Early Detection and Intervention of Orthopedic Implant Loosening using Polymer Th

描述（由申请人提供）：本项目的总体目标是开发一种新型治疗诊断工具，用于植入物周围骨科磨损颗粒诱导的骨质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植入物无菌性松动和临床失败的主要原因。Ou先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要素：1）通过与炎症相关的增强的血管渗漏的特异性外渗和2）大分子的炎性细胞介导的隔离。为了进一步利用这种靶向炎症性疾病的新机制，我们将优化水溶性N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物系统的结构参数，以开发一种高度敏感和有效的治疗诊断剂，用于早期种植体周围骨质溶解的检测和治疗。具体而言，我们将首先系统地修改聚合物治疗诊断剂的结构和功能特性，以优化细胞摄取，保留和药物裂解动力学。然后将研究控制聚合物治疗诊断剂在炎症部位外渗/淋巴清除的因素。基于这两个步骤的发现，我们将开发一种优化的聚合物治疗诊断系统，用于使用骨内股骨植入物模型高灵敏度检测磨损颗粒诱导的植入物周围骨质溶解。为了开发具有最佳体内疗效和安全性的基于HPMA共聚物的药物递送系统，我们将进行药代动力学/生物分布研究，以确定HPMA共聚物-地塞米松缀合物（P-Dex）的最佳结构参数，其最大限度地保护种植体周围骨质，同时最小化与Dex相关的良好表征的脱靶毒性。我们开发的大分子治疗诊断方法代表了当前骨科植入物管理模式的重大转变，并且可以在未来适应于开发用于成像疾病活动和其他炎性疾病进展的新方法。重要的是，该系统还可以用于靶向参与炎症和自身免疫性疾病的其他细胞内信号传导分子。

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.