Thrombopoietic agents enhance bone healing in mice, rats, and pigs.

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration.

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.

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.

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.

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.

Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis.

Objectives: Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF).

Bone-Fracture-Targeted Dasatinib-Oligoaspartic Acid Conjugate Potently Accelerates Fracture Repair.

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.

Healing efficacy of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture repair.

Aim: To evaluate the fracture healing capabilities of a GSK3β inhibitor, 6-bromoindirubin-3'-oxime, coupled with an aspartic acid octapeptide in a micellar delivery system.

Materials & Methods: The efficacy of the intravenously administered micelles to accelerate healing of femoral fracture in mice was evaluated. Micro-computed tomography analysis was employed to obtain bone density, total volume, relative volume, trabecular thickness and trabecular spacing.

Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing.

Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application.

Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy.

Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic delivery of siRNA to solid tumors.

For small interfering RNA (siRNA)-based cancer therapies, we report an actively-targeted and stabilized polyion complex micelle designed to improve tumor accumulation and cancer cell uptake of siRNA following systemic administration. Improvement in micelle stability was achieved using two stabilization mechanisms; covalent disulfide cross-linking and non-covalent hydrophobic interactions. The polymer component was designed to provide disulfide cross-linking and cancer cell-targeting cyclic RGD peptide ligands, while cholesterol-modified siRNA (Chol-siRNA) provided additional hydrophobic stabilization to the micelle structure.

Targeting polymer therapeutics to bone.

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic.