Targeted Nanoprobes For Intraoperative optical Imaging of Breast Cancer Margins

描述（由申请人提供）：保乳手术，或乳房肿瘤切除术，是早期诊断为浸润性乳腺癌的患者最常见的外科手术。明确肿瘤边缘和完全手术切除肿瘤是预防局部复发和提高无病生存率的关键。目前，没有准确的方法来确定肿瘤边缘术前或术中。由于肿瘤边缘呈阳性，大约20%到30%接受乳房肿瘤切除术的患者需要额外的手术切除任何剩余的肿瘤。为了开发一种检测乳腺组织肿瘤边缘的灵敏方法，我们提出用近红外（NIR）染料标记含有尿激酶纤溶酶原激活物（uPA）受体结合域（ATF）的肽，然后将这些复合物偶联到磁性氧化铁（IO）纳米颗粒上，从而设计一种肿瘤靶向纳米颗粒成像探针。本研究的目的是：1)开发新的靶向uPA细胞受体的近红外光学成像纳米探针；2)开发一种灵敏的荧光断层成像系统，用于成像引导手术，目的是完全切除乳腺组织内的肿瘤病变；3)在小鼠乳腺肿瘤模型中探讨光学成像引导下乳腺肿瘤切除术对肿瘤局部复发和转移的影响。新型肿瘤靶向近红外成像纳米探针的开发，结合灵敏、高分辨率的近红外荧光断层扫描系统，在手术中确定肿瘤边缘，预防肿瘤复发，从而提高乳腺癌患者的生存率方面具有很大的潜力。

DESCRIPTION (provided by applicant): Breast-conserving surgery, or lumpectomy, is the most common surgical procedure for patients diagnosed with an early stage of invasive breast cancer. Clearly defined tumor margins and complete surgical removal of tumors are critical for preventing local recurrence and increasing disease-free survival. Currently, there is no accurate method to identify tumor margins pre- or intra-operatively. About 20% to 30% of the patients who undergo lumpectomy require additional surgery to excise any remaining tumors due to the presence of positive tumor margins. To develop a sensitive approach for detecting tumor margins in breast tissues, we propose to engineer a tumor targeted nanoparticle imaging probe by labeling a peptide containing the receptor binding domain (ATF) of urokinase plasminogen activator (uPA) with a near infrared (NIR) dye and then conjugating these complexes to a magnetic iron oxide (IO) nanoparticle. The objectives of this proposed study are: 1) to develop new NIR optical imaging nanoprobes targeting the cellular receptor for uPA; 2) to develop a sensitive fluorescence tomography system for imaging-guided surgery aimed at completely removing tumor lesions within breast tissue; and 3) to examine the effect of the optical imaging guided resection of mammary tumors on local tumor recurrence and metastasis in a mouse mammary tumor model. The development of novel tumor targeted NIR imaging nanoprobes, in combination with a sensitive and high resolution NIR fluorescence tomography system, should have great potential for determining tumor margins during surgery, preventing tumor recurrence and therefore, increasing the survival rate of breast cancer patients. PUBLIC HEALTH RELEVANCE The objective of this proposed study is to develop a novel optical imaging approach that combines tumor targeted optical imaging probes with advanced optical imaging instrumentation for the detection of breast cancer and for outlining the tumor border during breast conserving surgery. In this study, we will develop urokinase plasminogen activator receptor (uPAR) targeted near infrared (NIR) dye-labeled nanoparticles to deliver the imaging probes into breast tumors, the location and depth of the tumors will be detected using 3D diffuse fluorescence tomography. Success in this proposed study should provide us with novel optical imaging agents as well as instruments to address the urgent need for preventing tumor recurrence after breast conserving surgery and ultimately, to improve the survival rate of breast cancer patients.