Integrin AVB3 Targeted Nanoparticles as a Novel Therapy of Bone Metastases

描述（由申请人提供）：在预防和治疗转移性乳腺癌方面进展甚微，转移性乳腺癌是癌症相关死亡的主要原因。骨是乳腺癌最常见也是唯一的转移部位。因此，迫切需要创新的骨靶向治疗方法。微环境在促进肿瘤生长中的作用已经得到了很好的证实，但很少有靶向治疗方法可用。纳米颗粒（NPs）代表了一种靶向药物递送到肿瘤和肿瘤支持细胞微环境的新技术。我们的长期目标是开发针对肿瘤细胞和宿主细胞治疗骨转移的新型NP疗法。我们已经开发了新的靶向胶束（20nm） NPs，可以更好地离开肿瘤血管。我们的NPs有一种新的药物传递方法，可以直接将药物传递到细胞质中，增加细胞内药物浓度。具体目标对这些np的有效性至关重要。我们将使用RGD拟肽靶向活化的整合素。¿v¿3在预后不良的乳腺癌和肿瘤微环境的肿瘤支持宿主细胞（破坏骨骼的破骨细胞、肿瘤诱导的血管和肿瘤原髓细胞）中被激活并高度表达。我们假设激活的整合素靶向NPs将药物递送到骨微环境的肿瘤细胞和肿瘤支持细胞。我们提出了以下具体目标：1)靶向纳米颗粒是否能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¿v¿3的小鼠和患者肿瘤系和髓系细胞的结合和功能影响。我们将检测活力、粘连和骨吸收的变化。2)在早期和晚期肿瘤中，定向纳米颗粒针对的是哪些类型的骨转移生态位细胞？NP结合取决于细胞类型的可用性和¿v¿3的表达和激活水平。我们将评估与肿瘤细胞、破骨细胞、肿瘤相关巨噬细胞（tam）和内皮细胞的结合。3)整合素靶向纳米颗粒技术治疗骨转移的治疗潜力是什么？我们将评估携带传统化疗药物多西紫杉醇的NPs和/或携带骨和基质靶向药物唑来膦酸的NPs对骨肿瘤生长和进展的影响。我们将使用原位原发性乳腺癌骨转移模型和心内转移模型来确定转移预防和已建立的骨转移的效果。纳米颗粒定位及其对肿瘤细胞凋亡、血管数量、破骨细胞数量、骨质流失和TAM人群变化的特异性影响将被评估。该研究项目通过开发治疗和预防转移性乳腺癌的新疗法，与NCI的使命相关。

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.