Targeted Gold Nanoparticle-Bioconjugates for Imaging Breast Cancer

描述(申请人提供)：本申请描述了从合成蛙皮素(BBN)类似物中提取的新的基于金纳米颗粒的生物结合物的设计，以生产用于特定体内靶向乳腺癌细胞的新一代定点计算机断层扫描(CT)显像剂。这项工作的首要目标是以更好的特异性可视化较小的病变(因此更早发现癌症)，这项工作有可能提高乳腺癌的存活率。具体地说，这项应用将探索目标金纳米颗粒是否能够产生对比度增强(增加X射线衰减)，以便CT可以用于精确和准确的乳腺癌功能/分子成像。我们拟议项目的具体目标是：(I)优化与肿瘤特异性多肽结合的靶向纳米金(AuNPs)的合成方案；(Ii)利用人体乳腺(包括恶性肿瘤)的拟人模型，确定在CT成像中诱导图像对比所需的金纳米颗粒的浓度；以及(Iii)研究蛙素偶联的AuNPs作为图像增强剂在植入人乳腺癌异种移植的SCID小鼠乳腺肿瘤的计算机断层扫描(CT)成像中的应用。将进行体模研究，以评估产生足够对比度以有效检测乳腺癌所需的AuNP浓度，以用于专门设计的乳房CT扫描仪。这项评估将根据辐射剂量和病变的大小进行；预计增强的对比度将导致早期发现微小乳腺癌(原位和微创)。不同大小和形状的金纳米颗粒(AuNPs)与合成的BBN类似物偶联的途径和方法将被开发，这些合成的BBN类似物在体外和体内具有良好的稳定性，保持或增强高结合的乳腺癌细胞。最有希望的靶向AuNP-BBN候选将在植入乳腺癌异种移植的SCID小鼠中进行评估，以评估它们靶向乳腺肿瘤的能力。这些研究的目标是提供有针对性的AuNP-BBN类似物，这些类似物可以通过人体临床试验开发成有效的分子显像剂，用于乳腺癌患者的早期诊断。我们应用程序的具体目标包括利用纳米技术原理开发用于乳腺癌早期检测的新分子成像探针，这与当前RFA“PAR-06-475-生物和医学中的纳米科学和纳米技术(R21)”所寻求的总体结果直接相关。这项拟议的工作将对目前的乳房计算机断层扫描(CT)成像进行增强。这项研究将利用比人体细胞小约1000倍的纳米金粒子来产生X射线对比度，这种对比度将被体外的CT成像仪器检测到。如果特定于乳腺癌的分子被连接到金纳米颗粒上，使它们位于乳腺癌的细胞中，产生的对比度将使癌症更容易被检测到。这有可能提高乳腺癌的早期发现和诊断。

DESCRIPTION (provided by applicant): This application describes the design of new gold nanoparticle based bioconjugates derived from synthetic bombesin (BBN) analogues to produce a new generation of site-directed computed tomography (CT) imaging agents for specific in vivo targeting of breast cancer cells. With the overarching goal of visualizing smaller lesion (and therefore earlier cancer detection) with better specificity, this work has the potential to increase the survival rate from breast cancer. Specifically, this application will explore whether targeted gold nanoparticles are capable of producing contrast enhancement (increased x-ray attenuation) so that CT can be used in precise and accurate functional/molecular imaging of breast cancer. Our specific aims for the proposed project are to: (i) Optimize synthetic protocols for targeted gold nanoparticles (AuNPs) conjugated to tumor specific peptide; (ii) Determine the concentrations of gold nanoparticles necessary to induce image contrast in CT imaging using anthropomorphic phantom models of the human breast, including malignant lesions; and (iii) Investigate the utility of Bombesin conjugated AuNPs as image enhancers in computer tomographic (CT) imaging of breast tumors in SCID mice implanted with human breast cancer xenografts. Phantom studies will be performed to evaluate the concentration of AuNP required to produce sufficient contrast to effectively detect breast cancer for a specifically designed Breast CT scanner. This assessment will be done with respect to radiation dose and the size of the lesion; it is anticipated that improved contrast will lead to earlier detection of minimal breast cancer (in situ and minimally invasive). Approaches and methods to conjugate different sizes and shapes of gold nanoparticles (AuNPs) with synthetic BBN analogues that maintain or enhance high breast cancer cell binding with good in vitro and in vivo stability, will be developed. The most promising targeted AuNP-BBN candidates will be evaluated in SCID mice implanted with breast tumor xenografts, to assess their ability to target breast tumors. The goal of these studies is to provide targeted AuNP-BBN analogues that could be developed, via human clinical trials, into effective molecular imaging agents for early diagnostic application in breast tumor patients. The specific objective of our application encompassing the development of new molecular imaging probes, for the early detection of breast cancer, using nanotechnology principles is directly relevant to the overall outcomes sought within the current RFA "PAR-06-475- Nanoscience and nanotechnology in Biology and Medicine (R21)". The proposed work will develop an enhancement of current Computer Tomography (CT) imaging of the breast. The research will utilize nanosized gold particles that are approximately 1000 times smaller than a human cell to generate X-ray contrast that would be detected by a CT-imaging instrument external to the body. If molecules specific to breast cancer are attached to the gold nanoparticles so that they locate in the cells of breast cancer, the contrast generated would allow the cancer to be more readily detected. This has the potential to improve the early detection and diagnosis of breast cancer.