Whitlockite nanoparticle-based immunotherapy for bone metastasis

基于白磷矿纳米颗粒的骨转移免疫疗法

• 批准号: 10370370
• 负责人: Hae Lin Jang
• 金额: $ 53.19万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370370
• 关键词: 3-Dimensional; Ablation; Address; American; Antibodies; Biological; Biomedical Engineering; Bone Cements; Bone Diseases; Bone Pain; Bone Regeneration; Bone Resorption; Bone Tissue; Breast; CSF1 gene; CSF1R gene; Cancer Etiology; Cells; Charge; Clinical; Disease; Disseminated Malignant Neoplasm; Drops; Drug Delivery Systems; Drug usage; Eating; Endocrine; Engineering; Exhibits; Fracture; Goals; Graph; Hydrogels; ITGAM gene; Immune Targeting; Immune response; Immune system; Immunomodulators; Immunotherapy; In Vitro; Inflammatory; Injectable; Injections; Lead; Left; Lesion; Lytic Metastatic Lesion; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of thyroid; Mechanics; Metastatic Neoplasm to the Bone; Metastatic to; Modeling; Molecular Weight; Morphology; Nanostructures; Nature; Neoplasm Metastasis; Organ; Osteoclasts; Osteogenesis; Osteolysis; Pain; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Polymethyl Methacrylate; Powder dose form; Process; Prognosis; Property; Prostate; Quality of life; Reporting; Research; Research Project Grants; Roentgen Rays; Role; Route; Shapes; Signal Transduction; Solubility; Structure; Testing; Time; Tissues; Toxic effect; Toxicology; anti-cancer; autonomic reflex; base; biological adaptation to stress; biomaterial compatibility; bone; cancer cell; confocal imaging; debilitating pain; density; direct application; effective therapy; efficacy study; efficacy testing; immunoregulation; improved; in vivo; inhibitor; innovation; insight; kinase inhibitor; macrophage; mechanical properties; mortality; nanobiomaterial; nanomaterials; nanoparticle; novel; osteogenic; pain reduction; receptor; reconstruction; repaired; transcriptomics; tumor

PROJECT SUMMARY Metastasis is the major cause of cancer mortality. Over 70% of all cancers metastasize to the bone, and the prognosis dramatically drops following bone metastasis. More than 350,000 Americans die every year due to bone metastasis. Colonization of the bone by the cancer cells leads to bone resorption, which results in microfractures from routine activities. Patients suffer debilitating pain, which decreases somatic, endocrine, and autonomic reflexes that further suppresses the immune system and accelerates metastasis. Currently, there is no effective treatment for bone metastasis. We propose to challenge this status quo by engineering the first bionanomaterial (Whitlockite)-based bone cement loaded with an immunotherapy drug for direct application to the bone. This is based on recent clinical evidences that show that the direct injection of polymethylmethacrylate (PMMA) bone cement at the metastatic osteolytic lesion can reduce pain by stabilizing microfracture. However, classical bone cements are not optimized for metastatic lesions, and suffer from major drawbacks. In contrast, Whitlockite (WH) nanoparticles are a major component of bone, are stable in the acidic metastatic niche, and can be used for drug delivery. In preliminary studies, we have already demonstrated that WH nanoparticle-based bone cements exhibit desirable properties for an ideal bone cement. In Aim.1. we will further identify the optimal structure of WH nanoparticles for formulating into a bone cement, and characterize the application of a WH nanoparticle-based bone cement for treating metastatic bone pain; in Aim 2. We will characterize WH nanoparticles as a drug-delivery platform. We will use immunotherapies that target the immune cells implicated in bone metastasis. We will rigorously test the pain-reducing efficacy, bone regeneration, and anti-metastatic effect of our immunomodulatory WH bone cement; in Aim 3, we will conduct a comprehensive toxicological test by analyzing stress response on bone and other organs to identify potential toxicities of using direct injection into the bone as a route of administration for nanoparticles. We envisage that this project will lead to fundamental insights into a novel nanomaterial (WH) and its application in drug delivery via a novel route (directly into bone lesion) of administration. The integration of immunotherapy with Whitlockite nanoparticles can lead to a paradigm shift in the treatment of bone metastasis, and directly impact a major unmet clinical need.

项目摘要 转移是癌症死亡率的主要原因。超过70％的癌症转移到骨骼，而 骨转移后预后大幅下降。每年有超过35万美国人死亡 骨转移。癌细胞对骨骼的定殖导致骨吸收，从而导致 常规活动的微裂纹。患者疼痛会衰弱，可减轻躯体，内分泌和 自主反射进一步抑制免疫系统并加速转移。目前，有 没有有效的骨转移治疗。我们建议通过工程第一个来挑战这种现状 基于Bionanomamatial（Whitlockite）的基于免疫疗法药物的骨水泥直接应用于 骨头。这是基于最近的临床证据，表明直接注射聚甲基丙烯酸酯 （PMMA）转移性骨化病变处的骨水泥可以通过稳定微裂缝来减轻疼痛。然而， 经典的骨骼水泥未针对转移性病变进行优化，并且患有主要缺点。相比之下， whitloctite（WH）纳米颗粒是骨骼的主要组成部分，在酸性转移性小众中是稳定的，并且 可用于药物输送。在初步研究中，我们已经证明了基于纳米颗粒的 骨水泥具有理想骨水泥的理想特性。在AIM.1。我们将进一步确定最佳 WH纳米颗粒的结构用于制定成骨水泥，并表征了WH的应用 基于纳米颗粒的骨水泥，用于治疗转移性骨痛；在AIM 2中。我们将描述WH 纳米颗粒作为药物交付平台。我们将使用针对涉及免疫细胞的免疫疗法 在骨转移中。我们将严格测试减轻疼痛的功效，骨骼再生和抗转移性 我们的免疫调节骨水泥的影响；在AIM 3中，我们将进行全面的毒理学测试 通过分析对骨骼和其他器官的压力反应，以确定将直接注入直接注射到 骨头是纳米颗粒的给药途径。我们设想这个项目将导致基本 对新型纳米材料（WH）的见解及其在药物输送中的应用（直接进入骨骼） 病变）。免疫疗法与惠特洛锁纳米颗粒的整合会导致范式 骨转移治疗的转移，直接影响主要未满足的临床需求。