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.