Research Project
8058385
DESCRIPTION (provided by applicant): "Bone-seeking" radiopharmaceuticals are used extensively for bone pain palliation and have shown promise for treating bone metastases. They typically combine a radioactive metal such as samarium-153 with a chelator. The chelator part of the molecule is taken up by growing bone and carries the radioactive "payload" along with it. Approximately 50% of the radioactivity in the radiopharmaceutical concentrates in bone. The radioactive atoms that are taken up by the bone irradiate the adjacent tumor and micrometastases. This radiation absorbed dose produces the therapeutic benefit. Two bone-seeking radiopharmaceuticals have been investigated for treating bone tumors and micrometastases and have shown promising clinical results but they have proven to be either too weak or too strong. One has an inefficient chelator that limits how much radioactivity may be delivered to the bone. The other has a radionuclide that is so strong that it causes intolerable side effects. We are developing the radiopharmaceutical, samarium-153-DOTMP (CycloSamTM), for the treatment of bone metastases. Compared to the two compounds that have already been tried, CycloSam combines the better radionuclide, samarium-153, with the better phosphonic acid chelator, DOTMP. We anticipate that CycloSam will be able to deliver the prescribed radiation absorbed dose to bone tumors and micrometastases while avoiding intolerable irradiation of normal tissues. Phase I of our work will demonstrate that 1. CycloSam may be used at whatever strength is needed to achieve the prescribed treatment, 2. CycloSam has the requisite biological distribution properties to enable it to deliver high radiation to the skeleton and low radiation to the rest of the body, and 3. CycloSam concentrates in bone tumors even more than in normal bones. In this Phase I proposal, we will measure the time- and concentration-dependent biodistribution properties of CycloSam and theoretically assess its curative capability in rats in Aims 1 and 2. In Aim 3, we will administer CycloSam to dogs with osteosarcomas to demonstrate its concentration in skeletal lesions. In Phase II, we will perform dose escalation, efficacy and late effects studies in dogs and toxicology studies. In Phase III we will conduct clinical trials. PUBLIC HEALTH RELEVANCE: Bone metastases have been treated by radioactive drugs, or radiopharmaceuticals. Thus far, their effects have been primarily palliative. We are developing the radiopharmaceutical, CycloSamTM, to act directly upon and resolve metastatic lesions instead of providing only pain palliation.
