Application of QDs-based nanotyping technology in the evaluation of chemotherapy

描述(申请人提供)：这个SBIR项目的目标是开发一种多重方法来同时量化不同类型肿瘤组织中生物标记物的表达水平。目前对生物标记物进行诊断和预后分类的方法是基于免疫组织化学(IHC)。然而，免疫酶(基于HRP的)IHC方法具有单一的颜色性质，不能执行多重分子图谱。此外，IHC仍然是半定量的和主观的，导致观察者之间的结果有相当大的差异。量子点(QD)是一类新型的生物检测标记，具有广泛的生物医学应用。它允许在高度异质样本和稀有细胞群中进行生物标记物检测和分析。多路QD技术可以用来在单细胞水平上检测一组癌症生物标志物(原位分析)，这是其他类型的基于纳米技术的分析所不可能做到的。这项NIH SBIR项目旨在开发一种基于量子点的纳米分型方法来监测前列腺癌的化疗效果。特别是，抗凋亡的缓激肽-Survivin信号通路的激活在前列腺癌细胞对多西他赛(Taxotere)耐药中起关键作用，因此，缓激肽-Survivin可以作为预测激素非依赖性前列腺癌患者化疗反应的新的生物标志物。我们将建立一种基于多个量子点的微创技术来监测缓激蛋白-Survivin通路的激活状态，以评估前列腺癌模型的化疗效果。在这个SBIR第一期项目中，我们将制备高质量的具有高生物亲和力和低非特异性结合的量子点。此外，QD-抗体结合物将在人前列腺癌异种移植模型中用于预测多西紫杉醇化疗的反应。在第二阶段，我们的重点将转移到提高拟议系统的灵敏度和开发量化方法上。该项目的最终交付将是一种用于前列腺癌成像的高灵敏度、临床适用的抗体-QD结合试剂盒，它将预测化疗的反应。公共卫生相关性：前列腺癌(PCA)是美国男性中最常见的癌症。2007年，美国估计有218,890例新诊断的前列腺癌病例。加强对癌症治疗的监测对于提高患者的存活率至关重要。拟议的QD纳米分型技术将提供一个平台来监测化疗效果，并指导医生做出适当治疗的决定。该项目的成功开发可以极大地提高这些患者的存活率。

DESCRIPTION (provided by applicant): The goal of this SBIR project is to develop a multiplexing method to simultaneously quantify the expression levels of biomarkers in heterogeneous tumor tissue. The current method for diagnostic and prognostic classifications of biomarkers is based on immunohistochemistry (IHC). However, the immunoenzyme (HRP- based) IHC method has a single color nature and is unable to perform multiplexed molecular profiling. Moreover, IHC remains semi-quantitative and subjective, resulting in considerable inter-observer variation in results. Quantum dots (QD) are a new class of biological detection labels which present a broad range of biomedical applications. It allows biomarker detection and analysis in highly heterogeneous samples and rare cell populations. The multiplexed QD technology can be used to examine a panel of cancer biomarkers on the level of single cells (in situ analysis), which is not possible with other types of nanotechnology-based assays. This NIH SBIR project intends to develop a QDs-based nanotyping method to monitor the chemotherapy efficacy in prostate cancer. Specifically, activation of the anti-apoptotic bradykinin-survivin signaling pathway was found to be critical to Docetaxel (Taxotere) resistance in prostate cancer cells, therefore, bradykinin- survivin could be used as novel biomarkers to predict the chemotherapy response in hormone-refractory prostate cancer patients. We will establish a multiplexed QDs-based, minimally-invasive technology to monitor the activation status of the bradykinin-survivin pathway for evaluating chemotherapy efficacy in prostate cancer models. In this SBIR phase I project, we will prepare high quality QDs with high bio-affinities and low non- specific binding. Furthermore, the QD-antibody conjugates will be tested in the prediction of response to docetaxel chemotherapy in a human prostate cancer xenograft model. In Phase II, our focus will be shifted to improving the sensitivity of the proposed system and developing a quantification method. The final delivery of this project will be a highly sensitive, clinically applicable Ab-QD conjugation kit for prostate tumor imaging that will predict the response of chemotherapy. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the most common cancer occurring among men in the United States. In 2007, an estimated 218,890 new cases of PCa were diagnosed in the U.S. Enhancing monitoring cancer therapy is very critical to increase the survival rate of patients. The proposed QD nanotyping technology will provide a platform to monitor chemotherapy efficacy and guide physicians in making decisions for the appropriate therapy. The successful development of this project can greatly increase the survival rate of these patients.