Cationic Peptoids for Systemic In Vivo Cartilage-Targeting

Although cartilage damage is key to the pathogenesis of many musculoskeletal diseases, including osteoarthritis and rheumatoid arthritis (RA), imaging and drug delivery to cartilage remain a demanding challenge. Cartilage is an avascular tissue with a dense matrix constraining the penetration of imaging and targeting agents. Here, a unique class of cationic peptidomimetics featuring peptoid residue Nlys (N-substituted butyl-amino glycine) is reported for cartilage targeting. Sulfo-Cyanine5 (Cy5) labeled Nlys-rich sequences are found to penetrate and be retained within millimeter-deep cartilage plugs in vitro by specific binding to the tissue's polyanionic glycosaminoglycan (GAG) chains. Owing to the unnatural sequences being undegradable by common proteases, these Nlys-peptidomimetics overcome the problem of low serum stability of existing benchmark cartilage-binding peptides (e.g., octa-arginine) and allow systemic administration. Intravenously delivered Cy5-(NlysO)₇ (O: hydroxyproline) is taken up by the cartilage across the body of living mice and zebrafish, enabling whole-body 3D light-sheet microscopy scans of neonatal mice undergoing bone development as well as in vivo detection of GAG loss in mice's aged knee joints and inflamed RA ankles. The Nlys-compounds also show no cytotoxicity in chondrocytes and good biocompatibility in vivo, paving the way for applications in GAG-targeted molecular imaging, drug delivery, and biomaterials for cartilage-related diseases.