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: 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
• 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

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.

项目概要 转移是癌症死亡的主要原因。超过 70% 的癌症会转移至骨骼， 骨转移后预后急剧下降。每年有超过 350,000 名美国人因以下原因死亡 骨转移。癌细胞在骨中的定植会导致骨吸收，从而导致 日常活动造成的微骨折。患者遭受令人衰弱的疼痛，这会降低躯体、内分泌和功能 自主反射进一步抑制免疫系统并加速转移。目前，有 对于骨转移尚无有效治疗方法。我们建议通过设计第一个来挑战这一现状 基于生物纳米材料（Whitlockite）的骨水泥，负载有免疫治疗药物，可直接应用于 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甲酯 转移性溶骨性病变处的（PMMA）骨水泥可以通过稳定微骨折来减轻疼痛。然而， 经典骨水泥并未针对转移性病变进行优化，并且存在重大缺陷。相比之下， Whitlockite (WH) 纳米粒子是骨的主要成分，在酸性转移生态位中稳定，并且 可用于药物输送。在初步研究中，我们已经证明基于 WH 纳米颗粒的 骨水泥表现出理想骨水泥所​​需的特性。在目标 1 中。我们将进一步确定最佳方案 用于配制骨水泥的WH纳米颗粒的结构，并表征WH的应用 用于治疗转移性骨痛的纳米颗粒骨水泥；在目标 2 中，我们将描述 WH 的特征 纳米粒子作为药物传递平台。我们将使用针对相关免疫细胞的免疫疗法 在骨转移中。我们会严格测试止痛功效、骨再生功效、抗转移功效 我们的免疫调节WH骨水泥的效果；在目标3中，我们将进行全面的毒理学测试 通过分析骨骼和其他器官的应激反应来识别直接注射的潜在毒性 骨骼作为纳米颗粒的给药途径。我们预计该项目将带来根本性的成果 深入了解新型纳米材料 (WH) 及其通过新途径（直接进入骨骼）在药物输送中的应用 病变）的给药。免疫疗法与 Whitlockite 纳米粒子的整合可以形成一个范例 骨转移治疗的转变，并直接影响重大的未满足的临床需求。

项目成果

Organ-on-a-Chip for Cancer and Immune Organs Modeling.

用于癌症和免疫器官建模的器官芯片。

• 发表时间: 2019-02
• 影响因子: 10
• 作者: Sun, Wujin;Luo, Zhimin;Lee, Junmin;Kim, Han;Lee, KangJu;Tebon, Peyton;Feng, Yudi;Dokmeci, Mehmet R;Sengupta, Shiladitya;Khademhosseini, Ali
• 通讯作者: Khademhosseini, Ali

Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.

细胞间纳米管介导癌症和免疫细胞之间的线粒体运输。

• 发表时间: 2022-01
• 影响因子: 38.3
• 作者: Saha, Tanmoy;Dash, Chinmayee;Jayabalan, Ruparoshni;Khiste, Sachin;Kulkarni, Arpita;Kurmi, Kiran;Mondal, Jayanta;Majumder, Pradip K;Bardia, Aditya;Jang, Hae Lin;Sengupta, Shiladitya
• 通讯作者: Sengupta, Shiladitya

A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections.

一种有效的负载抗生素的骨水泥植入物，可抵抗葡萄球菌骨感染。

• 发表时间: 2022-10
• 影响因子: 28.1
• 作者: Ghosh, Sumana;Sinha, Mau;Samanta, Ritwik;Sadhasivam, Suresh;Bhattacharyya, Anamika;Nandy, Ashis;Saini, Swamini;Tandon, Nupur;Singh, Himanshi;Gupta, Swati;Chauhan, Anjali;Aavula, Keerthi Kumar;Varghese, Sneha Susan;Shi, Pujie;Ghosh, Sudip;Ga
• 通讯作者: Ga