Doctor of Philosophy, Purdue University (2019)
Bachelor of Science, Tsinghua University (2013)
Ph.D., Purdue University (2019)
Jianghong Rao, Postdoctoral Faculty Sponsor
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.
View details for DOI 10.1021/acs.bioconjchem.8b00660
View details for Web of Science ID 000451496400033
View details for PubMedID 30380292