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诊断为早期浸润性乳腺癌患者最常见的外科手术。明确的肿瘤边缘和完整的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，还没有准确的方法来确定术前或术中的肿瘤边缘。大约20%至30%的接受肿块切除术的患者由于存在阳性肿瘤边缘而需要额外的手术来切除任何剩余的肿瘤。为了开发一种检测乳腺组织中肿瘤边缘的灵敏方法，我们建议通过用近红外（NIR）染料标记含有尿激酶纤溶酶原激活剂（uPA）的受体结合结构域（ATF）的肽，然后将这些复合物缀合到磁性氧化铁（IO）纳米颗粒上，来设计肿瘤靶向纳米颗粒成像探针。这项拟议研究的目的是：1）开发靶向uPA细胞受体的新型NIR光学成像纳米探针; 2）开发用于成像引导手术的灵敏荧光断层扫描系统，旨在完全去除乳腺组织内的肿瘤病变; 3）检查光学成像引导的乳腺肿瘤切除术对小鼠乳腺肿瘤模型中局部肿瘤复发和转移的影响。新型肿瘤靶向近红外成像纳米探针的开发，结合灵敏和高分辨率的近红外荧光断层扫描系统，应该具有在手术期间确定肿瘤边缘，预防肿瘤复发，从而提高乳腺癌患者生存率的巨大潜力。 公共卫生相关性这项拟议研究的目的是开发一种新的光学成像方法，将肿瘤靶向光学成像探头与先进的光学成像仪器相结合，用于检测乳腺癌，并在保乳手术期间勾画肿瘤边界。在本研究中，我们将开发尿激酶纤溶酶原激活物受体（uPAR）靶向的近红外（NIR）染料标记的纳米粒子，将成像探针递送到乳腺肿瘤中，使用3D扩散荧光断层扫描检测肿瘤的位置和深度。这项研究的成功将为我们提供新的光学成像剂和仪器，以解决保乳手术后预防肿瘤复发的迫切需要，并最终提高乳腺癌患者的生存率。

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.