Identification and application of targeting peptides for systemic nanoparticle delivery to osteoarthritic joints

PROJECT SUMMARY Disease-modifying therapies for osteoarthritis (OA) remain a significant clinical challenge. Though numerous promising drug candidates are discovered, they suffer from persistent delivery challenges. The timing and dosing of multiple therapeutics targeting different disease mechanisms must be considered for effective management of OA. Due to issues with joint bioavailability and systemic toxicity, most OA therapies are studied by direct injections into affected joints. Intra-articular injections, however, require image-guidance and specialized personnel, and carry a risk of mis-injection and tissue injury. As such, this approach is limited, especially for repeat and/or timed treatments. Further, in patients with multi-joint disease, these intra-articular injections may not be feasible or tolerable. In contrast, intravenous injections are relatively easier and cheaper to administer, and are less painful and risky. However, to be successful, the drug must cross numerous physiological barriers to localize to diseased OA joints and with minimal off-target or systemic effects. Towards this goal, this proposal will identify peptides that preferentially localize to OA joints after intravenous injection, and leverage these peptides in for the development of targeted OA drug carriers. Aim 1 will use an in vivo phage display to select peptides that home to OA joints from the systemic circulation in an animal model of post-traumatic (PT) OA. In Aim 2, we will attach the selected peptide(s) to nanoparticle drug carriers and evaluate their ability to target to OA joints after intravenous injection. Nanoparticle tracking will be accomplished using conventional optical imaging techniques, and an emerging imaging modality, Magnetic Particle Imaging (MPI) to enable robust and quantitative assessment of nanoparticle biodistribution. Overall, this work will make important advances in systemic delivery systems for OA, which are needed to expand clinical options for comprehensive, long-term therapeutic strategies for OA.