Table 1.

Delivery ligands targeting bone matrix

Ligand	Binding feature	Advantage	Disadvantage	Ref
Bisphosphonate	Less influenced by the crystallinity of HAP	Higher binding ratio Intrinsic anti-resorption effect Easy conjugation with drugs or drug vectors through R1 or R2 Economic convenience	Long-term presence in HAP Side effects such as ONJ, atypical femoral fractures, esophageal cancer, and nephrotoxicity Potency to reduce the secretion of insulin-like growth factors and BMPs to promote osteoblast formation	243,244
Phytic acid	Less influenced by the crystallinity of HAP	Natural existing compounds in vivo Inherent antitumor and anti-osteoclastogenesis ability Reduced gastrointestinal disturbance	Low oral bioavailability	258
Tetracycline	Prefers low crystallinity HAP and growing surface	Intrinsic anti-collagenolytic ability Upregulating the expression of procollagen mRNA, thus activating more osteoblasts Strong affinity toward bone with a high remodeling rate	Teeth staining and enamel hypoplasia Dose-dependent dual effect on osteogenesis Permanent chelation Low chemical stability to conjugate with drugs or vectors	264
Acidic Oligopeptide	HAP on bone-resorbing surface	Faster binding rate Better drug release and less side effect due to high biodegradation Usage in virus vectors	Not orally bioavailable Higher drug release but lower concentration due to lysis of enzymes to linkages	275,286,288
DSS	HAP on bone formation surface			241,297,346
Collagen-binding domain (CBD)	Collagen in bone	Easy combination for agents, cell adhesion and retention effect, especially when used in implant coating	Distribution in skin	306
WYRGRL	Collagen II	Cartilage specific	Much lower collagen II content in cartilage than skin Rely on intra-articular injection	312