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

描述（由申请人提供）：该SBIR项目的目标是开发一种多重方法，以同时定量异质性肿瘤组织中生物标志物的表达水平。目前用于生物标志物的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）IHC方法具有单一颜色性质，无法进行多重分子分析。此外，IHC仍然是半定量和主观的，导致观察者之间的结果差异很大。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。它允许在高度异质的样品和稀有细胞群体中进行生物标志物检测和分析。多重QD技术可用于在单细胞水平上检查一组癌症生物标志物（原位分析），这对于其他类型的基于纳米技术的测定是不可能的。该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疗效。具体地，发现抗凋亡缓激肽-存活素信号通路的激活对于前列腺癌细胞中的多西他赛（泰索帝）抗性至关重要，因此，缓激肽-存活素可用作新的生物标志物来预测难治性前列腺癌患者的化疗反应。我们将建立一种基于量子点的多重微创技术来监测缓激肽-生存素通路的激活状态，以评估前列腺癌模型中化疗的疗效。在这个SBIR第一阶段项目中，我们将制备具有高生物亲和性和低非特异性结合的高质量量子点。此外，将在人前列腺癌异种移植模型中测试QD-抗体缀合物对多西他赛化疗的响应的预测。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。该项目的最终交付将是一个高灵敏度，临床适用的Ab-QD结合试剂盒，用于前列腺肿瘤成像，将预测化疗的反应。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例新的PCa病例被诊断出来。加强对癌症治疗的监测对提高患者的生存率至关重要。拟议的QD纳米分型技术将提供一个平台来监测化疗疗效，并指导医生做出适当的治疗决定。该项目的成功开发可以大大提高这些患者的生存率。

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.