Theranostic Nanomedicine for Breast Cancer Prevention and Image-Guided Therapy

用于乳腺癌预防和图像引导治疗的治疗诊断纳米医学

基本信息

批准号：
8551639
负责人：
Prakash R Rai
金额：
$ 23.07万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551639
关键词：
Aromatase Inhibitors Avastin Biodistribution Biological Availability Biological Products Biological Response Modifier Therapy Borderline Personality Disorder Breast Cancer Model Breast Cancer Prevention Bronchopulmonary Dysplasia Cancer Patient Cetuximab Chemoprevention Chemopreventive Agent Combined Modality Therapy Cytotoxic Chemotherapy Diagnostic Disease Dose Drug Formulations Drug Kinetics ERBB2 gene Encapsulated Epidermal Growth Factor Receptor Estrogen Receptors FDA approved Fenretinide High Risk Woman Image Imagery In Vitro Indocyanine Green Malignant Neoplasms Mammary Neoplasms Membrane Metformin Modeling Molecular Target Mus Nanotechnology Nuclear Protein Operative Surgical Procedures Outcome PTGS2 gene Paclitaxel Patient Care Patients Phase Photochemotherapy Prevention Prevention strategy Preventive Raloxifene Recurrent disease Residual Tumors Retinoids Roche brand of trastuzumab System Therapeutic Time Toxic effect Treatment Efficacy Treatment outcome Vascular Endothelial Growth Factors Woman abstracting anastrozole arm base cancer imaging cancer prevention cancer therapy celecoxib cell killing chemotherapy cytokine cytotoxicity design fluorescence microscope image guided therapy improved in vivo inhibitor/antagonist innovation light treatment malignant breast neoplasm molecular marker nanomedicine nanoparticle neoplastic cell optical imaging receptor binding screening technology development theranostics triple-negative invasive breast carcinoma

项目摘要

Abstract This proposal uses a nanotechnology and optical imaging-based strategy for prevention (AIM 1) and image- guided treatment (Aim 2) of breast cancer (BrCa) by targeting several key molecular targets in 3D cultures and orthotopic murine models. In Aim 1, for BrCa prevention, we propose to use nanotechnology for enhancing outcome by improving bioavailability and limiting toxicity of chemo-preventive agents which include selective estrogen receptor antagonists, aromatase inhibitors, retinoids, COX-2 inhibitors and metformin. The strategy is to use Chemopreventive Nanocells (CPNC) that encapsulate raloxifene, anastrazole, metformin, fenretinide and celecoxib as preventive agents with indocyanine green (ICG) as the imaging agent. In Aim 2, from a treatment perspective the proposal exploits nanotechnology encapsulated chemotherapy for systemic cytotoxic therapy, photodynamic therapy (PDT) for localized cytotoxicity and simultaneous biological therapy to improve the treatment outcomes against HER2 positive and triple negative BrCa. The underlying hypothesis is that cytotoxic therapies combined with simultaneous intracellular targeting of multiple BrCa-associated molecular markers will be an effective combination therapy and will be most useful when incorporated with an imaging system that guides the treatment. The selected markers for the study range from secreted cytokines, vascular endothelial growth factor (VEGF), to membrane bound receptors, epidermal growth factor receptors (EGFR and HER2), their intracellular counterparts (intracellular VEGF ,EGFR and HER2), and the sub-nuclear protein PARP. Our surprising findings of dramatically enhanced tumor cell killing in vitro and in vivo when VEGF or EGFR is targeted intracellularly form the basis of the proposed study. Our strategy is to use a Theranostic Nanocell (TNC) that includes a PDT agent (benzoporphyrin derivative/ BPD, FDA approved agent) and biological agents (Avastin, Cetuximab, Herceptin, Lapatanib and Olapraib) as therapeutics with ICG as the diagnostic component. Nab-paclitaxel, a FDA approved nanoparticle formulation of paclitaxel forms the systemic therapeutic arm. We will use a hyperspectral fluorescence microscope capable of non-invasively imaging BPD and ICG for simultaneous, background-free, quantitative in vivo visualization of breast tumors. This will allow us to establish the pharmacokinetics of TNC and its biodistribution, disease assessment and the initiation of light treatments thus helping enhance overall survival. If successful, this study will impact women at high risk for developing breast cancer, primary BrCa patients or those with residual disease at the time of surgery, as well as women with recurrent disease. The technology development of CPNC and TNC is adaptable to other cancers with potential for impact on cancer prevention and treatment. Deliverables include i) CPNC and TNC fabrication and dosing; ii) 3D and in vivo orthotopic BrCa models for therapeutic screening. This provides the potential for rapid screening to establish individualized patient-specific molecular targets and forms the basis for designing personalized prevention and treatments.

抽象的该提案使用纳米技术和基于光学成像的预防策略（AIM 1）和图像- 通过靶向 3D 培养中的几个关键分子靶点来指导乳腺癌 (BrCa) 的治疗（目标 2）原位小鼠模型。在目标 1 中，对于 BrCa 预防，我们建议使用纳米技术来增强通过提高化学预防剂的生物利用度和限制毒性来实现结果，其中包括选择性雌激素受体拮抗剂、芳香酶抑制剂、类维生素A、COX-2抑制剂和二甲双胍。策略是使用封装有雷洛昔芬、阿那曲唑、二甲双胍、芬维A胺的化学预防纳米细胞 (CPNC) 和塞来昔布作为预防剂，吲哚菁绿（ICG）作为显像剂。在目标 2 中，从治疗观点该提案利用纳米技术封装化疗来治疗全身细胞毒性疗法，光动力疗法（PDT）用于局部细胞毒性和同步生物疗法以改善针对 HER2 阳性和三阴性 BrCa 的治疗结果。基本假设是细胞毒性疗法与同时细胞内靶向多种 BrCa 相关分子相结合标记物将是一种有效的联合疗法，并且与影像学结合时将是最有用的指导治疗的系统。研究选择的标记物包括分泌细胞因子、血管内皮生长因子 (VEGF)、膜结合受体、表皮生长因子受体 (EGFR) 和 HER2）、其细胞内对应物（细胞内 VEGF、EGFR 和 HER2）以及亚核蛋白 PARP。我们令人惊讶的发现是，当 VEGF 或 EGFR 是细胞内靶向的，构成了拟议研究的基础。我们的策略是使用 Theranostic Nanocell (TNC)，包含 PDT 药物（苯并卟啉衍生物/BPD，FDA 批准的药物）和生物制剂（阿瓦斯汀、西妥昔单抗、赫赛汀、拉帕他尼和奥拉普拉布）作为治疗药物，ICG 作为治疗药物诊断组件。 Nab-紫杉醇是 FDA 批准的紫杉醇纳米颗粒制剂全身治疗臂。我们将使用能够非侵入性地观察的高光谱荧光显微镜 BPD 和 ICG 成像可实现乳腺肿瘤的同步、无背景、定量体内可视化。这将使我们能够建立 TNC 的药代动力学及其生物分布、疾病评估和开始光治疗，从而有助于提高总体生存率。如果成功，这项研究将影响女性患乳腺癌的高风险、原发性 BrCa 患者或在接受治疗时有残留疾病的患者手术以及患有复发性疾病的女性。 CPNC和TNC的技术发展适用于其他癌症，对癌症预防和治疗具有潜在影响。可交付成果包括 i) CPNC 和 TNC 的制备和配料； ii) 用于治疗筛选的 3D 和体内原位 BrCa 模型。这提供了快速筛选以建立个性化患者特异性分子靶标和构成设计个性化预防和治疗的基础。