Bone targeting therapy gets US funding
that directs therapeutics directly to bone, raising the possibility
of improved treatment for osteoporosis and other diseases affecting
bone, including cancer, reports Phil Taylor.
The US Department of Defense has awarded a three-year, $1.6 million (€1.2m) contract to the researchers, from the Southwest Research Institute in San Antonio, Texas, to develop bone-targeting treatments for multiple myeloma - a cancer of the blood plasma cells that causes tumours to form in bone marrow - and metastatic bone cancers. These secondary bone cancers are more common and deadly than primary bone cancer, which is rare.
The delivery technology is based on nanocapsules that seek out areas of bone resorption - or bone breakdown. This is a characteristic of myeloma, in which bone disease is one of the most visible symptoms of the disease. In the majority of patients with myeloma, soft spots develop where the bone structure has been damaged, causing pain and increasing the risk of fractures.
"Our technology can potentially increase the localisation of drug in the bone microenvironment," said Dr Neal Vail, a principal engineer in the microencapsulation, nanomaterials and process engineering department in SwRI's Chemistry and Chemical Engineering Division.
SwRI's technology is based on the use of bone-targeting agents - either methylene bisphosphonate or an aspartic acid oligomer - that bind to hydroxyapatite, one of the main constituents of calcified bone tissue. They are attached to the surface of liposomes, a spherical, lipid particle that carries the active drug on the inside. Once bound to bone, the liposome disrupts and its payload is released.
The government-funded programme will cover preclinical studies to determine the potential of skeletally targeted proteasome inhibitors as a treatment for myeloma.
Proteasome inhibitors have been under study as a treatment for myeloma and other cancers. They limit the function of the proteasome, part of the cell machinery responsible for cleaning up proteins involved in cellular function once they have completed their task. The first drug in this class, Millennium Pharmaceuticals' Velcade (bortezomib), was cleared for multiple myeloma in the US for in 2003 and achieved sales of $143m last year.
Due to their broad cellular functions, proteasome inhibitors can have diverse and serious side effects. For example, Velcade can cause reactions such as nausea, vomiting, fatigue, diarrhoea, decreased blood platelets and red blood cells, and numbness or tingling in the extremities. The SwRI researchers hope that by targeting proteasome inhibitors to a specific site to act on the necessary cells, their effectiveness in treating cancer could be greatly increased, and the side effect burden reduced.
The three-year study will formulate bone-targeting nanocapsules, determine their in vivo biodistribution and evaluate the success of using them to target proteasome inhibitors to myeloma lesions. Combinations of radiolabel imaging and micro-computed tomography to map the distribution of the nanocapsules. The potential of the targeted therapy will be assessed using a myeloma cell line engineered to fluoresce.
"Bone targeting has the potential to significantly reduce systemic exposure, reduce dosage requirements, and mitigate possible toxicity of proteasome inhibitors and other agents," Vail said. "This technology has tremendous potential for new therapies for bone pathologies including osteoporosis, fracture repair, implant fixation and tissue engineering."
