Bone-targeted bortezomib increases bone formation within Calvarial trans-sutural distraction osteogenesis.

Abstract

The high rate of relapse in craniofacial disharmony treatment via trans-sutural distraction osteogenesis (TSDO) is due to the failure to form a stable bone bridge in the suture gap. Bisphosphonates (BP) have a high propensity to localize to hydroxyapatite in the bone matrix and are commonly used as targeting ligands for local delivery of therapeutics into bone microenvironment. Bone-targeted Bortezomib (BP-Btz) is chemosynthetic by linking Btz (Bortezomib) to a BP residue and could target bone tissue to promote osteoblast differentiation and inhibit osteoclastogenesis. Here, suture-derived mesenchymal stem cells (SuSCs) and osteoclasts were treated with Btz and BP-Btz. Aforesaid drugs were injected locally into the sagittal sutures to explore their effects in TSDO. Further, pharmacological properties of BP-Btz in the suture expansion model were assessed by fluorescent BP analogs and levels of total ubiquitinated (Ub)-proteins. The results showed that BP-Btz could stimulate osteogenic differentiation of SuSCs, bind to bone matrix and inhibit osteoclastogenesis. Biological effects of BP-Btz were similar with those of Btz in osteoblast differentiation and osteoclastogenesis inhibition in vitro. Activated bone metabolism were detected after 14 days in the sagittal suture expansion model. Increased osteoid area, remarkably decreased osteoclast surface and enhanced osteogenesis were detected in vivo after treatment with BP-Btz. Green fluorescence signal detection and pharmacodynamic studies revealed that BP-Btz bound to suture edge, released Btz in remodeling conditions, had a higher local concentration and sustained longer than free Btz. This study delineated the clinical potential of bone-targeted Btz conjugate as an efficacious strategy to promote trans-sutural distraction osteogenesis.