Targeted Gold Nanoparticle-Bioconjugates for Imaging Breast Cancer

描述（由申请人提供）：本申请描述了一种基于金纳米颗粒的新型生物偶联物的设计，该生物偶联物来源于合成bombesin （BBN）类似物，用于生产新一代针对乳腺癌细胞特异性体内靶向的定点计算机断层扫描（CT）显像剂。以更好的特异性观察较小的病变（从而早期发现癌症）为首要目标，这项工作有可能提高乳腺癌的存活率。具体来说，该应用将探索靶向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。我们提出的项目的具体目标是：(i)优化靶向金纳米颗粒（AuNPs）与肿瘤特异性肽结合的合成方案；（ii）确定必要的金纳米颗粒浓度，以便在使用人类乳房拟人化幻影模型（包括恶性病变）的CT成像中诱导图像对比度；（iii）研究Bombesin结合的AuNPs作为图像增强剂在植入人类乳腺癌异种移植物的SCID小鼠乳腺肿瘤的计算机断层扫描（CT）成像中的应用。幻影研究将进行评估所需的AuNP浓度，以产生足够的造影剂，有效地检测乳腺癌专门设计的乳腺CT扫描仪。这种评估将根据辐射剂量和病变的大小进行；预计提高造影剂将导致早期发现最小的乳腺癌（原位和微创）。将不同大小和形状的金纳米颗粒（AuNPs）与合成的BBN类似物结合的方法和方法将被开发出来，这些类似物可以维持或增强乳腺癌细胞的高结合，并具有良好的体外和体内稳定性。最有希望的靶向AuNP-BBN候选药物将在植入乳腺肿瘤异种移植物的SCID小鼠中进行评估，以评估其靶向乳腺肿瘤的能力。这些研究的目标是提供靶向AuNP-BBN类似物，通过人体临床试验，可以开发成有效的分子显像剂，用于乳腺肿瘤患者的早期诊断。我们应用的具体目标包括开发新的分子成像探针，用于乳腺癌的早期检测，使用纳米技术原理与当前RFA“PAR-06-475-生物学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。建议的工作将开发一个增强目前的计算机断层扫描（CT）成像的乳房。该研究将利用比人体细胞小1000倍左右的纳米级金粒子，产生x射线造影剂，通过体外的ct成像仪器检测。如果将针对乳腺癌的分子附着在金纳米颗粒上，使其定位在乳腺癌细胞中，所产生的对比将使癌症更容易被发现。这有可能改善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.