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.

Public Health Relevance

We have developed a highly sensitive diagnostic system for identification of early stage osteolysis associated with orthopedic implants. Moreover, this same system has been exploited to deliver potent anti- inflammatory drugs specifically to the site of early osteolysis and prevent further bone loss. Implementation of this novel theranostic system in orthopedic practice will significantly improve the quality of life of patients who receive orthopedic implants, prolong implant survival times and reduce the financial burden to society.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Washabaugh, Charles H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Other Basic Sciences
Schools of Pharmacy
United States
Zip Code
Wei, Xin; Wu, Jianbo; Zhao, Gang et al. (2018) Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis. Mol Pharm 15:3456-3467
Liu, Yan-Zhi; Akhter, Mohammed P; Gao, Xiang et al. (2018) Glucocorticoid-induced delayed fracture healing and impaired bone biomechanical properties in mice. Clin Interv Aging 13:1465-1474
Zimel, Melissa N; Horowitz, Chloe B; Rajasekhar, Vinagolu K et al. (2017) HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer. Mol Cancer Ther 16:2701-2710
Wei, Xin; Li, Fei; Zhao, Gang et al. (2017) Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model. Mol Pharm 14:1418-1428
Bradley, Aaron D; Zhang, Yijia; Jia, Zhenshan et al. (2016) Effect of Simvastatin Prodrug on Experimental Periodontitis. J Periodontol 87:577-82
Zhang, Yijia; Jia, Zhenshan; Yuan, Hongjiang et al. (2016) The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model. Pharm Res 33:1959-71
Dusad, Anand; Thiele, Geoffrey M; Klassen, Lynell W et al. (2015) Vitamin D supplementation protects against bone loss following inhalant organic dust and lipopolysaccharide exposures in mice. Immunol Res 62:46-59
Jia, Zhenshan; Zhang, Yijia; Chen, Yen Hsun et al. (2015) Simvastatin prodrug micelles target fracture and improve healing. J Control Release 200:23-34
Knudsen, Mitchell; Bury, Matthew; Holwegner, Callie et al. (2015) Effect of dexamethasone prodrug on inflamed temporomandibular joints in juvenile rats. Arthritis Res Ther 17:267
Ren, Ke; Dusad, Anand; Zhang, Yijia et al. (2014) Early diagnosis of orthopedic implant failure using macromolecular imaging agents. Pharm Res 31:2086-94

Showing the most recent 10 out of 12 publications