Approximately 6.3 million bone fractures
occur annually in the
United States, resulting in considerable morbidity, deterioration
in quality of life, loss of productivity and wages, and sometimes
death (e.g., hip fractures). Although anabolic and antiresorptive
agents have been introduced for treatment of osteoporosis, no systemically
administered drug has been developed to accelerate the fracture-healing
process. To address this need, we have undertaken to target a bone
anabolic agent selectively to fracture surfaces in order to concentrate
the drug’s healing power directly on the fracture site. We
report here that conjugation of dasatinib to a bone fracture-homing
oligopeptide via a releasable linker reduces fractured femur healing
times in mice by ∼60% without causing overt off-target toxicity
or remodeling of nontraumatized bones. Thus, achievement of healthy
bone density, normal bone volume, and healthy bone mechanical properties
at the fracture site is realized after only 3–4 weeks in dasatinib-targeted
mice, but it
requires ∼8 weeks in PBS-treated controls. We conclude that
targeting of dasatinib to bone fracture surfaces can significantly
accelerate the healing process at dasatinib concentrations that are
known to be safe in oncological applications.
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