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100万例乳腺癌病例中，超过170，000例是一种独特的三阴性乳腺癌（TNBC）。TNBC缺乏雌激素（ER）、孕激素（PR）和Her-2/neu的表达。它不是乳腺癌两种常见疗法的候选者：激素（他莫昔芬）和Her-2靶向（赫赛汀）疗法。TNBC通常在晚期被发现，并且具有局部和远处复发的更高可能性和不良预后。本研究的目的是开发一种完整的治疗方法，将有针对性的术前辅助治疗和图像引导治疗与手术相结合，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颗粒平台，它携带治疗剂，靶向肿瘤细胞和基质组织，并产生光学和MR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作用的能力。在拟议的研究中，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粒子（IONP）。这些纳米颗粒将携带DNA损伤药物，不含或含有聚ADP核糖聚合酶（PARP）抑制剂，用于治疗TNBC，药物递送和反应的MRI监测以及光学图像引导手术。我们假设，使用治疗诊断纳米颗粒靶向递送高浓度的组合治疗剂，并及时评估药物递送和对治疗的反应，可能会增强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留肿瘤病灶，这可以防止局部复发和远处转移的发展。首先，将使用两个大群组（>3000例）的乳腺癌组织（Aim 1）验证尿激酶纤溶酶原激活物受体（uPAR）和表皮生长因子受体（EGFR）作为靶向治疗的分子靶标。我们将生产新一代的治疗诊断纳米颗粒，通过避免巨噬细胞摄取和增加药物装载和释放来增强药物递送到肿瘤中。我们将使用不同的治疗诊断IONP确定生物分布和靶向治疗的效果，MRI引导的药物递送和评估TNBC动物模型中的反应，以选择用于进一步临床前研究的主要治疗诊断IONP（目的2）。我们将使用携带原位TNBC的小鼠研究术前靶向新辅助治疗的整合，通过非侵入性MRI监测治疗反应，以及给予治疗诊断性IONP后肿瘤病变的术中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）。我们将在正常和荷瘤小鼠中检查所选先导治疗诊断IONP的全身毒性和药代动力学/药效学（目的4）。临床影响：拟议的研究解决了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.