Targeted Gold Nanoparticle-Bioconjugates for Imaging Breast Cancer

描述（由申请人提供）：本申请描述了衍生自合成蛙皮素（BBN）类似物的新的基于金纳米颗粒的生物缀合物的设计，以产生新一代定点计算机断层扫描（CT）成像剂，用于乳腺癌细胞的特异性体内靶向。由于总体目标是以更好的特异性可视化更小的病变（从而更早地检测癌症），这项工作有可能提高乳腺癌的生存率。具体而言，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可用于乳腺癌的精确和准确的功能/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）确定使用人类乳房（包括恶性病变）的拟人模型在CT成像中诱导图像对比度所需的金纳米颗粒浓度;和（iii）研究蛙皮素缀合的AuNP在植入人乳腺癌异种移植物的SCID小鼠中的乳腺肿瘤的计算机断层摄影（CT）成像中作为图像增强剂的效用。将进行体模研究，以评价产生足够对比度所需的AuNP浓度，从而有效检测专门设计的乳腺CT扫描仪的乳腺癌。将根据辐射剂量和病变大小进行评估;预计对比度的提高将导致早期检测到微小乳腺癌（原位和微创）。将开发将不同尺寸和形状的金纳米颗粒（AuNPs）与合成的BBN类似物缀合的方法和途径，所述合成的BBN类似物以良好的体外和体内稳定性维持或增强高乳腺癌细胞结合。最有希望的靶向AuNP-BBN候选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的AuNP-BBN类似物，其可以通过人体临床试验开发成有效的分子成像剂，用于乳腺肿瘤患者的早期诊断应用。我们申请的具体目标包括开发新的分子成像探针，用于早期检测乳腺癌，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）”中寻求的总体结果直接相关。拟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。该研究将利用比人类细胞小约1000倍的纳米级金颗粒来产生X射线对比度，该对比度将由体外CT成像仪器检测到。如果将乳腺癌特异性分子附着在金纳米粒子上，使其定位在乳腺癌细胞中，则所产生的对比度将使癌症更容易被检测到。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.