Whitlockite nanoparticle-based immunotherapy for bone metastasis

项目摘要 转移是癌症死亡的主要原因。超过70%的癌症转移到骨骼， 骨转移后预后显著下降。每年有超过35万美国人死于 骨转移癌细胞在骨中的定植导致骨吸收，这导致 日常活动造成的微骨折患者遭受使人衰弱的疼痛，这会降低躯体、内分泌和 自主神经反射进一步抑制免疫系统并加速转移。目前还 没有有效的治疗骨转移的方法。我们建议挑战这一现状， 生物纳米材料（Whitlockite）基骨水泥，装载免疫治疗药物，用于直接应用于 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， 在转移性溶骨性病变处使用聚甲基丙烯酸甲酯（PMMA）骨水泥可通过稳定微骨折来减轻疼痛。然而，在这方面， 传统的骨粘固剂对于转移性病变不是最佳的，并且具有主要的缺点。与此相反， 白磷钙石（WH）纳米颗粒是骨的主要成分，在酸性转移灶中稳定， 可用于药物输送。在初步研究中，我们已经证明了基于WH纳米颗粒的 骨粘固剂表现出理想骨粘固剂所需的性能。目标1.我们将进一步确定 用于配制成骨水泥的WH纳米颗粒的结构，并表征WH纳米颗粒的应用。 用于治疗转移性骨痛的基于纳米颗粒的骨水泥;目的2.我们将描述WH 纳米颗粒作为药物输送平台。我们将使用免疫疗法，针对涉及的免疫细胞 骨转移我们将严格测试止痛功效、骨再生、抗转移 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试验 通过分析骨骼和其他器官的应激反应，以确定使用直接注射到 骨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 深入了解一种新型纳米材料（WH）及其在通过新途径（直接进入骨骼）给药中的应用 管理）。免疫疗法与白磷钙石纳米颗粒的整合可以导致一种范例 骨转移治疗的转变，并直接影响主要未满足的临床需求。

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.