Cartilage-Homing Cationic Nanocarriers to Deliver a Broad Range of Drugs for OA Therapy
Abstract
Problem: Osteoarthritis (OA) is a debilitating joint disease that attacks cartilage, an avascular negatively charged dense tissue, which provides cushioning between joints, and acts as a shock absorber during high impact and loading. Cartilage, however, has a limited ability to repair itself, and thus following acute joint injuries, it rapidly begins to degenerate irreversibly. This causes extreme pain, inflammation, and loss of mobility. Since current treatment options only provide a short-term pain relief and offer no protection against OA-associated cartilage degeneration, patients eventually have to get their joints replaced. Compared to the general population, the military population has a higher incidence of early onset of post-traumatic osteoarthritis (appearing at ages less than 40 years old) due to joint wear and tear from excessive training and multiple injuries. Potential drugs have been identified that can reverse OA progression by enabling cartilage regeneration; however, their clinical use has been limited by the lack of effective methods to deliver them locally into the joint. These drugs are potent, and thus approaches that can locally and safely deliver drugs to their target cell and matrix cites inside the affected tissue (cartilage) are a critical prerequisite for Food and Drug Administration clinical trials. Direct injections of pain relievers are currently used, but due to their rapid clearance from the joint space, only a small fraction is available to induce therapeutic effect. This requires multiple injections of high drug doses, which causes both local and systemic toxicity in patients. Innovation: Since the synovial joint space has negatively charged groups and because cartilage is one of the most negatively charged tissues, this project will develop a wide range of positively charged nanocarriers that can be conjugated with a wide range of pain relievers and OA drugs by using simple click chemistry to create sustained release formulations with long residence times. Their design is based on the optimal size, charge, and binding parameters determined to enable their penetration and binding inside negatively charged cartilage to reach their cell and matrix target sites. Our approach utilizes naturally occurring proteins and polypeptides as nanocarriers and aqueous-based click chemistry methods for bioconjugation, thereby providing a safe path for clinical trials. Application and Impact: This charge-based delivery platform converts cartilage from a barrier that prevents drug penetration to an intra-tissue depot that can enable sustained delivery. It also enables drug binding with other joint components like the synovium membrane, fat pad, articular tissue surfaces, etc., thereby using them as natural drug depots. It can, thus, for the first time enable disease-modifying characteristics of drugs as well as enhance their joint residence time so therapeutic effect can be achieved in a single injection of low dose. This can enable clinical trials of potential OA drugs and prevent patients with acute joint injuries from developing post-traumatic OA. The immediate application of this research is in increasing joint residence time of pain-inflammation relievers, which is critical for providing long-term symptomatic relief to patients. This delivery platform and results from this work can also be applied to other connective tissues like meniscus, ligaments, tendons, and tissues from hip, ankle, shoulder joints, etc.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710085
Entities
People
- Ambika G. Bajpayee
Organizations
- Northeastern University
- United States Army