Targeted Delivery of Abaloparatide to Spinal Fusion Site Accelerates Fusion Process in Rats.

Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration.

An engineered dual function peptide to repair fractured bones.

Targeted drug delivery, often referred to as "smart" drug delivery, is a process whereby a therapeutic drug is delivered to specific parts of the body in a manner that increases its concentration at the desired sites relative to others. This approach is poised to revolutionize medicine as exemplified by the recent FDA approval of Cytalux (FDA approves pioneering drug for ovarian cancer surgery - Purdue University News) which is a folate-receptor targeted intraoperative near infrared (NIR) imaging agent that was developed in our laboratories. Fracture-associated morbidities and mortality affect a significant portion of world population. United states, Canada and Europe alone spent $48 billion in treating osteoporosis related fractures although this number doesn't count the economic burden due to loss in productivity. It is estimated that by 2050 ca 21 million hip fractures would occur globally which will be leading cause of premature death and disability. Despite the need for improvement in the treatment for fracture repair, methods for treating fractures have changed little in recent decades. Systemic delivery of fracture-homing bone anabolics holds great promise as a therapeutic strategy in this regard. Here we report the design of a fracture-targeted peptide comprised of a payload that binds and activates the parathyroid hormone receptor (PTHR1) and is linked to a targeting ligand comprised of 20 D-glutamic acids (D-Glu20) that directs accumulation of the payload specifically at fracture sites. This targeted delivery results in reduction of fracture healing times to <1/2 while creating repaired bones that are >2-fold stronger than saline-treated controls in mice. Moreover, this hydroxyapatite-targeted peptide can be administered without detectable toxicity to healthy tissues or modification of healthy bones in dogs. Additionally, since similar results are obtained upon treatment of osteoporotic and diabetic fractures in mice, and pain resolution is simultaneously accelerated by this approach, we conclude that this fracture-targeted anabolic peptide displays significant potential to revolutionize the treatment of bone fractures.

Analysis of the bone fracture targeting properties of osteotropic ligands.

PURPOSE: Although more than 18,000,000 fractures occur each year in the US, methods to promote fracture healing still rely primarily on fracture stabilization, with use of bone anabolic agents to accelerate fracture repair limited to rare occasions when the agent can be applied to the fracture surface. Because management of broken bones could be improved if bone anabolic agents could be continuously applied to a fracture over the entire course of the healing process, we undertook to identify strategies that would allow selective concentration of bone anabolic agents on a fracture surface following systemic administration. Moreover, because hydroxyapatite is uniquely exposed on a broken bone, we searched for molecules that would bind with high affinity and specificity for hydroxyapatite. We envisioned that by conjugating such osteotropic ligands to a bone anabolic agent, we could acquire the ability to continuously stimulate fracture healing. RESULTS: Although bisphosphonates and tetracyclines were capable of localizing small amounts of peptidic payloads to fracture surfaces 2-fold over healthy bone, their specificities and capacities for drug delivery were significantly inferior to subsequent other ligands, and were therefore considered no further. In contrast, short oligopeptides of acidic amino acids were found to localize a peptide payload to a bone fracture 91.9 times more than the control untargeted peptide payload. Furthermore acidic oligopeptides were observed to be capable of targeting all classes of peptides, including hydrophobic, neutral, cationic, anionic, short oligopeptides, and long polypeptides. We further found that highly specific bone fracture targeting of multiple peptidic cargoes can be achieved by subcutaneous injection of the construct. CONCLUSIONS: Using similar constructs, we anticipate that healing of bone fractures in humans that have relied on immobilization alone can be greately enhanced by continuous stimulation of bone growth using systemic administration of fracture-targeted bone anabolic agents.

Bone-Targeting Systems to Systemically Deliver Therapeutics to Bone Fractures for Accelerated Healing.

PURPOSE OF REVIEW: Compared with the current standard of implanting bone anabolics for fracture repair, bone fracture-targeted anabolics would be more effective, less invasive, and less toxic and would allow for control over what phase of fracture healing is being affected. We therefore sought to identify the optimal bone-targeting molecule to allow for systemic administration of therapeutics to bone fractures. RECENT FINDINGS: We found that many bone-targeting molecules exist, but most have been developed for the treatment of bone cancers, osteomyelitis, or osteoporosis. There are a few examples of bone-targeting ligands that have been developed for bone fractures that are selective for the bone fracture over the body and skeleton. Acidic oligopeptides have the ideal half-life, toxicity profile, and selectivity for a bone fracture-targeting ligand and are the most developed and promising of these bone fracture-targeting ligands. However, many other promising ligands have been developed that could be used for bone fractures.