{"title":"一种ph响应和mri功能纳米药物,可在动脉粥样硬化中靶向递送辛伐他汀","authors":"J W Wang, Y Z Lin, J J Liu, S Y Chong, J C Y Kah","doi":"10.1093/eurheartj/ehad655.3273","DOIUrl":null,"url":null,"abstract":"Abstract Background Simvastatin is commonly used for the treatment of atherosclerosis. However, it causes side effects in some patients and not always effective. Moreover, although its treatment effects are often attributed to its cholesterol-lowering activity, some in vitro studies suggest that simvastatin also exerts antioxidant and anti-inflammatory effects. Purpose To develop an atherosclerotic plaque microenvironment-responsive nanoparticular system to deliver and release Gadolinium (Gd3+) for magnetic resonance imaging (MRI) and simvastatin for treatment within the plaque. Methods A nanoparticle was synthesized with nanoscale coordination polymers (NCPs), a pH-responsive linker, Gd3+, and simvastatin (ST), i.e. a ST/NCP-PEG nanoparticle. The biological effects of ST/NCP-PEG nanoparticle were tested on RAW264.7 macrophages. Four weeks old ApoE-/- mice were fed on high fat diet for 4 weeks and then randomly divided into three groups for a 8-week treatment regime via weekly intravenous administration of: 1) NCP-PEG nanoparticle without ST (control); 2) ST/NCP-PEG nanoparticles; or 3) free ST. Results We have developed a pH-responsive ST/NCP-PEG nanoparticle carrying an MRI contrast agent Gd3+ and a drug molecule ST, with an 80 nm diameter in spherical shape. This nanoparticle collapsed into biodegradable components while releasing both Gd3+ and ST under the atherosclerotic plaque microenvironment with a pH 5.6. ST/NCP-PEG nanoparticles exerted strong anti-oxidant and anti-inflammatory effects in vitro, as determined by an intracellular ROS indicator DCF-DA and expression levels of cytokines (e.g. IL-6, TNF-α and MCP-1), respectively. Upon intravenous administration, ST/NCP-PEG nanoparticles, as demonstrated by IVIS imaging system, accumulated specifically in the plaques in a time-dependent manner, reaching the peak concentration at 24 hours post administration. The plaques were readily visualized by MR imaging (T1-weighted signal) due to the enrichment of Gd3+. After 8 weeks treatment, compared to the empty NCP-PEG nanoparticle, treatment with ST/NCP-PEG and free ST reduced plaque lesion size by 55% (p<0.001) and 29% (p<0.05), respectively. Moreover, ST/NCP-PEG nanoparticles showed a larger reduction in plaque lesions than free ST (p<0.05). Oil red O staining of both the whole aorta and the aortic roots generated similar results in terms of plaque lesion changes. Mechanistically, both ST/NCP-PEG and free ST reduced ROS production and increased the ratios of M2/M1 macrophages within the plaque, with ST/NCP-PEG nanoparticle treatment exerted larger therapeutic effects. Moreover, long-term treatment with ST/NCP-PEG nanoparticles did not show obvious toxicity in all major organs. Conclusions An atherosclerotic plaque microenvironment-responsive MR imaging functional nanoparticle for targeted delivery of ST to the plaque could diagnose atherosclerotic plaque and improve treatment efficacy of ST.","PeriodicalId":11976,"journal":{"name":"European Heart Journal","volume":null,"pages":null},"PeriodicalIF":37.6000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A pH-Responsive and MRI-Functional nanomedicine enabling targeted delivery of simvastatin in atherosclerosis\",\"authors\":\"J W Wang, Y Z Lin, J J Liu, S Y Chong, J C Y Kah\",\"doi\":\"10.1093/eurheartj/ehad655.3273\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Abstract Background Simvastatin is commonly used for the treatment of atherosclerosis. However, it causes side effects in some patients and not always effective. Moreover, although its treatment effects are often attributed to its cholesterol-lowering activity, some in vitro studies suggest that simvastatin also exerts antioxidant and anti-inflammatory effects. Purpose To develop an atherosclerotic plaque microenvironment-responsive nanoparticular system to deliver and release Gadolinium (Gd3+) for magnetic resonance imaging (MRI) and simvastatin for treatment within the plaque. Methods A nanoparticle was synthesized with nanoscale coordination polymers (NCPs), a pH-responsive linker, Gd3+, and simvastatin (ST), i.e. a ST/NCP-PEG nanoparticle. The biological effects of ST/NCP-PEG nanoparticle were tested on RAW264.7 macrophages. Four weeks old ApoE-/- mice were fed on high fat diet for 4 weeks and then randomly divided into three groups for a 8-week treatment regime via weekly intravenous administration of: 1) NCP-PEG nanoparticle without ST (control); 2) ST/NCP-PEG nanoparticles; or 3) free ST. Results We have developed a pH-responsive ST/NCP-PEG nanoparticle carrying an MRI contrast agent Gd3+ and a drug molecule ST, with an 80 nm diameter in spherical shape. This nanoparticle collapsed into biodegradable components while releasing both Gd3+ and ST under the atherosclerotic plaque microenvironment with a pH 5.6. ST/NCP-PEG nanoparticles exerted strong anti-oxidant and anti-inflammatory effects in vitro, as determined by an intracellular ROS indicator DCF-DA and expression levels of cytokines (e.g. IL-6, TNF-α and MCP-1), respectively. Upon intravenous administration, ST/NCP-PEG nanoparticles, as demonstrated by IVIS imaging system, accumulated specifically in the plaques in a time-dependent manner, reaching the peak concentration at 24 hours post administration. The plaques were readily visualized by MR imaging (T1-weighted signal) due to the enrichment of Gd3+. After 8 weeks treatment, compared to the empty NCP-PEG nanoparticle, treatment with ST/NCP-PEG and free ST reduced plaque lesion size by 55% (p<0.001) and 29% (p<0.05), respectively. Moreover, ST/NCP-PEG nanoparticles showed a larger reduction in plaque lesions than free ST (p<0.05). Oil red O staining of both the whole aorta and the aortic roots generated similar results in terms of plaque lesion changes. Mechanistically, both ST/NCP-PEG and free ST reduced ROS production and increased the ratios of M2/M1 macrophages within the plaque, with ST/NCP-PEG nanoparticle treatment exerted larger therapeutic effects. Moreover, long-term treatment with ST/NCP-PEG nanoparticles did not show obvious toxicity in all major organs. Conclusions An atherosclerotic plaque microenvironment-responsive MR imaging functional nanoparticle for targeted delivery of ST to the plaque could diagnose atherosclerotic plaque and improve treatment efficacy of ST.\",\"PeriodicalId\":11976,\"journal\":{\"name\":\"European Heart Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":37.6000,\"publicationDate\":\"2023-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Heart Journal\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/eurheartj/ehad655.3273\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Heart Journal","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/eurheartj/ehad655.3273","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
A pH-Responsive and MRI-Functional nanomedicine enabling targeted delivery of simvastatin in atherosclerosis
Abstract Background Simvastatin is commonly used for the treatment of atherosclerosis. However, it causes side effects in some patients and not always effective. Moreover, although its treatment effects are often attributed to its cholesterol-lowering activity, some in vitro studies suggest that simvastatin also exerts antioxidant and anti-inflammatory effects. Purpose To develop an atherosclerotic plaque microenvironment-responsive nanoparticular system to deliver and release Gadolinium (Gd3+) for magnetic resonance imaging (MRI) and simvastatin for treatment within the plaque. Methods A nanoparticle was synthesized with nanoscale coordination polymers (NCPs), a pH-responsive linker, Gd3+, and simvastatin (ST), i.e. a ST/NCP-PEG nanoparticle. The biological effects of ST/NCP-PEG nanoparticle were tested on RAW264.7 macrophages. Four weeks old ApoE-/- mice were fed on high fat diet for 4 weeks and then randomly divided into three groups for a 8-week treatment regime via weekly intravenous administration of: 1) NCP-PEG nanoparticle without ST (control); 2) ST/NCP-PEG nanoparticles; or 3) free ST. Results We have developed a pH-responsive ST/NCP-PEG nanoparticle carrying an MRI contrast agent Gd3+ and a drug molecule ST, with an 80 nm diameter in spherical shape. This nanoparticle collapsed into biodegradable components while releasing both Gd3+ and ST under the atherosclerotic plaque microenvironment with a pH 5.6. ST/NCP-PEG nanoparticles exerted strong anti-oxidant and anti-inflammatory effects in vitro, as determined by an intracellular ROS indicator DCF-DA and expression levels of cytokines (e.g. IL-6, TNF-α and MCP-1), respectively. Upon intravenous administration, ST/NCP-PEG nanoparticles, as demonstrated by IVIS imaging system, accumulated specifically in the plaques in a time-dependent manner, reaching the peak concentration at 24 hours post administration. The plaques were readily visualized by MR imaging (T1-weighted signal) due to the enrichment of Gd3+. After 8 weeks treatment, compared to the empty NCP-PEG nanoparticle, treatment with ST/NCP-PEG and free ST reduced plaque lesion size by 55% (p<0.001) and 29% (p<0.05), respectively. Moreover, ST/NCP-PEG nanoparticles showed a larger reduction in plaque lesions than free ST (p<0.05). Oil red O staining of both the whole aorta and the aortic roots generated similar results in terms of plaque lesion changes. Mechanistically, both ST/NCP-PEG and free ST reduced ROS production and increased the ratios of M2/M1 macrophages within the plaque, with ST/NCP-PEG nanoparticle treatment exerted larger therapeutic effects. Moreover, long-term treatment with ST/NCP-PEG nanoparticles did not show obvious toxicity in all major organs. Conclusions An atherosclerotic plaque microenvironment-responsive MR imaging functional nanoparticle for targeted delivery of ST to the plaque could diagnose atherosclerotic plaque and improve treatment efficacy of ST.
期刊介绍:
The European Heart Journal is a renowned international journal that focuses on cardiovascular medicine. It is published weekly and is the official journal of the European Society of Cardiology. This peer-reviewed journal is committed to publishing high-quality clinical and scientific material pertaining to all aspects of cardiovascular medicine. It covers a diverse range of topics including research findings, technical evaluations, and reviews. Moreover, the journal serves as a platform for the exchange of information and discussions on various aspects of cardiovascular medicine, including educational matters.
In addition to original papers on cardiovascular medicine and surgery, the European Heart Journal also presents reviews, clinical perspectives, ESC Guidelines, and editorial articles that highlight recent advancements in cardiology. Additionally, the journal actively encourages readers to share their thoughts and opinions through correspondence.