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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR062680-02
Application #
8627117
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Panagis, James S
Project Start
2013-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$342,125
Indirect Cost
$62,241
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Quan, Lingdong; Zhang, Yijia; Crielaard, Bart J et al. (2014) Nanomedicines for inflammatory arthritis: head-to-head comparison of glucocorticoid-containing polymers, micelles, and liposomes. ACS Nano 8:458-66
Ren, Ke; Dusad, Anand; Zhang, Yijia et al. (2014) Early diagnosis of orthopedic implant failure using macromolecular imaging agents. Pharm Res 31:2086-94
Ren, Ke; Dusad, Anand; Yuan, Fang et al. (2014) Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects. J Control Release 175:1-9