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Whitlockite nanoparticle-based immunotherapy for bone metastasis

基于白磷矿纳米颗粒的骨转移免疫疗法

基本信息

批准号：
10616475
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
项目类别：
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/10616475
关键词：
3-Dimensional Ablation Acceleration 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 Cementation 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 Immunotherapy In Vitro Injectable Injections Left Lesion Lytic Metastatic Lesion Macrophage Malignant Bone Neoplasm Malignant neoplasm of thyroid Mechanics Metastasis Induction Metastatic Neoplasm to the Bone Minerals Modeling Molecular Weight Morphology Nanostructures Nature Neoplasm Metastasis Organ Osteoclasts Osteogenesis Osteolysis PTPNS1 gene 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 biological adaptation to stress biomaterial compatibility bone cancer cell confocal imaging debilitating pain density direct application effective therapy efficacy study efficacy testing immune modulating agents immunoregulation improved in vivo inhibitor innovation insight kinase inhibitor mechanical properties mortality nanobiomaterial nanomaterials nanoparticle novel osteogenic pain reduction programs receptor reconstruction repaired systemic inflammatory response transcriptomics tumor

项目摘要

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.

项目总结