NEXT GENERATION APPROACHES TO BREAST CANCER USING IMAGE GUIDED DRUG DELIVERY

使用图像引导药物输送的下一代乳腺癌治疗方法

• 批准号: 8848042
• 负责人: Gregory M Lanza
• 金额: $ 48.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848042
• 关键词: 4T1; Acute; Adjuvant Therapy; Adverse effects; Angiogenesis Inhibitors; Angiogenic Factor; Apoptosis; Bioluminescence; Breast; Breast Cancer Patient; Breast Carcinoma; Clinic; Clinical; Clinical Trials; Data; Dependence; Dose; Drug Delivery Systems; Endothelium; Exhibits; Fatty acid glycerol esters; Fluorescence; Injection of therapeutic agent; Ligands; Lipase; Location; Magnetic Resonance Imaging; Maintenance Therapy; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Mammary Neoplasms; Mammary gland; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Modeling; Myeloid Cells; Neoplasm Metastasis; Nuclear; Oryctolagus cuniculus; Osteoclasts; Osteolysis; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Play; Prodrugs; Recommendation; Recruitment Activity; Resistance; Role; Safety; Solid Neoplasm; Staging; System; TRANCE protein; Therapeutic; Treatment Cost; Tumor Angiogenesis; Tumor Burden; Tumor necrosis factor receptor 11b; Tyrosine Kinase Inhibitor; Visceral; Woman; Xenograft Model; Zoledronic Acid; angiogenesis; antiangiogenesis therapy; base; bevacizumab; bioluminescence imaging; bisphosphonate; bone; chemotherapy; compare effectiveness; cytotoxic; density; fumagillin; image guided; implantation; improved; malignant breast neoplasm; molecular imaging; nanomedicine; nanoparticle; neovascular; neovasculature; next generation; receptor; response; soft tissue; theranostics; therapeutic angiogenesis; treatment response; tumor; tumor growth; tumor progression

Angiogenesis is a critical feature of malignant tumor growth and metastasis and anti-angiogenesis targeting has improved survival in numerous solid tumor malignancies. However, anti-angiogenesis therapy cannot be expected to be equally effective across tumor types, sizes, locations, stages and grades. The utility of antiangiogenesis treatment with bevacizumab in breast cancer has been hotly debated in the press and scientific forums based on recent clinical trial data, however, current clinical recommendations affirm bevacizumab as an appropriate therapeutic option in combination with paclitaxel for metastatic breast cancer. In this proposal, we hypothesize that the identification of breast cancers with active neoangiogenesis will enhance the efficacy of targeted antiangiogenesis therapy. We contend that a compelling clinical need exists for quantitative molecular imaging to identify and follow breast cancer patients likely to respond to anti-angiogenic treatment. Although anti-VEGF monoclonal and receptor tyrosine kinase inhibitor drugs are approved in the clinic as antiangiogenic treatments, costing >$100,000/patient and exhibiting well documented adverse effects, alternative theranostic nanomedicine approaches specifically targeting neovessel endothelium with minute doses of highly potent, compounds, such as fumagillin, may represent an improved approach. We hypothesize that the efficacy of theranostic nanoparticles targeted to neovessel endothelium will reflect tumor dependence on angiogenesis for progression. We further hypothesize that the benefits of theranostic antiangiogenic nanoparticles can be enhanced using non-cross resistant anti-angiogeneic compounds,such as amino-bisphosphonates that have direct and indirect cytotoxic effects on neoangiogenesis and tumor-recruited myeloid cells that secrete pro-angiogeneic factors. Osteoprotegerin (OPG) receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL) pathway plays a central role in bone destruction through osteoclast differentiation and osteolysis due to bone metastasis, which occurs in 70% of women with breast cancer. While amino-bisphosphonates (N-BP) and RANKL-Ab disrupt the OPG-RANK-RANKL system, inhibiting osteoclast formation or function, they can also induce apoptosis and antiangiogenesis in some cancers, including breast. We hypothesize that acute nanomedicine-based antiangiogenic therapy combined with N-BP treatment would be effective as pre-adjuvant and maintenance therapy. The specific aims of this study are: Aim 1. Compare the effectiveness of anti-angiogenesis and tumor progression with bevacizumab versus ¿v¿3- fumagillin-prodrug nanoparticles in soft tissue, visceral, and metastases and correlate treatment response with pretreatment tumor size and neovasculature character. Aim 2. Determine the efficacy of N-BP in combination with theranostic nanoparticles targeted to neovessel endothelium on breast cancer tumor growth, metastasis and survival.

