{"title":"靶向输送可激活的 131I 放射性药物,改善药代动力学,实现持续放疗。","authors":"","doi":"10.1016/j.jconrel.2024.07.005","DOIUrl":null,"url":null,"abstract":"<div><p><span><span>Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering </span>legumain is overexpressed in multiple types of human cancers, a </span><sup>131</sup><span>I-labeled radiopharmaceutical (</span><strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong>) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)<sub>3</sub>) into <strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong><span> to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic </span><strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> could react with its precursor to form heterologous dimer <strong>[</strong><sup><strong>131</strong></sup><strong>I]H-Dimer</strong> that is highly hydrophobic. Cerenkov imaging revealed that <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> displayed superior tumor selectivity and longer tumor retention time as compared with <strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong>, with a significant reduction in the liver uptake. After an 18-day treatment with <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong><span>, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that </span><strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> could serve as a promising drug candidate for treating legumain-overexpressed tumors.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics\",\"authors\":\"\",\"doi\":\"10.1016/j.jconrel.2024.07.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span>Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering </span>legumain is overexpressed in multiple types of human cancers, a </span><sup>131</sup><span>I-labeled radiopharmaceutical (</span><strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong>) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)<sub>3</sub>) into <strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong><span> to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic </span><strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> could react with its precursor to form heterologous dimer <strong>[</strong><sup><strong>131</strong></sup><strong>I]H-Dimer</strong> that is highly hydrophobic. Cerenkov imaging revealed that <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> displayed superior tumor selectivity and longer tumor retention time as compared with <strong>[</strong><sup><strong>131</strong></sup><strong>I]MAAN</strong>, with a significant reduction in the liver uptake. After an 18-day treatment with <strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong><span>, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that </span><strong>[</strong><sup><strong>131</strong></sup><strong>I]IM(HE)</strong><sub><strong>3</strong></sub><strong>AAN</strong> could serve as a promising drug candidate for treating legumain-overexpressed tumors.</p></div>\",\"PeriodicalId\":15450,\"journal\":{\"name\":\"Journal of Controlled Release\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.5000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Controlled Release\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S016836592400436X\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Controlled Release","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S016836592400436X","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics
Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.
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