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TARGETED DELIVERY OF BONE ANABOLICS TO BONE FRACTURES FOR ACCELERATED HEALING
thesisposted on 2022-06-21, 14:17 authored by Jeffery J H NielsenJeffery J H Nielsen
Delayed fracture healing is a major health issue involved with aging. Therefore, strategies to improve the pace of repair and prevent non-union are needed in order to improve patient outcomes and lower healthcare costs. In order to accelerate bone fracture healing noninvasively, we sought to develop a drug delivery system that could safely and effectively be used to deliver therapeutics to the site of a bone fracture. We elected to pursue the promising strategy of using small-molecule drug conjugates that deliver therapeutics to bone in an attempt to increase the efficacy and safety of drugs for treating bone-related diseases.
This strategy also opened the door for new methods of administering drugs. Traditionally, administering bone anabolic agents to treat bone fractures has relied entirely on local surgical application. However, because it is so invasive, this method’s use and development has been limited. By conjugating bone anabolic agents to bone-homing molecules, bone fracture treatment can be performed through minimally invasive subcutaneous administration. The exposure of raw hydroxyapatite that occurs with a bone fracture allows these high-affinity molecules to chelate the calcium component of hydroxyapatite and localize primarily to the fracture site.
Many bone-homing molecules (such as bisphosphonates and tetracycline targeting) have been developed to treat osteoporosis. However, many of these molecules have toxicity associated with them. We have found that short oligopeptides of acidic amino acids can localize to bone fractures with high selectivity and with very low toxicity compared to bisphosphonates and tetracyclines.
We have also demonstrated that these molecules can be used to target peptides of all chemical classes: hydrophobic, neutral, cationic, anionic, short, and long. This ability is particularly useful because many bone anabolics are peptidic in nature. We have found that acidic oligopeptides have better persistence at the site of the fracture than bisphosphonate-targeted therapeutics. This method allows for a systemic administration of bone anabolics to treat bone fractures, which it achieves by accumulating the bone anabolic at the fracture site. It also opens the door for a new way of treating the prevalent afflictions of broken bones and the deaths associated with them.
We further developed this technology by using it to deliver anabolic peptides derived from growth factors, angiogenic agents, neuropeptides, and extracellular matrix fragments. We found several promising therapeutics that accelerated the healing of bone fractures by improving the mineralization of the callus and improving the overall strength. We optimized the performance of these molecules by improving their stability, targeting ligands, linkers, dose, and dosing frequency.
We also found that these therapeutics could be used to accelerate bone fracture repair even in the presence of severe comorbidities (such as diabetes and osteoporosis) that typically slow the repair process. We found that, unlike the currently approved therapeutic for fracture healing (BMP2), our therapeutics improved functionality and reduced pain in addition to strengthening the bone. These optimized targeted bone anabolics were not only effective at healing bone fractures but they also demonstrated that they could be used to speed up spinal fusion. Additionally, we demonstrated that acidic oligopeptides have potential to be used to treat other bone diseases with damaged bone.
With these targeted therapeutics, we no longer have to limit bone fracture healing to casts or invasive surgeries. Rather, we can apply these promising therapeutics that can be administered non-invasively to augment existing orthopedic practices. As these therapeutics move into clinical development, we anticipate that they will be able to reduce the immobilization time that is the source of so many of the deadly complications associated with bone fracture healing, particularly in the elderly.
- Doctor of Philosophy
- Medicinal Chemistry and Molecular Pharmacology
- West Lafayette
Advisor/Supervisor/Committee ChairPhilip S. Low
Additional Committee Member 2Zhong-Yin Zhang
Additional Committee Member 3Russell P. Main
Additional Committee Member 4Kathleen Hill Gallant
- Medicinal and biomolecular chemistry not elsewhere classified
- Molecular medicine
- Organic chemistry not elsewhere classified
- Proteins and peptides
- Radiation and matter
- Solid state chemistry
- Solution chemistry
- Biochemistry and cell biology not elsewhere classified
- Animal behaviour
- Agricultural biotechnology not elsewhere classified
- Medical biotechnology not elsewhere classified
- Genetics not elsewhere classified
- Other biomedical and clinical sciences not elsewhere classified
- Pharmacology and pharmaceutical sciences not elsewhere classified
- Biomechanical engineering
- Clinical microbiology
- Dental therapeutics, pharmacology and toxicology
- Medical biochemistry - proteins and peptides (incl. medical proteomics)
- Regenerative medicine (incl. stem cells)
bone fracture healingAnabolic Agents/pharmacologyTargeted Drug DeliveryDesignBone fracture targeted drugsBone theapeuticstargeted therapiesGrowth factorsNeuropepetidesExtracellular matrixExtracellular matrix fragmentsspinal fusionAngiogensisAcidic oligopeptidesosteoporosic fracturesdiabetic bone fracturesIntegrin alpha 5Acelerated Bone fracture healingHydroxyapatiteHydroxyapatite targetingTargeting peptidesPeptide drugsosteomyelitis (OM)Rheumatoid arthritisBone fracturesosteogenic therapiesosteotropicosteotropic nanomedicinesosteoinductive capacityMedicinal and Biomolecular Chemistry not elsewhere classifiedMolecular MedicineOrganic ChemistryProteins and PeptidesRadiochemistrySolid State ChemistrySolution ChemistryBiochemistryAnimal BehaviourBiological EngineeringBiotechnologyGeneticsMedicinePharmacologyBiomaterialsBiomechanical EngineeringBiomechanicsDental Therapeutics, Pharmacology and ToxicologyEndocrinologyMedical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)NanobiotechnologyNanomedicineRegenerative Medicine (incl. Stem Cells and Tissue Engineering)