血管生成是恶性肿瘤生长和转移的关键特征，抗血管生成靶向治疗 改善了多种实体瘤恶性肿瘤的生存率。然而，抗血管生成治疗不能 预计对于不同的肿瘤类型、大小、位置、阶段和级别同样有效。的效用 使用贝伐珠单抗治疗乳腺癌的抗血管生成治疗在媒体和媒体上引起了激烈争论 基于最近临床试验数据的科学论坛，然而，当前的临床建议肯定 贝伐珠单抗与紫杉醇联合治疗转移性乳腺癌是一种合适的治疗选择。 在这个提议中，我们假设鉴定具有活跃的新血管生成的乳腺癌 将增强靶向抗血管生成治疗的疗效。我们认为，令人信服的临床 需要定量分子成像来识别和跟踪可能患有乳腺癌的患者 对抗血管生成治疗有反应。虽然抗 VEGF 单克隆和受体酪氨酸激酶 抑制剂药物在临床上被批准作为抗血管生成治疗，每个患者的费用> 100,000 美元 表现出有据可查的副作用，替代治疗诊断纳米医学方法特别 用小剂量的高效化合物（例如夫马洁林）靶向新血管内皮，可能 代表一种改进的方法。我们假设治疗诊断纳米颗粒的功效针对 新血管内皮将反映肿瘤进展对血管生成的依赖。我们进一步 假设使用非交叉可以增强治疗诊断抗血管生成纳米颗粒的益处 耐药性抗血管生成化合物，例如具有直接和间接细胞毒性的氨基二膦酸盐 对新血管生成和肿瘤招募的分泌促血管生成因子的骨髓细胞的影响。 核因子 kB (RANK) 和 RANK 配体 (RANKL) 途径的骨保护素 (OPG) 受体激活剂 通过破骨细胞分化和骨溶解作用在骨质破坏中发挥核心作用 转移，70% 的乳腺癌女性会发生转移。而氨基二膦酸盐 (N-BP) 和 RANKL-Ab 破坏 OPG-RANK-RANKL 系统，抑制破骨细胞的形成或功能，它们还可以 在某些癌症（包括乳腺癌）中诱导细胞凋亡和抗血管生成。我们假设急性 基于纳米药物的抗血管生成治疗联合 N-BP 治疗作为预辅助治疗将是有效的 和维持治疗。本研究的具体目的是： 目标 1. 比较贝伐珠单抗抗血管生成和肿瘤进展的有效性 与软组织、内脏和转移中的 ¿v¿3-夫马洁林前药纳米颗粒相比并相互关联 治疗反应与治疗前肿瘤大小和新血管特征有关。 目标 2. 确定 N-BP 与治疗诊断纳米粒子结合的功效 新血管内皮对乳腺癌肿瘤生长、转移和存活的影响。

项目成果

Synthesis and characterization of membrane stable bis(arylimino)isoindole dyes and their potential application in nano-biotechnology.

膜稳定双(芳基亚氨基)异吲哚染料的合成和表征及其在纳米生物技术中的潜在应用。

• DOI: 10.1016/j.tetlet.2012.05.128
• 发表时间: 2012
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Kim,Benjamin;Yalaz,Ceren;Pan,Dipanjan
• 通讯作者: Pan,Dipanjan