An imageable retinoid acid derivative to detect human cancer xenografts and study therapeutic dosing to reduce its toxicity
An imageable retinoid acid derivative to detect human cancer xenografts and study therapeutic dosing to reduce its toxicity
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一种可成像的视黄酸衍生物，用于检测人类癌症异种移植物并研究治疗剂量以降低其毒性
DOI：
10.1002/cmmi.419
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发表时间：
2011-07-01
影响因子：
--
通讯作者：
Ke, Shi
中科院分区：
文献类型：
--
作者：
Wang, Wei;Qiu, Xiuchun;Ke, Shi
开发具有“寻找、治疗和观察”能力的药物是个性化分子医学的关键。这些试剂将特异性靶向疾病标志物进行诊断，并应用生物有效剂量进行治疗。类维生素A调节多种生物过程。此外，维甲酸可以逆转癌前病变，显著减少第二原发肿瘤，并在头颈部、肺癌、食道癌、结肠癌和膀胱癌中提供治疗益处。这些数据表明，癌细胞可以摄取类维生素A。因此，类维生素A是潜在的肿瘤显像剂。我们开发了近红外（NIR）标记的类维生素A药物，用于检测人类癌症，可视化药物在体内的再分布，确定最佳生物剂量并降低全身毒性。我们的数据表明，类维生素A剂，而不是游离染料，结合到人类肿瘤细胞和内化，在那里它允许人类癌症异种移植物的成像。高剂量的维甲酸药物与全身毒性显著相关。总之，合成的NIR标记的类维生素A剂可用于检测多种人类癌症异种移植物，因为该剂被癌细胞内化。药剂与肿瘤异种移植物的结合取决于药剂的再分布。标记有报告基因的治疗剂将询问肿瘤-药物相互作用，并允许真实的实时分析生物分布、药代动力学和药效学。同时，我们可以应用生物有效剂量进行治疗，而不是传统的最大耐受剂量，以减少全身毒性。版权所有（C）2010约翰威利父子有限公司
Developing agents with 'seek, treat and see' capability is critical for personalized molecular medicine. Those agents will specifically target the disease markers for diagnosis and apply the biologically effective dose for treatment. Retinoids regulate a multitude of biological processes. In addition, retinoic acid can reverse premalignancy, significantly decrease second primary tumors and provide a treatment benefit in head and neck, lung, esophagus, colon and bladder cancer. These data suggest that cancer cells can take up retinoids. Therefore, retinoids are potential tumor-imaging agents. We developed near-infrared (NIR)-labeled retinoid agents to detect human cancers, visualize drug redistribution within the body, determine the optimal biological dose and reduce systemic toxicity. Our data demonstrate that the retinoid agent, but not the free dye, binds to the human tumor cells and is internalized, where it permits the imaging of human cancer xenografts. The high dose of retinoid agent is significantly associated with systemic toxicity. In summary, synthetic NIR-labeled retinoid agents can be used to detect multiple human cancer xenografts as the agent is internalized by cancer cells. The binding of the agent to the tumor xenografts is dependent on the redistribution of the agent. Therapeutic agents labeled with reporters will interrogate tumor-drug interactions and permit analysis of biodistribution, pharmacokinetics and pharmacodynamics in real time. At the same time, we can apply the biologically effective dose for therapy, instead of the traditional maximum tolerated dose, to reduce systemic toxicity. Copyright (C) 2010 John Wiley & Sons, Ltd.