Detection, Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu

无论是在中枢神经系统内，还是在外周神经系统外，癌细胞都在生长 神经作为侵袭和转移的途径称为神经侵袭。这种生长在几种癌症中很常见。 包括乳腺癌，并与预后不良有关。细胞黏附分子的蛋白分解 发生在发育中，越来越多的证据表明这种翻译后修饰可能促进肿瘤 对神经的迁移和侵袭，最终导致各种肿瘤类型的脑转移，包括 乳腺癌。受体蛋白酪氨酸磷酸酶PTPµ是一种CAM，在癌细胞中被蛋白质分解以 产生细胞外片段，这是肿瘤微环境的唯一成像生物标记物。PTP？- 我们开发的靶向药物与这个生物标记物结合，识别人脑肿瘤以及侵袭性肿瘤 原发乳腺癌和已转移到脑的乳腺癌。系统交付PTP？- 在异种移植模型中，靶向制剂在几分钟内就能与肿瘤细胞结合。使用3D冷冻成像 系统中，我们分析了细胞在大脑中迁移和扩散的程度。我们发现PTP-靶向 在小鼠模型中，试剂标记远离主要肿瘤块的所有分散的肿瘤细胞的99%。 这项提议代表了我们在神经科学、细胞黏附、成像和癌症方面的专业知识的融合。 为了测试PTPµ生物标记物是否可以用于检测导致脑转移的神经肿瘤生长情况。 金纳米粒子(AuNPs)在生物医学应用中表现出了卓越的多功能性，包括 影像诊断、药物输送和放射治疗。在这份提案中，我们描述了 医用AuNPs用于乳腺癌转移的检测和治疗。我们将实现更敏感的目标 应用三组分消融剂检测和治疗侵袭性和转移性病变 纳米颗粒包含：1)肿瘤中PTP？生物标志物的高度特异性靶向剂 微环境；2)用于荧光成像的对蛋白酶敏感的近红外荧光团；以及3)a 用于放射增敏的金纳米颗粒(AuNP)。我们将测试PTP？目标代理是否检测到 使用3D单细胞分辨率冷冻成像精确跟踪个体迁移的神经相关生长 神经上的癌细胞。我们将利用我们已建立的人类患者来源的转移性异种移植模型 乳腺癌和从乳房转移到脑的模型。转移性肿瘤对几乎 所有的化疗药物，所以像辐射这样的“物理”杀死策略必须改进和使用，以便更好地使用。 治疗效果。通过将PTPµ靶向结合的AuNPs直接输送到原发和转移性乳房 我们将利用AuNP的放射增敏作用来减少所需的辐射剂量 放射治疗因此减少了对周围正常组织的附带损害。我们预计这些研究 将产生靶向纳米颗粒，在检测和治疗神经相关肿瘤生长的同时牵涉到CAM 蛋白分解是检测和治疗神经肿瘤侵袭的普遍机制。

Both inside the central nervous system and outside in the peripheral nervous system, cancer cells grow along nerves as routes of invasion and metastasis called neural invasion. This growth is common in several carcinomas including breast cancer and is associated with poor prognosis. Proteolysis of cell adhesion molecules (CAMs) occurs in development, and growing evidence suggests this post-translational modification may promote tumor migration and invasion on nerves that ultimately leads to metastasis to the brain in various tumor types including breast cancer. The receptor protein tyrosine phosphatase PTPµ is a CAM that is proteolyzed in cancer cells to generate an extracellular fragment that is a unique imaging biomarker of the tumor microenvironment. The PTPµ- targeted agents we developed bind to this biomarker and recognize human brain tumors as well as invasive primary breast cancer and breast cancer that has metastasized to the brain. Systemic delivery of the PTPµ- targeted agent results in binding to tumor cells within minutes in xenograft models. Using a 3D cryo-imaging system we analyzed the extent of cell migration and dispersal within the brain. We found that the PTPµ-targeted agent labels 99% of all dispersing tumor cells far away from the main tumor mass on nerves in mouse models. This proposal represents the convergence of our expertise in neuroscience, cell adhesion, imaging and cancer to test if the PTPµ biomarker can be used to detect tumor growth along nerves leading to brain metastases. Gold nanoparticles (AuNPs) have shown outstanding versatility in biomedical applications including imaging diagnostics, drug delivery, and radiation therapy. In this proposal, we describe the development of theranostic AuNPs for the detection and treatment of breast cancer metastases. We will achieve more sensitive detection and treatment of invasive and metastatic lesions through the use of a three component theranostic nanoparticle containing: 1) a highly specific targeting agent of the PTPµ biomarker in the tumor microenvironment; 2) a protease-sensitive quenched near infrared fluorophore for fluorescent imaging; and 3) a gold nanoparticle (AuNP) for sensitization to radiotherapy. We will test whether the PTPµ-targeted agents detects nerve associated growth using 3D single cell resolution cryo-imaging that precisely tracks migration of individual cancer cells on nerves. We will utilize our established human patient-derived xenograft models of metastatic breast cancer and models that metastasize from the breast to the brain. Metastatic tumors are resistant to almost all chemotherapeutics so “physical” killing strategies like radiation must be improved and employed for better therapeutic outcomes. By delivering PTPµ-targeted conjugated AuNPs directly to primary and metastatic breast cancer we will exploit the radiosensitization of AuNP to reduce the required dose of radiation needed for radiotherapy thereby reducing collateral damage to normal surrounding tissues. We expect that these studies will yield targeted nanoparticles that detect and treat nerve associated tumor growth while implicating CAM proteolysis as a generalizable mechanism for detecting and treating tumor invasion on nerves.