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Aptamer Enables Consistent Maytansine Delivery through Maintaining Receptor Homeostasis for HER2 Targeted Cancer Therapy.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-05-28 , DOI: 10.1021/acs.bioconjchem.0c00250 Yan Tan 1 , Yongbo Peng 1 , Lili Ai 1 , Yingying Li 1 , Yi-Xin Qu 1 , Dan Wang 1 , Yuanye Su 1 , Tanggang Deng 1 , Ting Fu 1 , Zilong Zhao 1 , Xue-Qiang Wang 1 , Weihong Tan 1, 2, 3
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-05-28 , DOI: 10.1021/acs.bioconjchem.0c00250 Yan Tan 1 , Yongbo Peng 1 , Lili Ai 1 , Yingying Li 1 , Yi-Xin Qu 1 , Dan Wang 1 , Yuanye Su 1 , Tanggang Deng 1 , Ting Fu 1 , Zilong Zhao 1 , Xue-Qiang Wang 1 , Weihong Tan 1, 2, 3
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Although the extensive clinical use of the ADC trastuzumab-DM1(T-DM1) for human epidermal growth factor receptor 2 (HER2) targeted cancer therapy, many patients who initially respond to T-DM1 treatment eventually met the insufficient efficacy issue, which is partly attributed to the decreased amount of surface HER2 caused by HER2 degradation in target cells. In our study, we have engineered a HER2 targeted DNA aptamer-DM1 conjugate (HApDC) that can maintain the homeostasis of surface HER2 on the target cancer cell. These conclusions are supported by determining the efficient internalization of HApDC into HER2 overexpressed BT474 and SKBR3 cancer cell lines and by identifying the membranal HER2 level on HApDC-treated BT474 cells. Consistent with the impressive in vitro properties of our newly developed anticancer agent, DM1 could precisely be delivered to the tumor tissue in BT474 xenografted mouse models, because of the specific recognition of aptamer. Noteworthy, HApDC exhibited excellent in vivo tumor inhibition function with much lower healthy organ toxicity, compared with the free drug, which might be explained by the persistently targeted DM1 delivery, which is attributed to the remaining HER2 levels on cells.
中文翻译：
Aptamer通过维持HER2靶向癌症治疗的受体稳态来实现稳定的美登素递送。
尽管ADC trastuzumab-DM1（T-DM1）在针对人类表皮生长因子受体2（HER2）的癌症治疗中得到了广泛的临床应用，但许多最初对T-DM1治疗有反应的患者最终遇到了疗效不足的问题，部分原因是这归因于靶细胞中HER2降解引起的表面HER2减少。在我们的研究中，我们设计了可靶向HER2的DNA适体-DM1共轭物（HApDC），可维持目标癌细胞表面HER2的稳态。通过确定HApDC在过表达HER2的BT474和SKBR3癌细胞系中的有效内在化以及在HApDC处理过的BT474细胞上鉴定膜性HER2水平，可以支持这些结论。与令人印象深刻的体外一致由于适体的特异性识别，我们新开发的抗癌药DM1的特性可以精确地传递到BT474异种移植小鼠模型的肿瘤组织中。值得注意的是，与游离药物相比，HApDC表现出优异的体内肿瘤抑制功能，而健康器官毒性则低得多，这可能是由于持久靶向DM1的传递所致，这归因于细胞上剩余的HER2水平。
更新日期：2020-07-15
中文翻译：
Aptamer通过维持HER2靶向癌症治疗的受体稳态来实现稳定的美登素递送。
尽管ADC trastuzumab-DM1（T-DM1）在针对人类表皮生长因子受体2（HER2）的癌症治疗中得到了广泛的临床应用，但许多最初对T-DM1治疗有反应的患者最终遇到了疗效不足的问题，部分原因是这归因于靶细胞中HER2降解引起的表面HER2减少。在我们的研究中，我们设计了可靶向HER2的DNA适体-DM1共轭物（HApDC），可维持目标癌细胞表面HER2的稳态。通过确定HApDC在过表达HER2的BT474和SKBR3癌细胞系中的有效内在化以及在HApDC处理过的BT474细胞上鉴定膜性HER2水平，可以支持这些结论。与令人印象深刻的体外一致由于适体的特异性识别，我们新开发的抗癌药DM1的特性可以精确地传递到BT474异种移植小鼠模型的肿瘤组织中。值得注意的是，与游离药物相比，HApDC表现出优异的体内肿瘤抑制功能，而健康器官毒性则低得多，这可能是由于持久靶向DM1的传递所致，这归因于细胞上剩余的HER2水平。
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