Targeted Therapy of Triple Negative Breast Cancer Using Theranostic Nanoparticles

使用治疗诊断纳米颗粒靶向治疗三阴性乳腺癌

• 批准号: 8333962
• 负责人: Lily Yang
• 金额: $ 33.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333962
• 关键词: Address; Adjuvant Therapy; Animal Model; Biodistribution; Cancer Patient; Cell Line; Cell surface; Clinical; Clinical Management; Clinical Protocols; Clinical Trials; DNA Damage; Data; Detection; Development; Diagnostic; Disease-Free Survival; Distant; Distant Metastasis; Dose; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Dyes; ERBB2 gene; Effectiveness; Encapsulated; Endothelial Cells; Epidermal Growth Factor Receptor; Estrogens; Excision; Figs - dietary; Gene Expression Profiling; Generations; Goals; Hormonal; Human; Image; Image-Guided Surgery; Imaging Device; Incidence; Individual; Label; Lead; Lesion; Magnetic Resonance Imaging; Magnetism; Mammary Neoplasms; Mammary gland; Measures; Modeling; Molecular Target; Monitor; Mus; Neoadjuvant Therapy; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Poly(ADP-ribose) Polymerases; Progesterone; Protocols documentation; Recurrence; Research Project Grants; Residual Tumors; Residual state; Roche brand of trastuzumab; Serological; Signal Transduction; Specificity; Staging; System; Tamoxifen; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Uses; Tissue Sample; Tissues; Toxic effect; Tumor Tissue; Urokinase Plasminogen Activator Receptor; antiangiogenesis therapy; cDNA Arrays; chemotherapy; cohort; dosage; effective therapy; gemcitabine; image guided therapy; imaging modality; improved; in vitro testing; inhibitor/antagonist; iron oxide; macrophage; malignant breast neoplasm; nanoparticle; nanotherapy; neoplastic cell; novel; optical imaging; outcome forecast; preclinical study; prevent; receptor; receptor expression; response; targeted delivery; theranostics; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; uptake

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.

描述(申请人提供)：在全世界每年新诊断的100万例乳腺癌中，超过17万例是一种独特的三阴性乳腺癌(TNBC)。TNBC缺乏雌激素(ER)、孕酮(PR)和HER-2/neu的表达。它不是乳腺癌两种常见疗法的候选者：激素疗法(他莫昔芬)和HER-2靶向疗法(赫赛汀)。TNBC通常发现于晚期，局部和远处复发的可能性较高，预后较差。这项研究的目标是开发一种完整的治疗方法，将术前有针对性的辅助治疗与影像引导治疗和手术相结合，以防止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，靶向肿瘤细胞和间质组织，并产生光学和磁共振成像信号。我们在TNBC动物模型中展示了靶向肿瘤成像、肿瘤生长抑制和抗血管生成的能力。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颗粒(IONPs)。这些纳米颗粒将携带DNA损伤药物，不使用或与聚ADP核糖聚合酶(PARP)抑制剂一起用于治疗TNBC，药物输送和反应的磁共振监测，以及光学图像引导手术。我们假设，使用抗肿瘤纳米粒靶向输送高浓度的联合治疗药物，并及时评估药物输送和治疗反应，可以增强耐药肿瘤细胞的治疗效果，同时将全身毒性降至最低。靶向治疗后的影像引导手术可以切除微小的耐药残留肿瘤病变，这可以防止局部复发和远处转移。首先，尿激酶型纤溶酶原激活剂受体(UPAR)和表皮生长因子受体(EGFR)将被确认为靶向治疗的分子靶点，使用两个大型队列(3000例)乳腺癌组织(目标1)。我们将生产新一代治疗纳米粒，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向肿瘤的输送。我们将确定生物分布，以及靶向治疗、MRI引导的药物传递和评估反应在使用不同治疗IONPs的TNBC动物模型中的效果，以选择用于进一步临床前研究的领先治疗IONPs(目标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、无创MRI监测治疗反应以及术中应用经鼻腔注射IONPs后肿瘤病变的光学成像对小鼠局部和远处复发以及总体生存的影响(目标3)。我们将在正常和荷瘤小鼠身上测试选定的铅消融IONPs的系统毒性和药代动力学/药效学(目标4)。临床影响：拟议的研究解决了TNBC临床管理中的迫切需要，以提高患有TNBC的患者的存活率。