Effects of chain lengths and backbone chirality on the bone-targeting ability of poly(glutamic acid)s

Anionic synthetic polypeptides are promising candidates as standalone bone-targeting drug carriers. Nevertheless, the structure-property relationship of the bone-targeting ability of polypeptides remains largely unexplored. Herein we report the optimization of the in vitro and in vivo bone-targeting ability of poly(glutamic acid)s (PGAs) by altering their chain lengths and backbone chirality. PGA 100-mers exhibited higher hydroxyapatite affinity in vitro, but their rapid macrophage clearance limited their targeting ability. Shorter PGA was therefore favored in terms of in vivo bone targeting. Meanwhile, the backbone chirality showed less significant impact on the in vitro and in vivo targeting behavior. This study highlights the modulation of structural parameters on the bone-targeting performance of anionic polypeptides, shedding light on the future design of polypeptide-based carriers.