited excellent anti-tumor effects both in primary and distant tumors through the abscopal effect, as well as significant lung metastasis inhibition in the 4 T1 mouse metastatic tumor model.
期刊介绍:
The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.