Tao Pan, Ming Wang, Linxi Yang, Yihan Zheng, Yuanding Liu, Yu Xiao, Xudong Qiu, Yanying Shen, Mahan Dawuren, Zhiqiang Ren, Keying Liu, Yang Sun, Lin Tu, Hui Cao, Weihong Tan
{"title":"基于适配体的靶向治疗伊马替尼耐药胃肠道间质瘤。","authors":"Tao Pan, Ming Wang, Linxi Yang, Yihan Zheng, Yuanding Liu, Yu Xiao, Xudong Qiu, Yanying Shen, Mahan Dawuren, Zhiqiang Ren, Keying Liu, Yang Sun, Lin Tu, Hui Cao, Weihong Tan","doi":"10.7150/thno.115496","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, are primarily driven by activating mutations in the KIT intracellular segment. The standard treatment with imatinib frequently results in acquired resistance due to secondary mutations. Besides mutations, KIT is also overexpressed in GIST. An aptamer that specifically binds to the extracellular segment of KIT (unaffected by these mutations) was promising in drug delivery and may overcome imatinib resistance. <b>Methods:</b> The microtubule inhibitor VcMMAE (mc-vc-PAB-MMAE) was conjugated with an optimized KIT-targeting aptamer (KIT-d) to generate an aptamer-drug conjugate (ApDC) named KIT-d-MMAE. This ApDC was then evaluated for its binding specificity, internalization via endocytosis, and cytotoxicity towards KIT-positive GIST cells. The therapeutic efficacy of KIT-d-MMAE was evaluated through both <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> KIT-d-MMAE exhibited specific binding and efficient internalization into KIT-positive GIST cells, including imatinib-resistant lines, inducing targeted cytotoxic effects. In animal studies, KIT-d-MMAE significantly suppressed tumor growth in GIST-T1 subcutaneous and liver metastasis models. Notably, in imatinib-resistant GIST-430/654 and multi-TKI-resistant patient-derived xenograft (PDX) models, KIT-d-MMAE demonstrated superior antitumor efficacy compared to imatinib. Additionally, therapeutic effects were also observed in genetically engineered mouse models, indicating effective inhibition of spontaneous tumor formation and progression. <b>Conclusion:</b> The aptamer-based drug delivery not only provides an innovative approach to overcome drug resistance but also simplifies treatment regimens, offering new therapeutic hope and marking a significant advancement in targeted therapy for GIST patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"8738-8756"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439145/pdf/","citationCount":"0","resultStr":"{\"title\":\"Aptamer-based drug delivery for targeted therapy of imatinib-resistant gastrointestinal stromal tumor.\",\"authors\":\"Tao Pan, Ming Wang, Linxi Yang, Yihan Zheng, Yuanding Liu, Yu Xiao, Xudong Qiu, Yanying Shen, Mahan Dawuren, Zhiqiang Ren, Keying Liu, Yang Sun, Lin Tu, Hui Cao, Weihong Tan\",\"doi\":\"10.7150/thno.115496\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale:</b> Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, are primarily driven by activating mutations in the KIT intracellular segment. The standard treatment with imatinib frequently results in acquired resistance due to secondary mutations. Besides mutations, KIT is also overexpressed in GIST. An aptamer that specifically binds to the extracellular segment of KIT (unaffected by these mutations) was promising in drug delivery and may overcome imatinib resistance. <b>Methods:</b> The microtubule inhibitor VcMMAE (mc-vc-PAB-MMAE) was conjugated with an optimized KIT-targeting aptamer (KIT-d) to generate an aptamer-drug conjugate (ApDC) named KIT-d-MMAE. This ApDC was then evaluated for its binding specificity, internalization via endocytosis, and cytotoxicity towards KIT-positive GIST cells. The therapeutic efficacy of KIT-d-MMAE was evaluated through both <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> KIT-d-MMAE exhibited specific binding