Near-Infrared Nanopolymer Agents for Real-Time, In Vivo Imaging of Tumor Margins

描述(申请人提供)：光学成像作为一种非侵入性诊断技术，在保乳手术中实时、活体检测肿瘤边缘是一种非常有前途的工具。这可以减少传统诊断和肿块切除术后癌症的假阴性诊断和局部复发。由于缺乏合适的显像剂，其临床应用一直受到阻碍。显然有必要开发显像剂以扩大光学成像方法在实时乳腺癌诊断中的应用。实时试剂的挑战需要深入的组织渗透和可视化，良好的生物兼容性和稳定性，以及区分恶性肿瘤细胞和周围健康细胞的能力。为了应对这一挑战，我们建议开发新型近红外(NIR)纳米聚合物试剂，通过识别肿瘤细胞中特异表达的分子来实时识别肿瘤边缘。一系列与癌细胞上的整合素特异结合的肿瘤归巢多肽将被引入到聚合物试剂中，并进行优化肿瘤结合特异性的测试。我们的概念是基于固有的近红外荧光共轭聚合物骨架，其特点是：a)高强度和光稳定性，b)深层组织穿透，c)对肿瘤细胞的特异性敏感性，d)生物兼容性和e)低成本生产。近红外荧光成像是一条已经建立的结合了化学和光学表征的共轭聚合物合成路线，将是协同工作的起点。在我们重要的初步结果的基础上，第一阶段的研究将首先通过将多个近红外荧光团和高密度生物相容侧链结合到共轭聚合物主链上来合成设计的试剂，而结合肽将共价连接到侧链上。其次，作为概念验证，我们将论证在更大的细胞群中对肿瘤细胞和小簇肿瘤细胞(1 Mm)进行成像检测的可行性。第二阶段的工作将集中在纳米聚合物试剂的进一步开发上，并提供合成近红外成像剂的成熟协议。我们将使用非侵入性光学成像系统(IVIS 50Fro Xenogen)在动物模型成像中验证我们的纳米聚合物试剂对乳腺肿瘤边缘的实时成像。第二阶段的成功将提供一系列适用于实时识别乳腺癌边缘的光学成像剂。这些药物将主要销售给制药公司，供FDA批准和临床测试。

DESCRIPTION (provided by applicant): Optical imaging as a noninvasive diagnosis technique is a highly promising tool for real-time, in-vivo detection of tumor margins during breast-conserving surgery. This can decrease false-negative diagnoses and local recurrences of the cancer that occur after conventional diagnoses and lumpectomy. Its clinical application has been held back by lack of suitable imaging agents. There is a clear need to develop imaging agents for extending applications of optical imaging method for real-time breast cancer diagnosis. The challenge of a real- time agent requires deep tissue penetration and visualization, good biocompatibility and stability, as well as capability to distinguish malignant cancer cells from surrounding healthy cells. To address the challenge, we propose to develop novel near-infrared (NIR) nanopolymer agents to real-time identify tumor margins through recognition of molecules that are specifically expressed in tumor cells. A series of tumor-homing peptides for specific binding integrins on cancer cells will be introduced to the polymer agent and tested for optimizing tumor-binding specificity. Our concept is based on an intrinsic NIR-fluorescent conjugated polymer backbone which features: a) high intensity and photostability, b) deep tissue penetration, c) specific sensitivity to tumor cells, d) biocompatibility and e) low cost production. An already established conjugated polymer synthetic route, incorporating chemical and optical characterization, NIR fluorescent imaging will be the starting point for the synergistic effort. Building on our significant preliminary results, the Phase I research will first synthesize the designed agent by incorporating multi-NIR fluorophores and high-density biocompatible side-chains to the conjugated polymer backbone, while the binding peptide will be covalently linked to the side chain. Secondly, we will demonstrate the feasibility of imaging-detection of tumor cells and small clusters of tumor cells (1 mm) within a larger population of cells as proof-of-concept. Phase II efforts will focus on further development of the nanopolymer agent, and deliver mature protocols for synthesis of the NIR imaging agent. We will validate the real-time imaging of breast tumor margin of our nanopolymer agents in animal model imaging using a non-invasive optical imaging system (IVIS 50 fro Xenogen). The success of Phase II will provide a list of optical imaging agents suitable for real-time identification of breast cancer margins. The agents will be primarily marketed to pharmaceutical companies for FDA approval and clinical testing.