Cartilage-Penetrating Nanocarrier-Drug Conjugate for Disease-Modifying Intervention in Post-Traumatic Osteoarthritis
Abstract
Patients suffering from osteoarthritis (OA) must deal with considerable pain and stiffness that affects their ability to undergo daily operations as the condition progresses and their cartilage breaks down. OA reduces their mobility and physical activity, which in turn reduces their quality of life. Approximately 40%-50% of young athletes who sustain joint injuries, such as an anterior cruciate ligament (ACL) tear, experience accelerated cartilage damage and develop post-traumatic osteoarthritis (PTOA) in 10-15 years after their initial injury. PTOA accounts for 12% of OA cases in the general population and active duty Soldiers are five times as likely to have PTOA due to joint injuries caused by training exercises and battlefield trauma. This proposed project addresses the Peer Reviewed Medical Research Program (PRMRP) Topic Area of PTOA and the PRMRP areas of encouragement in the generation of new innovative ways of treating this form of arthritis to help large numbers of Soldiers, Veterans, and military personnel as well as civilians who experience this form of arthritis. There have been numerous attempts to create a drug capable of protecting or regenerating cartilage to slow or stop OA, but have failed to work in humans because the body removes the drug from the joint before it has enough time to heal the cartilage and stop the disease. Our research focuses on developing and validating a positively charged nanoparticle that can be attached to the desired drug and carry it deep into the cartilage, which is negatively charged. Once administered in the body, the nanoparticle-drug combo will stick to the cartilage for an extended period of time, allowing the drug to engage the cells in cartilage to help protect and regenerate the cartilage, effectively stopping or healing OA. Utilizing this technology, we plan to develop the first drug capable of healing a patient’s osteoarthritis rather than merely treating their pain. Our previous research has shown that when a drug linked to our nanoparticle is administered into the joint, the nanoparticle-drug formulation is capable of residing in the cartilage ten times longer than the drug alone. To make the best nanoparticle-drug formulation, we first need to select the best drug possible. We will examine two promising drugs -- a drug that is capable of protecting cartilage from damage and a drug that is capable of regenerating cartilage after damage -- to determine which is more effective. Our experiments will be conducted using cow and human cadaver cartilage discs and will be used to determine the optimal nanoparticle-drug formulation. Next, the project will focus on making sure that the nanoparticle-drug formulation is not toxic at the dose needed to get effective results. These studies will help us identify the highest quantity of drug we can use to maximize cartilage healing without causing dangerous side effects. Finally, we will focus on studying how the nanoparticle-drug formulation performs in dogs, which experience osteoarthritis more like a human, to validate the system and enable approval to move the treatment to human clinical trials. These data will inform us on whether or not we are capable of protecting or regenerating cartilage and slowing or stopping the progression of OA. If this therapy is successful in clinical trials and approved as a drug by the Food and Drug Administration (FDA), this treatment option will help prevent younger active duty Soldiers from being discharged due to PTOA and increase the productive lives of all people who suffer from PTOA. Such a treatment would transform the prognosis and outlook for large numbers of patients who otherwise would not receive any form of preventative treatment against PTOA following a joint-damaging injury, or would be prescribed only pain medications as their OA worsens over time. Additionally, if successful, this nanoparticle-drug formulation could assist in reducing the use of opioids for pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010481
Entities
People
- Paula T. Hammond
Organizations
- Massachusetts Institute of Technology
- United States Army