Targeted Therapy of Triple Negative Breast Cancer Using Theranostic Nanoparticles

描述（由申请人提供）：在全球每年新诊断的100万例乳腺癌中，超过17万例是一种独特类型的三阴性乳腺癌（TNBC）。TNBC缺乏雌激素（ER）、孕激素（PR）和Her-2/neu的表达。它不是两种常见的乳腺癌治疗方法：激素（他莫昔芬）和Her-2靶向（赫赛汀）治疗的候选药物。TNBC通常在晚期发现，局部和远处复发的可能性较高，预后较差。本研究的目的是开发一种完整的治疗方法，将靶向术前辅助治疗与图像引导治疗和手术相结合，以预防局部复发和远处转移。我们的团队开发了一种多功能纳米粒子平台，可以携带治疗剂，靶向肿瘤细胞和基质组织，并产生光学和磁共振成像信号。我们在TNBC动物模型中证明了靶向肿瘤成像、肿瘤生长抑制和抗血管生成的能力。在本研究中，我们将开发受体靶向和近红外染料标记的磁性氧化铁纳米颗粒（IONPs）。这些纳米颗粒将携带不含或含聚ADP核糖聚合酶（PARP）抑制剂的DNA损伤药物，用于治疗TNBC， MRI监测药物传递和反应，以及光学图像引导手术。我们假设，使用治疗性纳米颗粒靶向递送高浓度的联合治疗剂，并及时评估药物递送和治疗反应，可以增强对耐药肿瘤细胞的治疗效果，同时最大限度地减少全身毒性。靶向治疗后的图像引导手术可以切除小的耐药残余肿瘤病灶，从而防止局部复发和远处转移。首先，尿激酶纤溶酶原激活剂受体（uPAR）和表皮生长因子受体（EGFR）将被验证为靶向治疗的分子靶点，使用两个大队列（约3000例）乳腺癌组织（Aim 1）。我们将生产新一代的治疗性纳米颗粒，通过避免巨噬细胞的摄取和增加药物的装载和释放，增强药物进入肿瘤的递送。我们将确定生物分布、靶向治疗效果、mri引导给药和评估TNBC动物模型中使用不同治疗性IONPs的反应，以选择用于进一步临床前研究的先导治疗性IONPs（目的2）。我们将使用携带原位TNBC的小鼠来研究术前靶向新辅助治疗、通过无创MRI监测治疗反应以及给予治疗性IONPs后术中肿瘤病变光学成像对小鼠局部和远处复发发生率以及总生存率的影响（目的3）。我们将在正常小鼠和荷瘤小鼠中检查所选择的铅治疗性IONPs的全身毒性和药代动力学/药效学（目的4）。临床影响：提出的研究解决了TNBC临床管理的迫切需要，以提高TNBC患者的生存率。

DESCRIPTION (provided by applicant): Of the 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases are a distinct type of triple-negative breast cancer (TNBC). TNBC lacks expression of estrogen (ER), progesterone (PR) and Her-2/neu. It is not a candidate for two common therapies for breast cancer: hormonal (tamoxifen) and Her-2 targeted (Herceptin) therapy. TNBC is usually found at the late stage and has a higher likelihood of local and distant recurrence and a poor prognosis. The goal of this study is to develop a complete therapeutic approach that merges targeted preoperative adjuvant therapy and image-guided treatment and surgery for preventing local recurrence and distant metastasis. Our team has developed a multifunctional nanoparticle platform that carries therapeutic agents, targets tumor cells and stromal tissues, and produces optical and MR imaging signals. We demonstrated the ability of targeted tumor imaging, tumor growth inhibition, and anti- angiogenesis effects in TNBC animal models. In the proposed study, we will develop receptor-targeted and near infrared dye labeled-magnetic iron oxide nanoparticles (IONPs). These nanoparticles will carry DNA damaging drugs without or with a poly ADP ribose polymerase (PARP) inhibitor for treatment of TNBC, MRI monitoring of drug delivery and response, and optical image-guided surgery. We hypothesize that targeted delivery of high concentrations of the combined therapeutic agents using theranostic nanoparticles and timely assessment of drug delivery and response to the treatment could lead to enhanced therapeutic effects in drug resistant tumor cells, while minimizing systemic toxicity. Image-guided surgery following the targeted therapy allows removal of small drug-resistant residual tumor lesions, which could prevent the development of local recurrence and distant metastasis. First, urokinase plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) will be validated as molecular targets for targeted therapeutics using two large cohorts (>3000 cases) of breast cancer tissues (Aim 1). We will produce a new generation of theranostic nanoparticles with enhanced drug delivery into the tumor by avoiding macrophage uptake and increasing in drug loading and release. We will determine biodistribution, and the effects of targeted therapy, MRI-guided drug delivery and evaluating response in TNBC animal models using different theranostic IONPs to select the lead theranostic IONPs for further preclinical studies (Aim 2). We will use the mice bearing orthotopic TNBC to study the effects of integration of preoperative targeted neoadjuvant therapy, monitoring therapeutic responses by non-invasive MRI, and intraoperative optical imaging of tumor lesions after administration of the theranostic IONPs on the incidences of local and distant recurrence as well as overall survival of the mice (Aim 3). We will examine systemic toxicity, and pharmacokinetics/pharmacodynamics of the selected lead theranostic IONPs in normal and tumor bearing mice (Aim 4). Clinical impact: The proposed study addresses the urgent need in clinical management of TNBC to improve the survival of patients afflicted with TNBC.