Integrin AVB3 Targeted Nanoparticles as a Novel Therapy of Bone Metastases

整合素 AVB3 靶向纳米颗粒作为骨转移的新疗法

• 批准号: 8783385
• 负责人: Alison Esser
• 金额: $ 5.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783385
• 关键词: Accounting; Adhesions; Adjuvant Therapy; Adverse effects; Aftercare; Apoptosis; Apoptotic; Binding; Biological Assay; Blood Circulation; Blood Vessels; Bone Resorption; Bone neoplasms; Breast Cancer Model; Cancer Etiology; Cell Communication; Cell Lineage; Cell Survival; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Cytoplasm; Development; Diagnostic Neoplasm Staging; Dose; Drug Delivery Systems; Drug Targeting; Effectiveness; Endothelial Cells; Goals; Grant; Human; Hypercalcemia; Image; In Vitro; Inflammatory; Integrins; Life; Ligands; Liposomal Doxorubicin; Malignant Neoplasms; Metastatic Neoplasm to the Bone; Methods; Micelles; Mission; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Neoplasm Metastasis; Nerve compression syndrome; Osteoclasts; Pain; Patients; Pharmaceutical Preparations; Population; Prevention; Public Health; Quality of life; Reporter; Research; Research Project Grants; Research Proposals; Role; Safety; Site; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transferrin Receptor; Tumor Burden; Tumor stage; Woman; Xenograft procedure; Zoledronic Acid; bone; bone cell; bone loss; bone turnover; cancer diagnosis; cell type; chemotherapy; docetaxel; improved; in vivo; innovation; macrophage; malignant breast neoplasm; metastasis prevention; mortality; nanoparticle; neoplastic cell; new technology; novel; outcome forecast; overexpression; particle; peptidomimetics; prevent; public health relevance; response; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Little progress has been made in the prevention and treatment of metastatic breast cancer, the primary cause of cancer related deaths. Bone is the most common and often only site of breast cancer metastasis. Thus, there is significant need for new and innovative bone targeted therapies. The role of the microenvironment in facilitating tumor growth is well established yet few targeted therapies are available. Nanoparticles (NPs) represent a new technology for targeted drug delivery to the tumor and tumor supportive cells of the microenvironment. Our long-term goal is to develop novel NP therapies that target both tumor cells and host cells for the treatment of bone metastases. We have developed novel targeted micelle (20nm) NPs that will better exit the tumor vasculature. Our NPs have a novel drug delivery method to deliver drug directly to the cell cytoplasm, increasing intracellular drug concentrations. Specific targeting is critical to the effectiveness of these NPs. We will use a RGD peptidomimetic to target activated ¿v¿3 integrin. ¿v¿3 becomes activated and is highly expressed in poor-prognosis breast cancers and on tumor supportive host cells of the tumor microenvironment particularly in bone (bone destroying osteoclasts, tumor induced blood vessels, and protumor myeloid cells). We hypothesize that activated ¿v¿3 integrin targeted NPs will deliver drug to both tumor and tumor supportive cells of the bone microenvironment. We have proposed the following specific aims: 1) Do ¿v¿3 targeted nanoparticles bind both tumor and host cell types at levels sufficient to produce inhibitory effects on the target cell? We will assess binding and functional effects of NP drug delivery to ¿v¿3 expressing murine and patient tumor lines and myeloid lineage cells. We will assay for changes in viability, adhesion and bone resorption. 2) What cell types of the bone metastatic niche are targeted by ¿v¿3 directed nanoparticles in early and late stage tumors? NP binding depends on the availability of cell types and level of ¿v¿3 expression and activation. We will assess binding to tumor cells, osteoclasts and tumor associated macrophages (TAMs) and endothelial cells. 3) What is the therapeutic potential of ¿v¿3 integrin targeted nanoparticle technologies for the treatment of bone metastases? We will evaluate effects on bone tumor growth and progression after treatment with ¿v¿3 NPs loaded with traditional chemotherapy,docetaxel, and/or ¿v¿3 NPs loaded with the bone and stromal targeted drug, zoledronic acid. We will use both orthotopic primary breast cancer models that metastasize to the bone and intracardiac metastasis models to determine effects on metastasis prevention and on established bone metastases. Nanoparticle localization and specific effects on tumor cell apoptosis, blood vessel number, osteoclast number, bone loss and changes in TAM populations will be assessed. This research project is relevant to the mission of the NCI through the development of novel therapies for the treatment and prevention of metastatic breast cancer.

描述（由申请人提供）：转移性乳腺癌的预防和治疗进展甚微，转移性乳腺癌是癌症相关死亡的主要原因。骨是乳腺癌转移最常见且通常唯一的部位。因此，非常需要新的和创新的骨靶向治疗。微环境在促进肿瘤生长中的作用已经得到了很好的证实，但很少有靶向治疗。纳米颗粒（NPs）代表了一种新的技术，用于靶向药物递送到肿瘤和微环境的肿瘤支持细胞。我们的长期目标是开发新的NP疗法，靶向肿瘤细胞和宿主细胞用于治疗骨转移。我们已经开发了新的靶向胶束（20 nm）纳米粒子，将更好地退出肿瘤脉管系统。我们的NP具有一种新的药物递送方法，将药物直接递送到细胞质，增加细胞内药物浓度。有针对性的针对性对于这些国家方案的有效性至关重要。我们将使用RGD肽模拟物靶向激活的整合素。¿v¿ 3在预后不良的乳腺癌中和肿瘤微环境的肿瘤支持宿主细胞上被激活并高度表达，特别是在骨中（骨破坏破骨细胞、肿瘤诱导的血管和前肿瘤骨髓细胞）。我们假设活化的整合素3靶向纳米颗粒将药物递送到骨微环境的肿瘤和肿瘤支持细胞。我们提出了以下具体目标：1）靶向纳米颗粒是否以足以对靶细胞产生抑制作用的水平结合肿瘤和宿主细胞类型？我们将评估NP药物递送对表达v3的小鼠和患者肿瘤细胞系和髓系细胞的结合和功能作用。我们将测定活力、粘附和骨吸收的变化。2)在早期和晚期肿瘤中，³ v ³ 3定向纳米颗粒针对骨转移小生境的哪些细胞类型？NP结合取决于细胞类型的可用性和V 3表达和激活的水平。我们将评估与肿瘤细胞、破骨细胞和肿瘤相关巨噬细胞（TAM）和内皮细胞的结合。3)整合素3靶向纳米颗粒技术治疗骨转移瘤的治疗潜力是什么？我们将评估用负载传统化疗药物多西他赛的<$v <$$> 3纳米颗粒和/或负载骨和基质靶向药物唑来膦酸的<$v <$3纳米颗粒治疗后对骨肿瘤生长和进展的影响。我们将使用转移到骨的原位原发性乳腺癌模型和心内转移模型来确定对转移预防和对已建立的骨转移的影响。将评估纳米颗粒定位和对肿瘤细胞凋亡、血管数量、破骨细胞数量、骨丢失和TAM群体变化的特异性影响。该研究项目与NCI的使命相关，通过开发治疗和预防转移性乳腺癌的新疗法。