{"title":"用于癌症靶向治疗的自组装亲和素-PROTAC共轭纳米药物","authors":"Qingrong Li, Xiaoyuan Yang, Mengqiao Zhao, Xuelin Xia, Wenhui Gao, Wei Huang, Xiaoxia Xia, Deyue Yan","doi":"10.1007/s12274-024-6974-x","DOIUrl":null,"url":null,"abstract":"<p>Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody Z<sub>HER2:342</sub> (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic Z<sub>HER2:342</sub>-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (Z<sub>HER2:342</sub>-MZ1 APCN) in water. Upon the excellent targeting property of Z<sub>HER2:342</sub> and HER2 receptor-mediated endocytosis, Z<sub>HER2:342</sub>-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively <i>in vitro</i>. Under the intracellular high level of glutathione (GSH), Z<sub>HER2:342</sub>-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, Z<sub>HER2:342</sub>-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy <i>in vivo</i> for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.\n</p>","PeriodicalId":713,"journal":{"name":"Nano Research","volume":"28 1","pages":""},"PeriodicalIF":9.5000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy\",\"authors\":\"Qingrong Li, Xiaoyuan Yang, Mengqiao Zhao, Xuelin Xia, Wenhui Gao, Wei Huang, Xiaoxia Xia, Deyue Yan\",\"doi\":\"10.1007/s12274-024-6974-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody Z<sub>HER2:342</sub> (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic Z<sub>HER2:342</sub>-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (Z<sub>HER2:342</sub>-MZ1 APCN) in water. Upon the excellent targeting property of Z<sub>HER2:342</sub> and HER2 receptor-mediated endocytosis, Z<sub>HER2:342</sub>-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively <i>in vitro</i>. Under the intracellular high level of glutathione (GSH), Z<sub>HER2:342</sub>-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, Z<sub>HER2:342</sub>-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy <i>in vivo</i> for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.\\n</p>\",\"PeriodicalId\":713,\"journal\":{\"name\":\"Nano Research\",\"volume\":\"28 1\",\"pages\":\"\"},\"PeriodicalIF\":9.5000,\"publicationDate\":\"2024-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nano Research\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1007/s12274-024-6974-x\",\"RegionNum\":2,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nano Research","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1007/s12274-024-6974-x","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy
Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody ZHER2:342 (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic ZHER2:342-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (ZHER2:342-MZ1 APCN) in water. Upon the excellent targeting property of ZHER2:342 and HER2 receptor-mediated endocytosis, ZHER2:342-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively in vitro. Under the intracellular high level of glutathione (GSH), ZHER2:342-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, ZHER2:342-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy in vivo for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.
期刊介绍:
Nano Research is a peer-reviewed, international and interdisciplinary research journal that focuses on all aspects of nanoscience and nanotechnology. It solicits submissions in various topical areas, from basic aspects of nanoscale materials to practical applications. The journal publishes articles on synthesis, characterization, and manipulation of nanomaterials; nanoscale physics, electrical transport, and quantum physics; scanning probe microscopy and spectroscopy; nanofluidics; nanosensors; nanoelectronics and molecular electronics; nano-optics, nano-optoelectronics, and nano-photonics; nanomagnetics; nanobiotechnology and nanomedicine; and nanoscale modeling and simulations. Nano Research offers readers a combination of authoritative and comprehensive Reviews, original cutting-edge research in Communication and Full Paper formats. The journal also prioritizes rapid review to ensure prompt publication.