Early Detection and Intervention of Orthopedic Implant Loosening using Polymer Th

描述(申请人提供)：本项目的总体目标是开发一种新的治疗工具，用于种植体周围骨科磨损颗粒诱导的骨溶解的早期诊断和有效治疗。骨科磨损颗粒引起的炎症被认为是全关节置换术后无菌植入物松动和临床失败的主要原因。我们以前的工作已经确定了大分子被动靶向炎症部位的两个关键因素：1)通过与炎症相关的血管渗漏增强而产生的特异性渗出；2)炎性细胞介导的大分子的隔离。为了进一步开发这种针对炎症性疾病的新机制，我们将优化N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚体系的结构参数，以开发一种高度敏感和有效的用于种植体周围骨溶解早期检测和治疗的治疗药物。具体地说，我们将首先系统地修改聚合物治疗药物的结构和功能性质，以优化细胞的摄取、保留和药物分解动力学。然后将研究影响聚合物治疗药物在炎症部位的渗出/淋巴清除的因素。基于这两个步骤的结果，我们将开发一种优化的聚合物热疗系统，用于使用股骨骨内种植体模型高灵敏地检测磨粒诱导的种植体周围骨溶解。为了开发一种具有最佳体内有效性和安全性的HPMA共聚物给药系统，我们将进行药代动力学/生物分布研究，以确定HPMA共聚物-地塞米松结合物(P-Dex)的最佳结构参数，从而最大限度地保护种植体周围骨质量，同时将与Dex相关的典型非靶向毒性降至最低。我们开发的大分子治疗方法代表了当前骨科植入物管理模式的重大转变，并可在未来适应于开发新的方法来成像其他炎症性疾病的疾病活动和进展。重要的是，这个系统也可能被用来靶向参与炎症和自身免疫疾病的额外细胞内信号分子。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel theranostic tool for early diagnosis and effective treatment of peri-implant orthopedic wear particle-induced osteolysis. Orthopedic wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. Ou previous work has identified two critical elements of macromolecular passive targeting to sites of inflammation: 1) specific extravasation through enhanced vascular leakage associated with inflammation and 2) inflammatory cell-mediated sequestration of the macromolecules. To further exploit this novel mechanism for targeting inflammatory disease, we will optimize the structural parameters of the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer system in order to develop a highly sensitive and efficacious theranostic for early peri-implant osteolysi detection and treatment. Specifically, we will first systematically modify the structural and functional properties of the polymer theranostics to optimize cellular uptake, retention and drug cleavage kinetics. The factors governing polymer theranostics' extravasation/lymphatic clearance at the site of inflammation will then be investigated. Based on the findings of these two steps, we will then develop an optimized polymer theranostic system for highly sensitive detection of wear particle-induced peri-implant osteolysis using an intraosseous femoral implant model. To develop a HPMA copolymer-based drug delivery system with an optimal in vivo efficacy and safety profile, we will then perform a pharmacokinetic/biodistribution study to identify the optimal structural parameters of HPMA copolymer-dexamethasone conjugates (P-Dex) that maximize protection of the peri-implant bone quality while minimizing the well characterized off-target toxicities associated with Dex. The macromolecular theranostic approach that we have developed represents a major shift of the current orthopedic implant management paradigm and can be adapted in the future to the development of novel approaches for imaging disease activity and progression in other inflammatory diseases. Importantly, this system may also be exploited for targeting additional intracellular signaling molecules involved in inflammatory and autoimmune disorders.