Dual-targeted alpha radioimmune nanomedicine in osteosarcoma
Osteosarcoma (OS) is the most common primary malignant bone tumour with high prevalence in adolescents. Survival rate of OS with overt metastasis at diagnosis is low (<20%). The aim of this project is to develop new radiopharmaceuticals for metastatic OS which is not curable with the current available treatments. This is based on alpha-particle-emitting radionuclides and monoclonal-antibodies (mAbs) that target circulating cells and micrometastases in patients with OS. Radium-224 (Ra-224) is a natural bone-seeking alpha-emitting radionuclide. Lead-212 (Pb-212) and bismuth-212 (Bi-212), daughter nuclides of Ra-224, are present as free radionuclides in the solution of Ra-224. They can cause toxicity following injection. A conjugated chelator with mAbs will be added to the solution of Ra-224 in equilibrium with Pb-212 to make Pb-212 OS-targeted. Following injection of our solution into a patient: 1) Unbound bone-seeking Ra-224 will target osteoblastic metastatic lesions; 2) tumour-seeking Pb-212-mAbs will target the circulating OS cells and micrometastasis in the lungs and bone-marrow of the skeleton by selective binding to the cancer cells. The dual action of the new formulation will increase the therapeutic potential, improve the safety of the product and reduce radiation exposure of the normal cells.
The project includes the evaluation of the targeting potential, the therapeutic efficacy and toxicity of the novel radioimmune medicine in mice. Its efficacy will be compared with the chemotherapeutics agents (doxorubicin, cisplatin and ifosfamide) used routinely to treat patients with OS. The preclinical testing will be done in different OS xenografts in mouse models with disseminated human OS expressing p80. Biodistribution, pharmacokinetics, dosimetry, therapeutic efficacy, optimal dosing and toxicity of the novel formulations will be tested.
Cancer patients who are in advanced stages of the disease with bone metastasis report that they experience significant pain, and the pain intensity appears to be related to the degree of bone destruction. Tumour growth models and metastasis assays in rodents typically do not produce signs of pain until the tumours become advanced and invasive, produce debilitation, and/or cause release of mediators of inflammation. In addition, pain can arise as a result of cancer cell injection (intratibial, paratibial modes), diagnostic or therapeutic procedures. We are going to carry out our experiments causing only moderate pain and distress to the animals by monitoring them daily, by selecting experimental endpoints that precede the onset of clinical illness and by early recognition of humane endpoints. Anaesthetics and analgesics will be also used to suppress pain in experimental animals.
If the preclinical programs are successful, this could lead to clinical development of new and more effective OS drugs addressing large unmet medical needs mentioned above.
We need to study these processes in a suitable in vivo system to design and implement better therapeutic strategies of bone and lung metastases. No alternative biological systems can be found to obtain such information. We are requesting 690 Foxn1 nu mice and 240 BALB/cOlaHsd mice to accomplish the proposed research objectives. The number of mice was determined based on preliminary experiments and by a Power and Sample Size program.
The project includes the evaluation of the targeting potential, the therapeutic efficacy and toxicity of the novel radioimmune medicine in mice. Its efficacy will be compared with the chemotherapeutics agents (doxorubicin, cisplatin and ifosfamide) used routinely to treat patients with OS. The preclinical testing will be done in different OS xenografts in mouse models with disseminated human OS expressing p80. Biodistribution, pharmacokinetics, dosimetry, therapeutic efficacy, optimal dosing and toxicity of the novel formulations will be tested.
Cancer patients who are in advanced stages of the disease with bone metastasis report that they experience significant pain, and the pain intensity appears to be related to the degree of bone destruction. Tumour growth models and metastasis assays in rodents typically do not produce signs of pain until the tumours become advanced and invasive, produce debilitation, and/or cause release of mediators of inflammation. In addition, pain can arise as a result of cancer cell injection (intratibial, paratibial modes), diagnostic or therapeutic procedures. We are going to carry out our experiments causing only moderate pain and distress to the animals by monitoring them daily, by selecting experimental endpoints that precede the onset of clinical illness and by early recognition of humane endpoints. Anaesthetics and analgesics will be also used to suppress pain in experimental animals.
If the preclinical programs are successful, this could lead to clinical development of new and more effective OS drugs addressing large unmet medical needs mentioned above.
We need to study these processes in a suitable in vivo system to design and implement better therapeutic strategies of bone and lung metastases. No alternative biological systems can be found to obtain such information. We are requesting 690 Foxn1 nu mice and 240 BALB/cOlaHsd mice to accomplish the proposed research objectives. The number of mice was determined based on preliminary experiments and by a Power and Sample Size program.