and efficient internalization into KIT-positive GIST cells, including imatinib-resistant lines, inducing targeted cytotoxic effects. In animal studies, KIT-d-MMAE significantly suppressed tumor growth in GIST-T1 subcutaneous and liver metastasis models. Notably, in imatinib-resistant GIST-430/654 and multi-TKI-resistant patient-derived xenograft (PDX) models, KIT-d-MMAE demonstrated superior antitumor efficacy compared to imatinib. Additionally, therapeutic effects were also observed in genetically engineered mouse models, indicating effective inhibition of spontaneous tumor formation and progression. <b>Conclusion:</b> The aptamer-based drug delivery not only provides an innovative approach to overcome drug resistance but also simplifies treatment regimens, offering new therapeutic hope and marking a significant advancement in targeted therapy for GIST patients.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 17\",\"pages\":\"8738-8756\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439145/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.115496\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.115496","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
理由:胃肠道间质瘤(GIST)是胃肠道最常见的间质肿瘤,主要是由KIT细胞内片段的激活突变驱动的。伊马替尼的标准治疗经常由于继发性突变导致获得性耐药。除了突变外,KIT在GIST中也过表达。一种特异性结合KIT细胞外片段(不受这些突变影响)的适体在药物输送中很有希望,并可能克服伊马替尼耐药性。方法:将微管抑制剂VcMMAE (mc-vc- bab - mmae)与优化后的kit靶向适配体(KIT-d)偶联,生成适配体-药物偶联物(ApDC),命名为KIT-d- mmae。然后评估该ApDC的结合特异性,通过内吞作用的内化以及对kit阳性GIST细胞的细胞毒性。通过体外和体内实验评价KIT-d-MMAE的治疗效果。结果:KIT-d-MMAE表现出特异性结合和有效内化到kit阳性的GIST细胞,包括伊马替尼耐药系,诱导靶向细胞毒性作用。在动物实验中,KIT-d-MMAE在GIST-T1皮下和肝脏转移模型中显著抑制肿瘤生长。值得注意的是,在伊马替尼耐药的GIST-430/654和多重tki耐药的患者源异种移植物(PDX)模型中,KIT-d-MMAE显示出比伊马替尼更优越的抗肿瘤疗效。此外,在基因工程小鼠模型中也观察到治疗效果,表明有效抑制自发肿瘤的形成和进展。结论:适配体给药不仅为克服耐药提供了创新途径,而且简化了治疗方案,为GIST患者的靶向治疗带来了新的希望,标志着GIST患者靶向治疗取得了重大进展。
Aptamer-based drug delivery for targeted therapy of imatinib-resistant gastrointestinal stromal tumor.
Rationale: Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, are primarily driven by activating mutations in the KIT intracellular segment. The standard treatment with imatinib frequently results in acquired resistance due to secondary mutations. Besides mutations, KIT is also overexpressed in GIST. An aptamer that specifically binds to the extracellular segment of KIT (unaffected by these mutations) was promising in drug delivery and may overcome imatinib resistance. Methods: The microtubule inhibitor VcMMAE (mc-vc-PAB-MMAE) was conjugated with an optimized KIT-targeting aptamer (KIT-d) to generate an aptamer-drug conjugate (ApDC) named KIT-d-MMAE. This ApDC was then evaluated for its binding specificity, internalization via endocytosis, and cytotoxicity towards KIT-positive GIST cells. The therapeutic efficacy of KIT-d-MMAE was evaluated through both in vitro and in vivo experiments. Results: KIT-d-MMAE exhibited specific binding and efficient internalization into KIT-positive GIST cells, including imatinib-resistant lines, inducing targeted cytotoxic effects. In animal studies, KIT-d-MMAE significantly suppressed tumor growth in GIST-T1 subcutaneous and liver metastasis models. Notably, in imatinib-resistant GIST-430/654 and multi-TKI-resistant patient-derived xenograft (PDX) models, KIT-d-MMAE demonstrated superior antitumor efficacy compared to imatinib. Additionally, therapeutic effects were also observed in genetically engineered mouse models, indicating effective inhibition of spontaneous tumor formation and progression. Conclusion: The aptamer-based drug delivery not only provides an innovative approach to overcome drug resistance but also simplifies treatment regimens, offering new therapeutic hope and marking a significant advancement in targeted therapy for GIST patients.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.